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The Andrews Lab
Control of Infectious Diseases in Resource-Limited Settings
Our laboratory aims to develop innovative approaches to the control of infectious diseases in resource-limited settings. Drawing upon the fields of epidemiology, microbiology and engineering, we strive to find solutions to extend the technologies that underlie diagnosis and treatment of infectious diseases to "last-mile" communities.
Publications
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Effect of BCG vaccination against Mycobacterium tuberculosis infection in adult Brazilian health-care workers: a nested clinical trial.
The Lancet. Infectious diseases
Dos Santos, P. C., Messina, N. L., de Oliveira, R. D., da Silva, P. V., Puga, M. A., Dalcolmo, M., Dos Santos, G., de Lacerda, M. V., Jardim, B. A., de Almeida E Val, F. F., Curtis, N., Andrews, J. R., Croda, J.
2024
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Abstract
The effectiveness of BCG vaccine for adult pulmonary tuberculosis remains uncertain. In this study, we aimed to evaluate the effect of vaccination with BCG-Denmark to prevent initial and sustained interferon-γ release assay conversion in Brazilian health-care workers.This substudy is a nested randomised controlled trial embedded within the BRACE trial (NCT04327206). Specifically, this substudy enrolled Brazilian health-care workers (aged ≥18 years) from three sites in Brazil (Manaus, Campo Grande, and Rio de Janeiro) irrespective of previously receiving BCG vaccination. Participants were excluded if they had contraindications to BCG vaccination, more than 1 month of treatment with specific tuberculosis treatment drugs, previous adverse reactions to BCG, recent BCG vaccination, or non-compliance with assigned interventions. Those eligible were randomly assigned (1:1) to either the BCG group (0·1 mL intradermal injection of BCG-Denmark [Danish strain 1331; AJ Vaccines, Copenhagen]) or the placebo group (intradermal injection of 0·9% saline) using a web-based randomisation process in variable-length blocks (2, 4, or 6), and were stratified based on the study site, age (<40, ≥40 to <60, ≥60 years), and comorbidity presence (diabetes, chronic respiratory disease, cardiac condition, hypertension). Sealed syringes were used to prevent inadvertent disclosure of group assignments. The QuantiFERON-TB Gold (QFT) Plus test (Qiagen; Hilden, Germany) was used for baseline and 12-month tuberculosis infection assessments. The primary efficacy outcome was QFT Plus conversion (≥0·35 IU/mL) by 12 months following vaccination in participants who had a negative baseline result (<0·35 IU/mL).Between Oct 7, 2020, and April 12, 2021, 1985 (77·3%) of 2568 participants were eligible for QFT Plus assessment at 12 months and were included in this substudy; 996 (50·2%) of 1985 were in the BCG group and 989 (49·8%) were in the placebo group. Overall, 1475 (74·3%) of 1985 participants were women and 510 (25·7%) were men, and the median age was 39 years (IQR 32-47). During the first 12 months, QFT Plus conversion occurred in 66 (3·3%) of 1985 participants, with no significant differences by study site (p=0·897). Specifically, 34 (3·4%) of 996 participants had initial QFT conversion in the BCG group compared with 32 (3·2%) of 989 in the placebo group (risk ratio 1·09 [95% CI 0·67-1·77]; p=0·791).BCG-Denmark vaccination did not reduce initial QFT Plus conversion risk in Brazilian health-care workers. This finding underscores the need to better understand tuberculosis prevention in populations at high risk.Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the United Health Group Foundation, Epworth Healthcare, and individual donors.For the Portuguese translation of the abstract see Supplementary Materials section.
View details for DOI 10.1016/S1473-3099(23)00818-6
View details for PubMedID 38423021
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Global, regional, and national estimates of tuberculosis incidence and case detection among incarcerated individuals from 2000 to 2019: a systematic analysis.
The Lancet. Public health
Martinez, L., Warren, J. L., Harries, A. D., Croda, J., Espinal, M. A., Olarte, R. A., Avedillo, P., Lienhardt, C., Bhatia, V., Liu, Q., Chakaya, J., Denholm, J. T., Lin, Y., Kawatsu, L., Zhu, L., Horsburgh, C. R., Cohen, T., Andrews, J. R.
2023; 8 (7): e511-e519
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Abstract
People who are incarcerated are at high risk of developing tuberculosis. We aimed to estimate the annual global, regional, and national incidence of tuberculosis among incarcerated populations from 2000 to 2019.We collected and aggregated data for tuberculosis incidence and prevalence estimates among incarcerated individuals in published and unpublished literature, annual tuberculosis notifications among incarcerated individuals at the country level, and the annual number of incarcerated individuals at the country level. We developed a joint hierarchical Bayesian meta-regression framework to simultaneously model tuberculosis incidence, notifications, and prevalence from 2000 to 2019. Using this model, we estimated trends in absolute tuberculosis incidence and notifications, the incidence and notification rates, and the case detection ratio by year, country, region, and globally.In 2019, we estimated a total of 125 105 (95% credible interval [CrI] 93 736-165 318) incident tuberculosis cases among incarcerated individuals globally. The estimated incidence rate per 100 000 person-years overall was 1148 (95% CrI 860-1517) but varied greatly by WHO region, from 793 (95% CrI 430-1342) in the Eastern Mediterranean region to 2242 (1515-3216) in the African region. Global incidence per 100 000 person-years between 2000 and 2012 among incarcerated individuals decreased from 1884 (95% CrI 1394-2616) to 1205 (910-1615); however, from 2013 onwards, tuberculosis incidence per 100 000 person-years was stable, from 1183 (95% CrI 876-1596) in 2013 to 1148 (860-1517) in 2019. In 2019, the global case detection ratio was estimated to be 53% (95% CrI 42-64), the lowest over the study period.Our estimates suggest a high tuberculosis incidence rate among incarcerated individuals globally with large gaps in tuberculosis case detection. Tuberculosis in incarcerated populations must be addressed with interventions specifically tailored to improve diagnoses and prevent transmission as a part of the broader global tuberculosis control effort.National Institutes of Health.
View details for DOI 10.1016/S2468-2667(23)00097-X
View details for PubMedID 37393090
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Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis.
The Lancet. Global health
Martinez, L., Cords, O., Liu, Q., Acuna-Villaorduna, C., Bonnet, M., Fox, G. J., Carvalho, A. C., Chan, P. C., Croda, J., Hill, P. C., Lopez-Varela, E., Donkor, S., Fielding, K., Graham, S. M., Espinal, M. A., Kampmann, B., Reingold, A., Huerga, H., Villalba, J. A., Grandjean, L., Sotgiu, G., Egere, U., Singh, S., Zhu, L., Lienhardt, C., Denholm, J. T., Seddon, J. A., Whalen, C. C., García-Basteiro, A. L., Triasih, R., Chen, C., Singh, J., Huang, L. M., Sharma, S., Hannoun, D., Del Corral, H., Mandalakas, A. M., Malone, L. L., Ling, D. L., Kritski, A., Stein, C. M., Vashishtha, R., Boulahbal, F., Fang, C. T., Boom, W. H., Netto, E. M., Lemos, A. C., Hesseling, A. C., Kay, A., Jones-López, E. C., Horsburgh, C. R., Lange, C., Andrews, J. R.
2022; 10 (9): e1307-e1316
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Abstract
BCG vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults. We therefore aimed to investigate the age-specific impact of infant BCG vaccination on tuberculosis (pulmonary and extrapulmonary) development and mortality.In this systematic review and individual participant data meta-analysis, we searched MEDLINE, Web of Science, BIOSIS, and Embase without language restrictions for case-contact cohort studies of tuberculosis contacts published between Jan 1, 1998, and April 7, 2018. Search terms included "mycobacterium tuberculosis", "TB", "tuberculosis", and "contact". We excluded cohort studies that did not provide information on BCG vaccination or were done in countries that did not recommend BCG vaccination at birth. Individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies. Our primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality. We derived adjusted odds ratios (aORs) using mixed-effects, binary, multivariable logistic regression analyses with study-level random effects, adjusting for the variable of interest, baseline age, sex, previous tuberculosis, and whether data were collected prospectively or retrospectively. We stratified our results by contact age and Mycobacterium tuberculosis infection status. This study is registered with PROSPERO, CRD42020180512.We identified 14 927 original records from our database searches. We included participant-level data from 26 cohort studies done in 17 countries in our meta-analysis. Among 68 552 participants, 1782 (2·6%) developed tuberculosis (1309 [2·6%] of 49 686 BCG-vaccinated participants vs 473 [2·5%] of 18 866 unvaccinated participants). The overall effectiveness of BCG vaccination against all tuberculosis was 18% (aOR 0·82, 95% CI 0·74-0·91). When stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR 0·63, 95% CI 0·49-0·81). Among contacts with a positive tuberculin skin test or IFNγ release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR 0·81, 95% CI 0·69-0·96), participants younger than 5 years (0·68, 0·47-0·97), and participants aged 5-9 years (0·62, 0·38-0·99). There was no protective effect among those with negative tests, unless they were younger than 5 years (0·54, 0·32-0·90). 14 cohorts reported on whether tuberculosis was pulmonary or extrapulmonary (n=57 421). BCG vaccination significantly protected against pulmonary tuberculosis among all participants (916 [2·2%] in 41 119 vaccinated participants vs 334 [2·1%] in 16 161 unvaccinated participants; aOR 0·81, 0·70-0·94) but not against extrapulmonary tuberculosis (106 [0·3%] in 40 318 vaccinated participants vs 38 [0·2%] in 15 865 unvaccinated participants; 0·96, 0·65-1·41). In the four studies with mortality data, BCG vaccination was significantly protective against death (0·25, 0·13-0·49).Our results suggest that BCG vaccination at birth is effective at preventing tuberculosis in young children but is ineffective in adolescents and adults. Immunoprotection therefore needs to be boosted in older populations.National Institutes of Health.
View details for DOI 10.1016/S2214-109X(22)00283-2
View details for PubMedID 35961354
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The international and intercontinental spread and expansion of antimicrobial-resistant Salmonella Typhi: a genomic epidemiology study.
The Lancet. Microbe
da Silva, K. E., Tanmoy, A. M., Pragasam, A. K., Iqbal, J., Sajib, M. S., Mutreja, A., Veeraraghavan, B., Tamrakar, D., Qamar, F. N., Dougan, G., Bogoch, I., Seidman, J. C., Shakya, J., Vaidya, K., Carey, M. E., Shrestha, R., Irfan, S., Baker, S., Luby, S. P., Cao, Y., Dyson, Z. A., Garrett, D. O., John, J., Kang, G., Hooda, Y., Saha, S. K., Saha, S., Andrews, J. R.
2022
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Abstract
The emergence of increasingly antimicrobial-resistant Salmonella enterica serovar Typhi (S Typhi) threatens to undermine effective treatment and control. Understanding where antimicrobial resistance in S Typhi is emerging and spreading is crucial towards formulating effective control strategies.In this genomic epidemiology study, we sequenced the genomes of 3489 S Typhi strains isolated from prospective enteric fever surveillance studies in Nepal, Bangladesh, Pakistan, and India (between 2014 and 2019), and combined these with a global collection of 4169 S Typhi genome sequences isolated between 1905 and 2018 to investigate the temporal and geographical patterns of emergence and spread of antimicrobial-resistant S Typhi. We performed non-parametric phylodynamic analyses to characterise changes in the effective population size of fluoroquinolone-resistant, extensively drug-resistant (XDR), and azithromycin-resistant S Typhi over time. We inferred timed phylogenies for the major S Typhi sublineages and used ancestral state reconstruction methods to estimate the frequency and timing of international and intercontinental transfers.Our analysis revealed a declining trend of multidrug resistant typhoid in south Asia, except for Pakistan, where XDR S Typhi emerged in 2016 and rapidly replaced less-resistant strains. Mutations in the quinolone-resistance determining region (QRDR) of S Typhi have independently arisen and propagated on at least 94 occasions, nearly all occurring in south Asia. Strains with multiple QRDR mutations, including triple mutants with high-level fluoroquinolone resistance, have been increasing in frequency and displacing strains with fewer mutations. Strains containing acrB mutations, conferring azithromycin resistance, emerged in Bangladesh around 2013 and effective population size of these strains has been steadily increasing. We found evidence of frequent international (n=138) and intercontinental transfers (n=59) of antimicrobial-resistant S Typhi, followed by local expansion and replacement of drug-susceptible clades.Independent acquisition of plasmids and homoplastic mutations conferring antimicrobial resistance have occurred repeatedly in multiple lineages of S Typhi, predominantly arising in south Asia before spreading to other regions.Bill & Melinda Gates Foundation.
View details for DOI 10.1016/S2666-5247(22)00093-3
View details for PubMedID 35750070
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Estimating typhoid incidence from community-based serosurveys: a multicohort study.
The Lancet. Microbe
Aiemjoy, K., Seidman, J. C., Saha, S., Munira, S. J., Islam Sajib, M. S., Sium, S. M., Sarkar, A., Alam, N., Zahan, F. N., Kabir, M. S., Tamrakar, D., Vaidya, K., Shrestha, R., Shakya, J., Katuwal, N., Shrestha, S., Yousafzai, M. T., Iqbal, J., Dehraj, I. F., Ladak, Y., Maria, N., Adnan, M., Pervaiz, S., Carter, A. S., Longley, A. T., Fraser, C., Ryan, E. T., Nodoushani, A., Fasano, A., Leonard, M. M., Kenyon, V., Bogoch, I. I., Jeon, H. J., Haselbeck, A., Park, S. E., Zellweger, R. M., Marks, F., Owusu-Dabo, E., Adu-Sarkodie, Y., Owusu, M., Teunis, P., Luby, S. P., Garrett, D. O., Qamar, F. N., Saha, S. K., Charles, R. C., Andrews, J. R.
2022
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Abstract
The incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae (Salmonella enterica serovars Typhi and Paratyphi), is largely unknown in regions without blood culture surveillance. The aim of this study was to evaluate whether new diagnostic serological markers for typhoidal Salmonella can reliably estimate population-level incidence.We collected longitudinal blood samples from patients with blood culture-confirmed enteric fever enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana between 2016 and 2021 and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to hemolysin E and S Typhi lipopolysaccharide. We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titres and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.The longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children younger than 5 years ranged between 58·5 per 100 person-years (95% CI 42·1-81·4) in Dhaka, Bangladesh, to 6·6 per 100 person-years (4·3-9·9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates.The approach described here has the potential to expand the geographical scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographical regions and time.Bill & Melinda Gates Foundation.For the Nepali, Bengali and Urdu translations of the abstract see Supplementary Materials section.
View details for DOI 10.1016/S2666-5247(22)00114-8
View details for PubMedID 35750069
The Blish Lab
Defining Natural Immunity in Viral Disease
The Blish laboratory is in the Department of Medicine, Division of Infectious Diseases and Geographic Medicine and in the interdisciplinary Stanford Immunology program. Our goal is to develop new methods to prevent and control infectious diseases through better understanding of human immunology. We have several major areas of ongoing investigation.
Publications
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Comparative analysis of cell-cell communication at single-cell resolution.
Nature biotechnology
Wilk, A. J., Shalek, A. K., Holmes, S., Blish, C. A.
2023
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Abstract
Inference of cell-cell communication from single-cell RNA sequencing data is a powerful technique to uncover intercellular communication pathways, yet existing methods perform this analysis at the level of the cell type or cluster, discarding single-cell-level information. Here we present Scriabin, a flexible and scalable framework for comparative analysis of cell-cell communication at single-cell resolution that is performed without cell aggregation or downsampling. We use multiple published atlas-scale datasets, genetic perturbation screens and direct experimental validation to show that Scriabin accurately recovers expected cell-cell communication edges and identifies communication networks that can be obscured by agglomerative methods. Additionally, we use spatial transcriptomic data to show that Scriabin can uncover spatial features of interaction from dissociated data alone. Finally, we demonstrate applications to longitudinal datasets to follow communication pathways operating between timepoints. Our approach represents a broadly applicable strategy to reveal the full structure of niche-phenotype relationships in health and disease.
View details for DOI 10.1038/s41587-023-01782-z
View details for PubMedID 37169965
View details for PubMedCentralID 8104132
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SARS-CoV-2 escapes direct NK cell killing through Nsp1-mediated downregulation of ligands for NKG2D.
Cell reports
Lee, M. J., Leong, M. W., Rustagi, A., Beck, A., Zeng, L., Holmes, S., Qi, L. S., Blish, C. A.
2022: 111892
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Abstract
Natural killer (NK) cells are cytotoxic effector cells that target and lyse virally infected cells; many viruses therefore encode mechanisms to escape such NK cell killing. Here, we interrogate the ability of SARS-CoV-2 to modulate NK cell recognition and lysis of infected cells. We find that NK cells exhibit poor cytotoxic responses against SARS-CoV-2-infected targets, preferentially killing uninfected bystander cells. We demonstrate that this escape is driven by downregulation of ligands for the activating receptor NKG2D (NKG2D-L). Indeed, early in viral infection, prior to NKG2D-L downregulation, NK cells are able to target and kill infected cells; however, this ability is lost as viral proteins are expressed. Finally, we find that SARS-CoV-2 non-structural protein 1 (Nsp1) mediates downregulation of NKG2D-L and that Nsp1 alone is sufficient to confer resistance to NK cell killing. Collectively, our work demonstrates that SARS-CoV-2 evades direct NK cell cytotoxicity and describes a mechanism by which this occurs.
View details for DOI 10.1016/j.celrep.2022.111892
View details for PubMedID 36543165
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SARS-CoV-2 infection drives an inflammatory response in human adipose tissue through infection of adipocytes and macrophages.
Science translational medicine
Martínez-Colón, G. J., Ratnasiri, K., Chen, H., Jiang, S., Zanley, E., Rustagi, A., Verma, R., Chen, H., Andrews, J. R., Mertz, K. D., Tzankov, A., Azagury, D., Boyd, J., Nolan, G. P., Schürch, C. M., Matter, M. S., Blish, C. A., McLaughlin, T. L.
2022: eabm9151
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Abstract
Obesity, characterized by chronic low-grade inflammation of the adipose tissue, is associated with adverse coronavirus disease 2019 (COVID-19) outcomes, yet the underlying mechanism is unknown. To explore whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of adipose tissue contributes to pathogenesis, we evaluated COVID-19 autopsy cases and deeply profiled the response of adipose tissue to SARS-CoV-2 infection in vitro. In COVID-19 autopsy cases, we identified SARS-CoV-2 RNA in adipocytes with an associated inflammatory infiltrate. We identified two distinct cellular targets of infection: adipocytes and a subset of inflammatory adipose tissue-resident macrophages. Mature adipocytes were permissive to SARS-CoV-2 infection; although macrophages were abortively infected, SARS-CoV-2 initiated inflammatory responses within both the infected macrophages and bystander preadipocytes. These data suggest that SARS-CoV-2 infection of adipose tissue could contribute to COVID-19 severity through replication of virus within adipocytes and through induction of local and systemic inflammation driven by infection of adipose tissue-resident macrophages.
View details for DOI 10.1126/scitranslmed.abm9151
View details for PubMedID 36137009
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Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19.
The Journal of experimental medicine
Wilk, A. J., Lee, M. J., Wei, B., Parks, B., Pi, R., Martinez-Colon, G. J., Ranganath, T., Zhao, N. Q., Taylor, S., Becker, W., Stanford COVID-19 Biobank, Jimenez-Morales, D., Blomkalns, A. L., O'Hara, R., Ashley, E. A., Nadeau, K. C., Yang, S., Holmes, S., Rabinovitch, M., Rogers, A. J., Greenleaf, W. J., Blish, C. A.
2021; 218 (8)
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Abstract
Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-kappaB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.
View details for DOI 10.1084/jem.20210582
View details for PubMedID 34128959
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A single-cell atlas of the peripheral immune response in patients with severe COVID-19.
Nature medicine
Wilk, A. J., Rustagi, A., Zhao, N. Q., Roque, J., Martinez-Colon, G. J., McKechnie, J. L., Ivison, G. T., Ranganath, T., Vergara, R., Hollis, T., Simpson, L. J., Grant, P., Subramanian, A., Rogers, A. J., Blish, C. A.
2020
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Abstract
There is an urgent need to better understand the pathophysiology of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, which has infected more than three million people worldwide1. Approximately 20% of patients with COVID-19 develop severe disease and 5% of patients require intensive care2. Severe disease has been associated with changes in peripheral immune activity, including increased levels of pro-inflammatory cytokines3,4 that may be produced by a subset of inflammatory monocytes5,6, lymphopenia7,8 and T cell exhaustion9,10. To elucidate pathways in peripheral immune cells that might lead to immunopathology or protective immunity in severe COVID-19, we applied single-cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) from seven patients hospitalized for COVID-19, four of whom had acute respiratory distress syndrome, and six healthy controls. We identify reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene signature, HLA class II downregulation and a developing neutrophil population that appears closely related to plasmablasts appearing in patients with acute respiratory failure requiring mechanical ventilation. Importantly, we found that peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines. Collectively, we provide a cell atlas of the peripheral immune response to severe COVID-19.
View details for DOI 10.1038/s41591-020-0944-y
View details for PubMedID 32514174
The Bollyky Lab
Immune Responses in Injured and Infected Tissues
Our lab studies how immune responses are regulated within injured and infected tissues. We work at the intersection of immunology, structural biology, bioengineering, and microbiology. Our goals are to understand the factors that drive chronic inflammation and to develop novel therapeutics to promote wound healing and immune tolerance.
Publications
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Phage diversity in cell-free DNA identifies bacterial pathogens in human sepsis cases.
Nature microbiology
Haddock, N. L., Barkal, L. J., Ram-Mohan, N., Kaber, G., Chiu, C. Y., Bhatt, A. S., Yang, S., Bollyky, P. L.
2023
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Abstract
Bacteriophages, viruses that infect bacteria, have great specificity for their bacterial hosts at the strain and species level. However, the relationship between the phageome and associated bacterial population dynamics is unclear. Here we generated a computational pipeline to identify sequences associated with bacteriophages and their bacterial hosts in cell-free DNA from plasma samples. Analysis of two independent cohorts, including a Stanford Cohort of 61 septic patients and 10 controls and the SeqStudy cohort of 224 septic patients and 167 controls, reveals a circulating phageome in the plasma of all sampled individuals. Moreover, infection is associated with overrepresentation of pathogen-specific phages, allowing for identification of bacterial pathogens. We find that information on phage diversity enables identification of the bacteria that produced these phages, including pathovariant strains of Escherichia coli. Phage sequences can likewise be used to distinguish between closely related bacterial species such as Staphylococcus aureus, a frequent pathogen, and coagulase-negative Staphylococcus, a frequent contaminant. Phage cell-free DNA may have utility in studying bacterial infections.
View details for DOI 10.1038/s41564-023-01406-x
View details for PubMedID 37308590
View details for PubMedCentralID 5594678
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Filamentous bacteriophage delays healing of Pseudomonas-infected wounds.
Cell reports. Medicine
Bach, M. S., de Vries, C. R., Khosravi, A., Sweere, J. M., Popescu, M. C., Chen, Q., Demirdjian, S., Hargil, A., Van Belleghem, J. D., Kaber, G., Hajfathalian, M., Burgener, E. B., Liu, D., Tran, Q., Dharmaraj, T., Birukova, M., Sunkari, V., Balaji, S., Ghosh, N., Mathew-Steiner, S. S., El Masry, M. S., Keswani, S. G., Banaei, N., Nedelec, L., Sen, C. K., Chandra, V., Secor, P. R., Suh, G. A., Bollyky, P. L.
2022; 3 (6): 100656
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Abstract
Chronic wounds infected by Pseudomonas aeruginosa (Pa) are characterized by disease progression and increased mortality. We reveal Pf, a bacteriophage produced by Pa that delays healing of chronically infected wounds in human subjects and animal models of disease. Interestingly, impairment of wound closure by Pf is independent of its effects on Pa pathogenesis. Rather, Pf impedes keratinocyte migration, which is essential for wound healing, through direct inhibition of CXCL1 signaling. In support of these findings, a prospective cohort study of 36 human patients with chronic Pa wound infections reveals that wounds infected with Pf-positive strains of Pa are more likely to progress in size compared with wounds infected with Pf-negative strains. Together, these data implicate Pf phage in the delayed wound healing associated with Pa infection through direct manipulation of mammalian cells. These findings suggest Pf may have potential as a biomarker and therapeutic target in chronic wounds.
View details for DOI 10.1016/j.xcrm.2022.100656
View details for PubMedID 35732145
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Phage Therapy for Limb-threatening Prosthetic Knee Klebsiella pneumoniae Infection: Case Report and In Vitro Characterization of Anti-biofilm Activity.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
Cano, E. J., Caflisch, K. M., Bollyky, P. L., Van Belleghem, J. D., Patel, R. n., Fackler, J. n., Brownstein, M. J., Horne, B. n., Biswas, B. n., Henry, M. n., Malagon, F. n., Lewallen, D. G., Suh, G. A.
2020
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Abstract
Prosthetic joint infection (PJI) is a potentially limb-threatening complication of total knee arthroplasty. Phage therapy is a promising strategy to manage such infections including those involving antibiotic-resistant microbes, and to target microbial biofilms. Experience with phage therapy for infections associated with retained hardware is limited. A 62-year-old diabetic man with a history of right total knee arthroplasty 11 years prior who had suffered multiple episodes of prosthetic knee infection despite numerous surgeries and prolonged courses of antibiotics, with progressive clinical worsening and development of severe allergies to antibiotics, had been offered limb amputation for persistent right prosthetic knee infection due to Klebsiella pneumoniae complex. Intravenous phage therapy was initiated as a limb-salvaging intervention.The patient received 40 intravenous doses of a single phage (KpJH46Φ2) targeting his bacterial isolate, alongside continued minocycline (which he had been receiving when he developed increasing pain, swelling, and erythema prior to initiation of phage therapy). Serial cytokine and biomarker measurements were performed before, during, and after treatment. The in vitro anti-biofilm activity of KpJH46Φ2, minocycline and the combination thereof was evaluated against a preformed biofilm of the patient's isolate and determined by safranin staining.Phage therapy resulted in resolution of local symptoms and signs of infection and recovery of function. The patient did not experience treatment-related adverse effects and remained asymptomatic 34 weeks after completing treatment while still receiving minocycline. A trend in biofilm biomass reduction was noted 22 hours after exposure to KpJH46Φ2 (P = .063). The addition of phage was associated with a satisfactory outcome in this case of intractable biofilm-associated prosthetic knee infection. Pending further studies to assess its efficacy and safety, phage therapy holds promise for treatment of device-associated infections.
View details for DOI 10.1093/cid/ciaa705
View details for PubMedID 32699879
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Filamentous bacteriophages are associated with chronic Pseudomonas lung infections and antibiotic resistance in cystic fibrosis
SCIENCE TRANSLATIONAL MEDICINE
Burgener, E. B., Sweere, J. M., Bach, M. S., Secor, P. R., Haddock, N., Jennings, L. K., Marvig, R. L., Johansen, H., Rossi, E., Cao, X., Tian, L., Nedelec, L., Molin, S., Bollyky, P. L., Milla, C. E.
2019; 11 (488)
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View details for DOI 10.1126/scitranslmed.aau9748
View details for Web of Science ID 000465116400003
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Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection.
Science (New York, N.Y.)
Sweere, J. M., Van Belleghem, J. D., Ishak, H. n., Bach, M. S., Popescu, M. n., Sunkari, V. n., Kaber, G. n., Manasherob, R. n., Suh, G. A., Cao, X. n., de Vries, C. R., Lam, D. N., Marshall, P. L., Birukova, M. n., Katznelson, E. n., Lazzareschi, D. V., Balaji, S. n., Keswani, S. G., Hawn, T. R., Secor, P. R., Bollyky, P. L.
2019; 363 (6434)
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Abstract
Bacteriophage are abundant at sites of bacterial infection, but their effects on mammalian hosts are unclear. We have identified pathogenic roles for filamentous Pf bacteriophage produced by Pseudomonas aeruginosa (Pa) in suppression of immunity against bacterial infection. Pf promote Pa wound infection in mice and are associated with chronic human Pa wound infections. Murine and human leukocytes endocytose Pf, and internalization of this single-stranded DNA virus results in phage RNA production. This triggers Toll-like receptor 3 (TLR3)- and TIR domain-containing adapter-inducing interferon-β (TRIF)-dependent type I interferon production, inhibition of tumor necrosis factor (TNF), and the suppression of phagocytosis. Conversely, immunization of mice against Pf prevents Pa wound infection. Thus, Pf triggers maladaptive innate viral pattern-recognition responses, which impair bacterial clearance. Vaccination against phage virions represents a potential strategy to prevent bacterial infection.
View details for PubMedID 30923196
The Einav Lab
Understanding Virus-Host Protein Interactions
The goals of our lab are to better understand virus-host protein interactions, identify host proteins or pathways required by multiple viruses, and translate this knowledge into the development of novel, broad-spectrum, host-centered antiviral approaches with a high genetic barrier for resistance.
Publications
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An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations.
Science translational medicine
Westberg, M., Su, Y., Zou, X., Huang, P., Rustagi, A., Garhyan, J., Patel, P. B., Fernandez, D., Wu, Y., Hao, C., Lo, C. W., Karim, M., Ning, L., Beck, A., Saenkham-Huntsinger, P., Tat, V., Drelich, A., Peng, B. H., Einav, S., Tseng, C. K., Blish, C., Lin, M. Z.
2024; 16 (738): eadi0979
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Abstract
Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C virus protease inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 Mpro more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.
View details for DOI 10.1126/scitranslmed.adi0979
View details for PubMedID 38478629
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Chemical inactivation strategies for SARS-CoV-2-infected cells and organoids.
STAR protocols
Karim, M., Pohane, A. A., Lo, C. W., Einav, S., Garhyan, J.
2024; 5 (1): 102906
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Abstract
Infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research, conducted in high-containment laboratories, requires transferring samples to lower containment labs for downstream applications, mandating sample inactivation. Here, we present a stepwise protocol for chemical inactivation of SARS-CoV-2 virus in culture supernatants or within infected cells and organoids, using eight chemical reagents validated via plaque assays. Additionally, we describe steps for troubleshooting virus inactivation, titer calculation, and log reduction. This protocol offers valuable resources for the COVID-19 research community, providing essential tools to advance research on this virus.
View details for DOI 10.1016/j.xpro.2024.102906
View details for PubMedID 38401122
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Back-pocket optimization of 2-aminopyrimidine-based macrocycles leads to potent dual EPHA2/GAK kinase inhibitors with antiviral activity.
bioRxiv : the preprint server for biology
Gerninghaus, J., Zhubi, R., Krämer, A., Karim, M., Tran, D. H., Joerger, A. C., Schreiber, C., Berger, L. M., Berger, B. T., Ehret, T. A., Elson, L., Lenz, C., Saxena, K., Müller, S., Einav, S., Knapp, S., Hanke, T.
2024
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Abstract
Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here, we developed a 2-aminopyrimidine-based macrocyclic dual EPHA2/GAK kinase inhibitor as a chemical tool to study the role of these two kinases in viral entry and assembly. Starting with a promiscuous macrocyclic inhibitor, 6, we performed a structure-guided activity relationship and selectivity study using a panel of over 100 kinases. The crystal structure of EPHA2 in complex with the developed macrocycle 23 provided a basis for further optimization by specifically targeting the back pocket, resulting in compound 55 as a potent dual EPHA2/GAK inhibitor. Subsequent front-pocket derivatization resulted in an interesting in cellulo selectivity profile, favoring EPHA4 over the other ephrin receptor kinase family members. The dual EPHA2/GAK inhibitor 55 prevented dengue virus infection of Huh7 liver cells, mainly via its EPHA2 activity, and is therefore a promising candidate for further optimization of its activity against dengue virus.
View details for DOI 10.1101/2024.02.18.580805
View details for PubMedID 38405908
View details for PubMedCentralID PMC10888910
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Systems immunology of transcriptional responses to viral infection identifies conserved antiviral pathways across macaques and humans.
Cell reports
Ratnasiri, K., Zheng, H., Toh, J., Yao, Z., Duran, V., Donato, M., Roederer, M., Kamath, M., Todd, J. M., Gagne, M., Foulds, K. E., Francica, J. R., Corbett, K. S., Douek, D. C., Seder, R. A., Einav, S., Blish, C. A., Khatri, P.
2024; 43 (2): 113706
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Abstract
Viral pandemics and epidemics pose a significant global threat. While macaque models of viral disease are routinely used, it remains unclear how conserved antiviral responses are between macaques and humans. Therefore, we conducted a cross-species analysis of transcriptomic data from over 6,088 blood samples from macaques and humans infected with one of 31 viruses. Our findings demonstrate that irrespective of primate or viral species, there are conserved antiviral responses that are consistent across infection phase (acute, chronic, or latent) and viral genome type (DNA or RNA viruses). Leveraging longitudinal data from experimental challenges, we identify virus-specific response kinetics such as host responses to Coronaviridae and Orthomyxoviridae infections peaking 1-3 days earlier than responses to Filoviridae and Arenaviridae viral infections. Our results underscore macaque studies as a powerful tool for understanding viral pathogenesis and immune responses that translate to humans, with implications for viral therapeutic development and pandemic preparedness.
View details for DOI 10.1016/j.celrep.2024.113706
View details for PubMedID 38294906
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Global and cell type-specific immunological hallmarks of severe dengue progression identified via a systems immunology approach.
Nature immunology
Ghita, L., Yao, Z., Xie, Y., Duran, V., Cagirici, H. B., Samir, J., Osman, I., Rebellón-Sánchez, D. E., Agudelo-Rojas, O. L., Sanz, A. M., Sahoo, M. K., Robinson, M. L., Gelvez-Ramirez, R. M., Bueno, N., Luciani, F., Pinsky, B. A., Montoya, J. G., Estupiñan-Cardenas, M. I., Villar-Centeno, L. A., Rojas-Garrido, E. M., Rosso, F., Quake, S. R., Zanini, F., Einav, S.
2023
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Abstract
Severe dengue (SD) is a major cause of morbidity and mortality. To define dengue virus (DENV) target cells and immunological hallmarks of SD progression in children's blood, we integrated two single-cell approaches capturing cellular and viral elements: virus-inclusive single-cell RNA sequencing (viscRNA-Seq 2) and targeted proteomics with secretome analysis and functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion as well as cell-cell communications point towards increased immune cell migration and inflammation in SD progressors. Concurrently, antigen-presenting cells from SD progressors demonstrate intact uptake yet impaired interferon response and antigen processing and presentation signatures, which are partly modulated by DENV. Increased activation, regulation and exhaustion of effector responses and expansion of HLA-DR-expressing adaptive-like NK cells also characterize SD progressors. These findings reveal DENV target cells in human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement.
View details for DOI 10.1038/s41590-023-01654-3
View details for PubMedID 37872316
View details for PubMedCentralID 3651993
Jagannathan Lab
Translational Immunology Focused on Malaria-Specific Immune Responses
The goals of this laboratory are to further our understanding of the correlates and mechanisms of clinical immunity to malaria through field-based studies, and to better understand the immunologic consequences of malaria control interventions.
These studies bridge immune profiling techniques including multiparameter flow cytometry, transcriptomics, epigenetics, and multiplex antibody profiling to epidemiologic studies of antimalarial immunity in children.
Publications
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Malaria-specific Type 1 regulatory T cells are more abundant in first pregnancies and associated with placental malaria.
EBioMedicine
Kirosingh, A. S., Delmastro, A., Kakuru, A., van der Ploeg, K., Bhattacharya, S., Press, K. D., Ty, M., Parte, L., Kizza, J., Muhindo, M., Devachanne, S., Gamain, B., Nankya, F., Musinguzi, K., Rosenthal, P. J., Feeney, M. E., Kamya, M., Dorsey, G., Jagannathan, P.
2023; 95: 104772
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Abstract
Malaria in pregnancy (MIP) causes higher morbidity in primigravid compared to multigravid women; however, the correlates and mechanisms underlying this gravidity-dependent protection remain incompletely understood. We aimed to compare the cellular immune response between primigravid and multigravid women living in a malaria-endemic region and assess for correlates of protection against MIP.We characterised the second trimester cellular immune response among 203 primigravid and multigravid pregnant women enrolled in two clinical trials of chemoprevention in eastern Uganda, utilizing RNA sequencing, flow cytometry, and functional assays. We compared responses across gravidity and determined associations with parasitaemia during pregnancy and placental malaria.Using whole blood RNA sequencing, no significant differentially expressed genes were identified between primigravid (n = 12) and multigravid (n = 11) women overall (log 2(FC) > 2, FDR < 0.1). However, primigravid (n = 49) women had higher percentages of malaria-specific, non-naïve CD4+ T cells that co-expressed IL-10 and IFNγ compared with multigravid (n = 85) women (p = 0.000023), and higher percentages of these CD4+ T cells were associated with greater risks of parasitaemia in pregnancy (Rs = 0.49, p = 0.001) and placental malaria (p = 0.0073). These IL-10 and IFNγ co-producing CD4+ T cells had a genomic signature of Tr1 cells, including expression of transcription factors cMAF and BATF and cell surface makers CTLA4 and LAG-3.Malaria-specific Tr1 cells were highly prevalent in primigravid Ugandan women, and their presence correlated with a higher risk of malaria in pregnancy. Understanding whether suppression of Tr1 cells plays a role in naturally acquired gravidity-dependent immunity may aid the development of new vaccines or treatments for MIP.This work was funded by NIH (PO1 HD059454, U01 AI141308, U19 AI089674, U01 AI155325, U01 AI150741), the March of Dimes (Basil O'Connor award), and the Bill and Melinda Gates Foundation (OPP 1113682).
View details for DOI 10.1016/j.ebiom.2023.104772
View details for PubMedID 37634385
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Malaria-driven expansion of adaptive-like functional CD56-negative NK cells correlates with clinical immunity to malaria.
Science translational medicine
Ty, M., Sun, S., Callaway, P. C., Rek, J., Press, K. D., van der Ploeg, K., Nideffer, J., Hu, Z., Klemm, S., Greenleaf, W., Donato, M., Tukwasibwe, S., Arinaitwe, E., Nankya, F., Musinguzi, K., Andrew, D., de la Parte, L., Mori, D. M., Lewis, S. N., Takahashi, S., Rodriguez-Barraquer, I., Greenhouse, B., Blish, C., Utz, P. J., Khatri, P., Dorsey, G., Kamya, M., Boyle, M., Feeney, M., Ssewanyana, I., Jagannathan, P.
2023; 15 (680): eadd9012
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Abstract
Natural killer (NK) cells likely play an important role in immunity to malaria, but the effect of repeated malaria on NK cell responses remains unclear. Here, we comprehensively profiled the NK cell response in a cohort of 264 Ugandan children. Repeated malaria exposure was associated with expansion of an atypical, CD56neg population of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56dim NK cells, including decreased expression of PLZF and the Fc receptor γ-chain, increased histone methylation, and increased protein expression of LAG-3, KIR, and LILRB1. CD56neg NK cells were highly functional and displayed greater antibody-dependent cellular cytotoxicity than CD56dim NK cells. Higher frequencies of CD56neg NK cells were associated with protection against symptomatic malaria and high parasite densities. After marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to Plasmodium falciparum is required to maintain this modified, adaptive-like NK cell subset.
View details for DOI 10.1126/scitranslmed.add9012
View details for PubMedID 36696483
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Early immune markers of clinical, virological, and immunological outcomes in patients with COVID-19: a multi-omics study.
eLife
Hu, Z., van der Ploeg, K., Chakraborty, S., Arunachalam, P. S., Mori, D. A., Jacobson, K. B., Bonilla, H., Parsonnet, J., Andrews, J. R., Holubar, M., Subramanian, A., Khosla, C., Maldonado, Y., Hedlin, H., de la Parte, L., Press, K., Ty, M., Tan, G. S., Blish, C., Takahashi, S., Rodriguez-Barraquer, I., Greenhouse, B., Butte, A. J., Singh, U., Pulendran, B., Wang, T. T., Jagannathan, P.
2022; 11
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Abstract
The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients.Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial.We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2-7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset.Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models.Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford's Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals.
View details for DOI 10.7554/eLife.77943
View details for PubMedID 36239699
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Age-dependent changes in circulating Tfh cells influence development of functional malaria antibodies in children.
Nature communications
Chan, J., Loughland, J. R., de la Parte, L., Okano, S., Ssewanyana, I., Nalubega, M., Nankya, F., Musinguzi, K., Rek, J., Arinaitwe, E., Tipping, P., Bourke, P., Andrew, D., Dooley, N., SheelaNair, A., Wines, B. D., Hogarth, P. M., Beeson, J. G., Greenhouse, B., Dorsey, G., Kamya, M., Hartel, G., Minigo, G., Feeney, M., Jagannathan, P., Boyle, M. J.
2022; 13 (1): 4159
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Abstract
T-follicular helper (Tfh) cells are key drivers of antibodies that protect from malaria. However, little is known regarding the host and parasite factors that influence Tfh and functional antibody development. Here, we use samples from a large cross-sectional study of children residing in an area of high malaria transmission in Uganda to characterize Tfh cells and functional antibodies to multiple parasites stages. We identify a dramatic re-distribution of the Tfh cell compartment with age that is independent of malaria exposure, with Th2-Tfh cells predominating in early childhood, while Th1-Tfh cell gradually increase to adult levels over the first decade of life. Functional antibody acquisition is age-dependent and hierarchical acquired based on parasite stage, with merozoite responses followed by sporozoite and gametocyte antibodies. Antibodies are boosted in children with current infection, and are higher in females. The children with the very highest antibody levels have increased Tfh cell activation and proliferation, consistent with a key role of Tfh cells in antibody development. Together, these data reveal a complex relationship between the circulating Tfh compartment, antibody development and protection from malaria.
View details for DOI 10.1038/s41467-022-31880-6
View details for PubMedID 35851033
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Malaria in 2022: Increasing challenges, cautious optimism.
Nature communications
Jagannathan, P., Kakuru, A.
2022; 13 (1): 2678
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View details for DOI 10.1038/s41467-022-30133-w
View details for PubMedID 35562368
Lo Lab
Modeling transmission of infectious diseases and public health control strategies.
Our research group studies the transmission of infectious diseases and
impact of public health strategies with an ultimate goal of informing public health policy. Our group applies diverse computational methodologies, including tools of epidemiology, modeling, pathogen genomics, and policy analysis. We study a broad set of pathogens including neglected tropical diseases, vaccine-preventable infections, and COVID-19.
The Parsonnet Lab
Investigating Chronic Disease-Infection Links
The laboratory's primary research interest is investigating the role of infectious agents in chronic diseases. Much of this work has revolved around Helicobacter pylori infection as a cause of adenocarcinomas and lymphomas of the stomach.
The Relman Lab
Host-Microbe Interactions & Human Microbial Ecology
David Relman's investigative program falls within the general themes of host-pathogen interactions and human microbial ecology, and is divided into two research areas:
- Ecology of microbial communities indigenous to humans and other mammalian hosts
- Genome-wide host response patterns in systemic infectious disease
The Shafer Lab
Virus Evolution focused on HIV Therapy and Drug Resistance
My group’s research is on the mechanisms and consequences of virus evolution with a focus on HIV therapy and drug resistance. We maintain a public HIV drug resistance database (http://hivdb.stanford.edu) as a resource for HIV drug resistance surveillance, interpreting HIV drug resistance tests, and HIV drug development. These three disciplines – epidemiology, clinical management, and basic science – reflect the interdisciplinary nature of antiviral drug resistance research and represent the range of our group’s activities.
Publications
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Recommendations on data sharing in HIV drug resistance research.
PLoS medicine
Inzaule, S. C., Siedner, M. J., Little, S. J., Avila-Rios, S., Ayitewala, A., Bosch, R. J., Calvez, V., Ceccherini-Silberstein, F., Charpentier, C., Descamps, D., Eshleman, S. H., Fokam, J., Frenkel, L. M., Gupta, R. K., Ioannidis, J. P., Kaleebu, P., Kantor, R., Kassaye, S. G., Kosakovsky Pond, S. L., Kouamou, V., Kouyos, R. D., Kuritzkes, D. R., Lessells, R., Marcelin, A., Mbuagbaw, L., Minalga, B., Ndembi, N., Neher, R. A., Paredes, R., Pillay, D., Raizes, E. G., Rhee, S., Richman, D. D., Ruxrungtham, K., Sabeti, P. C., Schapiro, J. M., Sirivichayakul, S., Steegen, K., Sugiura, W., van Zyl, G. U., Vandamme, A., Wensing, A. M., Wertheim, J. O., Gunthard, H. F., Jordan, M. R., Shafer, R. W.
2023; 20 (9): e1004293
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Abstract
Author summary Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens. HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens. Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines. Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing. In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions. Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV.
View details for DOI 10.1371/journal.pmed.1004293
View details for PubMedID 37738247
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Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review.
Viruses
Tao, K., Rhee, S. Y., Chu, C., Avalos, A., Ahluwalia, A. K., Gupta, R. K., Jordan, M. R., Shafer, R. W.
2023; 15 (9)
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Abstract
Background: Dolutegravir (DTG)-based antiretroviral therapy (ART) rarely leads to virological failure (VF) and drug resistance in integrase strand transfer inhibitor (INSTI)-naïve persons living with HIV (PLWH). As a result, limited data are available on INSTI-associated drug resistance mutations (DRMs) selected by DTG-containing ART regimens. Methods: We reviewed studies published through July 2023 to identify those reporting emergent major INSTI-associated DRMs in INSTI-naïve PLWH receiving DTG and those containing in vitro DTG susceptibility results using a standardized assay. Results: We identified 36 publications reporting 99 PLWH in whom major nonpolymorphic INSTI-associated DRMs developed on a DTG-containing regimen and 21 publications containing 269 in vitro DTG susceptibility results. DTG-selected DRMs clustered into four largely non-overlapping mutational pathways characterized by mutations at four signature positions: R263K, G118R, N155H, and Q148H/R/K. Eighty-two (82.8%) viruses contained just one signature DRM, including R263K (n = 40), G118R (n = 24), N155H (n = 9), and Q148H/R/K (n = 9). Nine (9.1%) contained ≥1 signature DRM, and eight (8.1%) contained just other DRMs. R263K and G118R were negatively associated with one another and with N155H and Q148H/K/R. R263K alone conferred a median 2.0-fold (IQR: 1.8-2.2) reduction in DTG susceptibility. G118R alone conferred a median 18.8-fold (IQR:14.2-23.4) reduction in DTG susceptibility. N155H alone conferred a median 1.4-fold (IQR: 1.2-1.6) reduction in DTG susceptibility. Q148H/R/K alone conferred a median 0.8-fold (IQR: 0.7-1.1) reduction in DTG susceptibility. Considerably higher levels of reduced susceptibility often occurred when signature DRMs occurred with additional INSTI-associated DRMs. Conclusions: Among INSTI-naïve PLWH with VF and treatment emergent INSTI-associated DRMs, most developed one of four signature DRMs, most commonly R263K or G118R. G118R was associated with a much greater reduction in DTG susceptibility than R263K.
View details for DOI 10.3390/v15091932
View details for PubMedID 37766338
View details for PubMedCentralID PMC10536831
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Genotypic Resistance Testing of HIV-1 DNA in Peripheral Blood Mononuclear Cells.
Clinical microbiology reviews
Chu, C., Armenia, D., Walworth, C., Santoro, M. M., Shafer, R. W.
2022: e0005222
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Abstract
HIV-1 DNA exists in nonintegrated linear and circular episomal forms and as integrated proviruses. In patients with plasma viremia, most peripheral blood mononuclear cell (PBMC) HIV-1 DNA consists of recently produced nonintegrated virus DNA while in patients with prolonged virological suppression (VS) on antiretroviral therapy (ART), most PBMC HIV-1 DNA consists of proviral DNA produced months to years earlier. Drug-resistance mutations (DRMs) in PBMCs are more likely to coexist with ancestral wild-type virus populations than they are in plasma, explaining why next-generation sequencing is particularly useful for the detection of PBMC-associated DRMs. In patients with ongoing high levels of active virus replication, the DRMs detected in PBMCs and in plasma are usually highly concordant. However, in patients with lower levels of virus replication, it may take several months for plasma virus DRMs to reach detectable levels in PBMCs. This time lag explains why, in patients with VS, PBMC genotypic resistance testing (GRT) is less sensitive than historical plasma virus GRT, if previous episodes of virological failure and emergent DRMs were either not prolonged or not associated with high levels of plasma viremia. Despite the increasing use of PBMC GRT in patients with VS, few studies have examined the predictive value of DRMs on the response to a simplified ART regimen. In this review, we summarize what is known about PBMC HIV-1 DNA dynamics, particularly in patients with suppressed plasma viremia, the methods used for PBMC HIV-1 GRT, and the scenarios in which PBMC GRT has been used clinically.
View details for DOI 10.1128/cmr.00052-22
View details for PubMedID 36102816
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Susceptibility of SARS-CoV-2 Omicron Variants to Therapeutic Monoclonal Antibodies: Systematic Review and Meta-analysis.
Microbiology spectrum
Tao, K., Tzou, P. L., Kosakovsky Pond, S. L., Ioannidis, J. P., Shafer, R. W.
2022: e0092622
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Abstract
SARS-CoV-2 Omicron variants contain many mutations in its spike receptor-binding domain, the target of all authorized monoclonal antibodies (MAbs). Determining the extent to which Omicron variants reduced MAb susceptibility is critical to preventing and treating COVID-19. We systematically reviewed PubMed and three preprint servers, last updated 11 April 2022, for the in vitro activity of authorized MAbs against the Omicron variants. Fifty-one studies were eligible, including 50 containing Omicron BA.1 susceptibility data and 17 containing Omicron BA.2 susceptibility data. The first two authorized MAb combinations, bamlanivimab/etesevimab and casirivimab/imdevimab, were largely inactive against the Omicron BA.1 and BA.2 variants. In 34 studies, sotrovimab displayed a median 4.0-fold (interquartile range [IQR]: 2.6 to 6.9) reduction in activity against Omicron BA.1, and in 12 studies, it displayed a median 17-fold (IQR: 13 to 30) reduction in activity against Omicron BA.2. In 15 studies, the combination cilgavimab/tixagevimab displayed a median 86-fold (IQR: 27 to 151) reduction in activity against Omicron BA.1, and in six studies, it displayed a median 5.4-fold (IQR: 3.7 to 6.9) reduction in activity against Omicron BA.2. In eight studies against Omicron BA.1 and six studies against Omicron BA.2, bebtelovimab displayed no reduction in activity. Disparate results between assays were common. For authorized MAbs, 51/268 (19.0%) results for wild-type control variants and 78/348 (22.4%) results for Omicron BA.1 and BA.2 variants were more than 4-fold below or 4-fold above the median result for that MAb. Highly disparate results between published assays indicate a need for improved MAb susceptibility test standardization or interassay calibration. IMPORTANCE Monoclonal antibodies (MAbs) targeting the SARS-CoV-2 spike protein are among the most effective measures for preventing and treating COVID-19. However, SARS-CoV-2 Omicron variants contain many mutations in their spike receptor-binding domains, the target of all authorized MAbs. Therefore, determining the extent to which Omicron variants reduced MAb susceptibility is critical to preventing and treating COVID-19. We identified 51 studies that reported the in vitro susceptibility of the two main Omicron variants BA.1 and BA.2 to therapeutic MAbs in advanced clinical development, including eight authorized individual MAbs and three authorized MAb combinations. We estimated the degree to which different MAbs displayed reduced activity against Omicron variants. The marked loss of activity of many MAbs against Omicron variants underscores the importance of developing MAbs that target conserved regions of spike. Highly disparate results between assays indicate the need for improved MAb susceptibility test standardization.
View details for DOI 10.1128/spectrum.00926-22
View details for PubMedID 35700134
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Public availability of HIV-1 drug resistance sequence and treatment data: a systematic review.
The Lancet. Microbe
Rhee, S., Kassaye, S. G., Jordan, M. R., Kouamou, V., Katzenstein, D., Shafer, R. W.
2022; 3 (5): e392-e398
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Abstract
HIV-1 pol sequences from antiretroviral therapy (ART)-naive and ART-experienced people living with HIV-1 are fundamental to understanding the genetic correlates and epidemiology of HIV-1 drug resistance (HIVDR). To assess the public availability of HIV-1 pol sequences and ART histories of the individuals from whom sequenced viruses were obtained, we performed a systematic review of PubMed and GenBank for HIVDR studies published between 2010 and 2019 that reported HIV-1 pol sequences. 934 studies met inclusion criteria, including 461 studies of ART-naive adults, 407 of ART-experienced adults, and 66 of ART-naive and ART-experienced children. Sequences were available for 317 (68·8%) studies of ART-naive individuals, 190 (46·7%) of ART-experienced individuals, and 45 (68·2%) of children. Among ART-experienced individuals, sequences plus linked ART histories were available for 82 (20·1%) studies. Sequences were available for 21 (29·2%) of 72 clinical trials. Among journals publishing more than ten studies, the proportion with available sequences ranged from 8·3% to 86·9%. Strengthened implementation of data sharing policies is required to increase the number of studies with available HIVDR data to support the enterprise of global ART in the face of emerging HIVDR.
View details for DOI 10.1016/S2666-5247(21)00250-0
View details for PubMedID 35544100
The Singh Lab
Identifying Virulence Mechanisms Parasites Develop to Cause Disease
Our lab studies the molecular basis of pathogenesis of two medically important parasites, Toxoplasma gondii and Entamoeba histolytica. The work is aimed at understanding the virulence determinant that each parasite uses in causing disease, specifically how T. gondii evades the human immune response by converting to a dormant bradyzoite stage and how E. histolyticacauses invasive colonic and hepatic disease.
Publications
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Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19: The ACTIV-6 Randomized Clinical Trial.
JAMA
Stewart, T. G., Rebolledo, P. A., Mourad, A., Lindsell, C. J., Boulware, D. R., McCarthy, M. W., Thicklin, F., Garcia Del Sol, I. T., Bramante, C. T., Lenert, L. A., Lim, S., Williamson, J. C., Cardona, O. Q., Scott, J., Schwasinger-Schmidt, T., Ginde, A. A., Castro, M., Jayaweera, D., Sulkowski, M., Gentile, N., McTigue, K., Felker, G. M., DeLong, A., Wilder, R., Rothman, R. L., Collins, S., Dunsmore, S. E., Adam, S. J., Hanna, G. J., Shenkman, E., Hernandez, A. F., Naggie, S.
2023
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Abstract
The effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain.To assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19.The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, a total of 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were 30 years or older with confirmed SARS-CoV-2 infection and at least 2 acute COVID-19 symptoms for 7 days or less.Participants were randomized to receive fluvoxamine, 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days (n = 601), or placebo (n = 607).The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell. Follow-up occurred through day 28.Among 1208 participants who were randomized and received the study drug, the median (IQR) age was 50 (40-60) years, 65.8% were women, 45.5% identified as Hispanic/Latino, and 76.8% reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo included in the primary analysis, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09]; P for efficacy = .40]). Additionally, unadjusted median time to sustained recovery was 10 (95% CI, 10-11) days in both the intervention and placebo groups. No deaths were reported. Thirty-five participants reported health care use events (a priori defined as death, hospitalization, or emergency department/urgent care visit): 14 in the fluvoxamine group compared with 21 in the placebo group (HR, 0.69 [95% credible interval, 0.27-1.21]; P for efficacy = .86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo) but no deaths.Among outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms.ClinicalTrials.gov Identifier: NCT04885530.
View details for DOI 10.1001/jama.2023.23363
View details for PubMedID 37976072
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Safety and efficacy of inhaled interferon-β1a (SNG001) in adults with mild-to-moderate COVID-19: a randomized, controlled, phase II trial.
EClinicalMedicine
Jagannathan, P., Chew, K. W., Giganti, M. J., Hughes, M. D., Moser, C., Main, M. J., Monk, P. D., Javan, A. C., Li, J. Z., Fletcher, C. V., McCarthy, C., Wohl, D. A., Daar, E. S., Eron, J. J., Currier, J. S., Singh, U., Smith, D. M., Fischer, W.
2023; 65: 102250
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Abstract
With the emergence of SARS-CoV-2 variants resistant to monoclonal antibody therapies and limited global access to therapeutics, the evaluation of novel therapeutics to prevent progression to severe COVID-19 remains a critical need.Safety, clinical and antiviral efficacy of inhaled interferon-β1a (SNG001) were evaluated in a phase II randomized controlled trial on the ACTIV-2/A5401 platform (ClinicalTrials.govNCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized and initiated either orally inhaled nebulized SNG001 given once daily for 14 days (n = 110) or blinded pooled placebo (n = 110) between February 10 and August 18, 2021.The proportion of participants reporting premature treatment discontinuation was 9% among SNG001 and 13% among placebo participants. There were no differences between participants who received SNG001 or placebo in the primary outcomes of treatment emergent Grade 3 or higher adverse events (3.6% and 8.2%, respectively), time to symptom improvement (median 13 and 9 days, respectively), or proportion with unquantifiable nasopharyngeal SARS-CoV-2 RNA at days 3 (28% [26/93] vs. 39% [37/94], respectively), 7 (65% [60/93] vs. 66% [62/94]) and 14 (91% [86/95] vs. 91% [83/81]). There were fewer hospitalizations with SNG001 (n = 1; 1%) compared with placebo (n = 7; 6%), representing an 86% relative risk reduction (p = 0.07). There were no deaths in either arm.In this trial, SNG001 was safe and associated with a non-statistically significant decrease in hospitalization for COVID-19 pneumonia.The ACTIV-2 platform study is funded by the NIH. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
View details for DOI 10.1016/j.eclinm.2023.102250
View details for PubMedID 37855026
View details for PubMedCentralID PMC10579289
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Extracellular Vesicles and Their Impact on the Biology of Protozoan Parasites.
Tropical medicine and infectious disease
Sharma, M., Lozano-Amado, D., Chowdhury, D., Singh, U.
2023; 8 (9)
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Abstract
Extracellular vesicles (EVs) are lipid-membrane-bound structures produced naturally by all cells and have a variety of functions. EVs act as vehicles for transporting important molecular signals from one cell to another. Several parasites have been shown to secrete EVs, and their biological functions have been extensively studied. EVs have been shown to facilitate communication with the host cells (such as modulation of the host's immune system or promoting attachment and invasion into the host cells) or for communication between parasitic cells (e.g., transferring drug-resistance genes or factors modulating stage conversion). It is clear that EVs play an important role in host-parasite interactions. In this review, we summarized the latest research on the EVs secreted by protozoan parasites and their role in host-parasite and parasite-parasite communications.
View details for DOI 10.3390/tropicalmed8090448
View details for PubMedID 37755909
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The Tomato Brown Rugose Fruit Virus Movement Protein Gene Is a Novel Microbial Source Tracking Marker.
Applied and environmental microbiology
Natarajan, A., Fremin, B. J., Schmidtke, D. T., Wolfe, M. K., Zlitni, S., Graham, K. E., Brooks, E. F., Severyn, C. J., Sakamoto, K. M., Lacayo, N. J., Kuersten, S., Koble, J., Caves, G., Kaplan, I., Singh, U., Jagannathan, P., Rezvani, A. R., Bhatt, A. S., Boehm, A. B.
2023: e0058323
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Abstract
Microbial source tracking (MST) identifies sources of fecal contamination in the environment using host-associated fecal markers. While there are numerous bacterial MST markers that can be used herein, there are few such viral markers. Here, we designed and tested novel viral MST markers based on tomato brown rugose fruit virus (ToBRFV) genomes. We assembled eight nearly complete genomes of ToBRFV from wastewater and stool samples from the San Francisco Bay Area in the United States. Next, we developed two novel probe-based reverse transcription-PCR (RT-PCR) assays based on conserved regions of the ToBRFV genome and tested the markers' sensitivities and specificities using human and non-human animal stool as well as wastewater. The ToBRFV markers are sensitive and specific; in human stool and wastewater, they are more prevalent and abundant than a commonly used viral marker, the pepper mild mottle virus (PMMoV) coat protein (CP) gene. We used the assays to detect fecal contamination in urban stormwater samples and found that the ToBRFV markers matched cross-assembly phage (crAssphage), an established viral MST marker, in prevalence across samples. Taken together, these results indicate that ToBRFV is a promising viral human-associated MST marker. IMPORTANCE Human exposure to fecal contamination in the environment can cause transmission of infectious diseases. Microbial source tracking (MST) can identify sources of fecal contamination so that contamination can be remediated and human exposures can be reduced. MST requires the use of host-associated MST markers. Here, we designed and tested novel MST markers from genomes of tomato brown rugose fruit virus (ToBRFV). The markers are sensitive and specific to human stool and highly abundant in human stool and wastewater samples.
View details for DOI 10.1128/aem.00583-23
View details for PubMedID 37404180
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Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design.
PloS one
Horwitz, L. I., Thaweethai, T., Brosnahan, S. B., Cicek, M. S., Fitzgerald, M. L., Goldman, J. D., Hess, R., Hodder, S. L., Jacoby, V. L., Jordan, M. R., Krishnan, J. A., Laiyemo, A. O., Metz, T. D., Nichols, L., Patzer, R. E., Sekar, A., Singer, N. G., Stiles, L. E., Taylor, B. S., Ahmed, S., Algren, H. A., Anglin, K., Aponte-Soto, L., Ashktorab, H., Bassett, I. V., Bedi, B., Bhadelia, N., Bime, C., Bind, M. C., Black, L. J., Blomkalns, A. L., Brim, H., Castro, M., Chan, J., Charney, A. W., Chen, B. K., Chen, L. Q., Chen, P., Chestek, D., Chibnik, L. B., Chow, D. C., Chu, H. Y., Clifton, R. G., Collins, S., Costantine, M. M., Cribbs, S. K., Deeks, S. G., Dickinson, J. D., Donohue, S. E., Durstenfeld, M. S., Emery, I. F., Erlandson, K. M., Facelli, J. C., Farah-Abraham, R., Finn, A. V., Fischer, M. S., Flaherman, V. J., Fleurimont, J., Fonseca, V., Gallagher, E. J., Gander, J. C., Gennaro, M. L., Gibson, K. S., Go, M., Goodman, S. N., Granger, J. P., Greenway, F. L., Hafner, J. W., Han, J. E., Harkins, M. S., Hauser, K. S., Heath, J. R., Hernandez, C. R., Ho, O., Hoffman, M. K., Hoover, S. E., Horowitz, C. R., Hsu, H., Hsue, P. Y., Hughes, B. L., Jagannathan, P., James, J. A., John, J., Jolley, S., Judd, S. E., Juskowich, J. J., Kanjilal, D. G., Karlson, E. W., Katz, S. D., Kelly, J. D., Kelly, S. W., Kim, A. Y., Kirwan, J. P., Knox, K. S., Kumar, A., Lamendola-Essel, M. F., Lanca, M., Lee-Lannotti, J. K., Lefebvre, R. C., Levy, B. D., Lin, J. Y., Logarbo, B. P., Logue, J. K., Longo, M. T., Luciano, C. A., Lutrick, K., Malakooti, S. K., Mallett, G., Maranga, G., Marathe, J. G., Marconi, V. C., Marshall, G. D., Martin, C. F., Martin, J. N., May, H. T., McComsey, G. A., McDonald, D., Mendez-Figueroa, H., Miele, L., Mittleman, M. A., Mohandas, S., Mouchati, C., Mullington, J. M., Nadkarni, G. N., Nahin, E. R., Neuman, R. B., Newman, L. T., Nguyen, A., Nikolich, J. Z., Ofotokun, I., Ogbogu, P. U., Palatnik, A., Palomares, K. T., Parimon, T., Parry, S., Parthasarathy, S., Patterson, T. F., Pearman, A., Peluso, M. J., Pemu, P., Pettker, C. M., Plunkett, B. A., Pogreba-Brown, K., Poppas, A., Porterfield, J. Z., Quigley, J. G., Quinn, D. K., Raissy, H., Rebello, C. J., Reddy, U. M., Reece, R., Reeder, H. T., Rischard, F. P., Rosas, J. M., Rosen, C. J., Rouphael, N. G., Rouse, D. J., Ruff, A. M., Saint Jean, C., Sandoval, G. J., Santana, J. L., Schlater, S. M., Sciurba, F. C., Selvaggi, C., Seshadri, S., Sesso, H. D., Shah, D. P., Shemesh, E., Sherif, Z. A., Shinnick, D. J., Simhan, H. N., Singh, U., Sowles, A., Subbian, V., Sun, J., Suthar, M. S., Teunis, L. J., Thorp, J. M., Ticotsky, A., Tita, A. T., Tragus, R., Tuttle, K. R., Urdaneta, A. E., Utz, P. J., VanWagoner, T. M., Vasey, A., Vernon, S. D., Vidal, C., Walker, T., Ward, H. D., Warren, D. E., Weeks, R. M., Weiner, S. J., Weyer, J. C., Wheeler, J. L., Whiteheart, S. W., Wiley, Z., Williams, N. J., Wisnivesky, J. P., Wood, J. C., Yee, L. M., Young, N. M., Zisis, S. N., Foulkes, A. S.
2023; 18 (6): e0286297
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SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.NCT05172024.
View details for DOI 10.1371/journal.pone.0286297
View details for PubMedID 37352211
View details for PubMedCentralID PMC10289397
The Wang Lab
Human Immune Functions & Susceptibility to Diseases
Taia Wang’s laboratory studies mechanisms underlying the heterogeneity in human immune function during vaccination and viral infection. We are particularly interested in antibody-mediated immunity and determinants of susceptibility to antibody-mediated diseases.
Publications
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Multi-omics analysis of mucosal and systemic immunity to SARS-CoV-2 after birth.
Cell
Wimmers, F., Burrell, A. R., Feng, Y., Zheng, H., Arunachalam, P. S., Hu, M., Spranger, S., Nyhoff, L. E., Joshi, D., Trisal, M., Awasthi, M., Bellusci, L., Ashraf, U., Kowli, S., Konvinse, K. C., Yang, E., Blanco, M., Pellegrini, K., Tharp, G., Hagan, T., Chinthrajah, R. S., Nguyen, T. T., Grifoni, A., Sette, A., Nadeau, K. C., Haslam, D. B., Bosinger, S. E., Wrammert, J., Maecker, H. T., Utz, P. J., Wang, T. T., Khurana, S., Khatri, P., Staat, M. A., Pulendran, B.
2023
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The dynamics of immunity to infection in infants remain obscure. Here, we used a multi-omics approach to perform a longitudinal analysis of immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in infants and young children by analyzing blood samples and weekly nasal swabs collected before, during, and after infection with Omicron and non-Omicron variants. Infection stimulated robust antibody titers that, unlike in adults, showed no sign of decay for up to 300 days. Infants mounted a robust mucosal immune response characterized by inflammatory cytokines, interferon (IFN) α, and T helper (Th) 17 and neutrophil markers (interleukin [IL]-17, IL-8, and CXCL1). The immune response in blood was characterized by upregulation of activation markers on innate cells, no inflammatory cytokines, but several chemokines and IFNα. The latter correlated with viral load and expression of interferon-stimulated genes (ISGs) in myeloid cells measured by single-cell multi-omics. Together, these data provide a snapshot of immunity to infection during the initial weeks and months of life.
View details for DOI 10.1016/j.cell.2023.08.044
View details for PubMedID 37776858
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Spheromers reveal robust T cell responses to the Pfizer/BioNTech vaccine and attenuated peripheral CD8+ T cell responses post SARS-CoV-2 infection.
Immunity
Gao, F., Mallajoysula, V., Arunachalam, P. S., van der Ploeg, K., Manohar, M., Röltgen, K., Yang, F., Wirz, O., Hoh, R., Haraguchi, E., Lee, J. Y., Willis, R., Ramachandiran, V., Li, J., Kathuria, K. R., Li, C., Lee, A. S., Shah, M. M., Sindher, S. B., Gonzalez, J., Altman, J. D., Wang, T. T., Boyd, S. D., Pulendran, B., Jagannathan, P., Nadeau, K. C., Davis, M. M.
2023
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Abstract
T cells are a critical component of the response to SARS-CoV-2, but their kinetics after infection and vaccination are insufficiently understood. Using "spheromer" peptide-MHC multimer reagents, we analyzed healthy subjects receiving two doses of the Pfizer/BioNTech BNT162b2 vaccine. Vaccination resulted in robust spike-specific T cell responses for the dominant CD4+ (HLA-DRB1∗15:01/S191) and CD8+ (HLA-A∗02/S691) T cell epitopes. Antigen-specific CD4+ and CD8+ T cell responses were asynchronous, with the peak CD4+ T cell responses occurring 1 week post the second vaccination (boost), whereas CD8+ T cells peaked 2 weeks later. These peripheral T cell responses were elevated compared with COVID-19 patients. We also found that previous SARS-CoV-2 infection resulted in decreased CD8+ T cell activation and expansion, suggesting that previous infection can influence the T cell response to vaccination.
View details for DOI 10.1016/j.immuni.2023.03.005
View details for PubMedID 36996809
View details for PubMedCentralID PMC10017386
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Autoantibodies are highly prevalent in non-SARS-CoV-2 respiratory infections and critical illness.
JCI insight
Feng, A., Yang, E. Y., Moore, A. R., Dhingra, S., Chang, S. E., Yin, X., Pi, R., Mack, E. K., Völkel, S., Geßner, R., Gündisch, M., Neubauer, A., Renz, H., Tsiodras, S., Fragkou, P. C., Asuni, A. A., Levitt, J. E., Wilson, J. G., Leong, M., Lumb, J. H., Mao, R., Pinedo, K., Roque, J., Richards, C. M., Stabile, M., Swaminathan, G., Salagianni, M. L., Triantafyllia, V., Bertrams, W., Blish, C. A., Carette, J. E., Frankovich, J., Meffre, E., Nadeau, K. C., Singh, U., Wang, T. T., Luning Prak, E. T., Herold, S., Andreakos, E., Schmeck, B., Skevaki, C., Rogers, A. J., Utz, P. J.
2023; 8 (3)
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The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non-SARS-CoV-2 infections and critical illness has not yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non-SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness.
View details for DOI 10.1172/jci.insight.163150
View details for PubMedID 36752204
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Early immune markers of clinical, virological, and immunological outcomes in patients with COVID-19: a multi-omics study.
eLife
Hu, Z., van der Ploeg, K., Chakraborty, S., Arunachalam, P. S., Mori, D. A., Jacobson, K. B., Bonilla, H., Parsonnet, J., Andrews, J. R., Holubar, M., Subramanian, A., Khosla, C., Maldonado, Y., Hedlin, H., de la Parte, L., Press, K., Ty, M., Tan, G. S., Blish, C., Takahashi, S., Rodriguez-Barraquer, I., Greenhouse, B., Butte, A. J., Singh, U., Pulendran, B., Wang, T. T., Jagannathan, P.
2022; 11
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Abstract
The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients.Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial.We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2-7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset.Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models.Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford's Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals.
View details for DOI 10.7554/eLife.77943
View details for PubMedID 36239699
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Durable protection against the SARS-CoV-2 Omicron variant is induced by an adjuvanted subunit vaccine.
Science translational medicine
Arunachalam, P. S., Feng, Y., Ashraf, U., Hu, M., Walls, A. C., Edara, V. V., Zarnitsyna, V. I., Aye, P. P., Golden, N., Miranda, M. C., Green, K. W., Threeton, B. M., Maness, N. J., Beddingfield, B. J., Bohm, R. P., Scheuermann, S. E., Goff, K., Dufour, J., Russell-Lodrigue, K., Kepl, E., Fiala, B., Wrenn, S., Ravichandran, R., Ellis, D., Carter, L., Rogers, K., Shirreff, L. M., Ferrell, D. E., Deb Adhikary, N. R., Fontenot, J., Hammond, H. L., Frieman, M., Grifoni, A., Sette, A., O'Hagan, D. T., Van Der Most, R., Rappuoli, R., Villinger, F., Kleanthous, H., Rappaport, J., Suthar, M. S., Veesler, D., Wang, T. T., King, N. P., Pulendran, B.
2022; 14 (658): eabq4130
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Despite the remarkable efficacy of COVID-19 vaccines, waning immunity and the emergence of SARS-CoV-2 variants such as Omicron represents a global health challenge. Here, we present data from a study in nonhuman primates demonstrating durable protection against the Omicron BA.1 variant induced by a subunit SARS-CoV-2 vaccine comprising the receptor binding domain of the ancestral strain (RBD-Wu) on the I53-50 nanoparticle adjuvanted with AS03, which was recently authorized for use in individuals 18 years or older. Vaccination induced neutralizing antibody (nAb) titers that were maintained at high concentrations for at least 1 year after two doses, with a pseudovirus nAb geometric mean titer (GMT) of 1978 and a live virus nAb GMT of 1331 against the ancestral strain but not against the Omicron BA.1 variant. However, a booster dose at 6 to 12 months with RBD-Wu or RBD-beta (RBD from the Beta variant) displayed on I53-50 elicited high neutralizing titers against the ancestral and Omicron variants. In addition, we observed persistent neutralization titers against a panel of sarbecoviruses, including SARS-CoV. Furthermore, there were substantial and persistent memory T and B cell responses reactive to Beta and Omicron variants. Vaccination resulted in protection against Omicron infection in the lung and suppression of viral burden in the nares at 6 weeks after the final booster immunization. Even at 6 months after vaccination, we observed protection in the lung and rapid control of virus in the nares. These results highlight the durable and cross-protective immunity elicited by the AS03-adjuvanted RBD-I53-50 nanoparticle vaccine.
View details for DOI 10.1126/scitranslmed.abq4130
View details for PubMedID 35976993