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.
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.
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.
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.
A 20-Gene Set Predictive of Progression to Severe Dengue.
Robinson, M., Sweeney, T. E., Barouch-Bentov, R., Sahoo, M. K., Kalesinskas, L., Vallania, F., Sanz, A. M., Ortiz-Lasso, E., Albornoz, L. L., Rosso, F., Montoya, J. G., Pinsky, B. A., Khatri, P., Einav, S.
2019; 26 (5): 1104
There is a need to identify biomarkers predictive of severe dengue. Single-cohort transcriptomics has not yielded generalizable results or parsimonious, predictive gene sets. We analyzed blood samples of dengue patients from seven gene expression datasets (446 samples, five countries) using an integrated multi-cohort analysis framework and identified a 20-gene set that predicts progression to severe dengue. We validated the predictive power of this 20-gene set in three retrospective dengue datasets (84 samples, three countries) and a prospective Colombia cohort (34 patients), with an area under the receiver operating characteristic curve of 0.89, 100% sensitivity, and 76% specificity. The 20-gene dengue severity scores declined during the diseasecourse, suggesting an infection-triggered host response. This 20-gene set is strongly associated with the progression to severe dengue and represents a predictive signature, generalizable across ages, host genetic factors, and virus strains, with potential implications for the development of a host response-based dengue prognostic assay.
View details for PubMedID 30699342
MARCH8 Ubiquitinates the Hepatitis C Virus Nonstructural 2 Protein and Mediates Viral Envelopment.
Kumar, S., Barouch-Bentov, R., Xiao, F., Schor, S., Pu, S., Biquand, E., Lu, A., Lindenbach, B. D., Jacob, Y., Demeret, C., Einav, S.
2019; 26 (7): 1800–1814.e5
The mechanisms that regulate envelopment of HCV and other viruses that bud intracellularly and/or lack late-domain motifs are largely unknown. We reported that K63 polyubiquitination of the HCV nonstructural (NS) 2 protein mediates HRS (ESCRT-0 component) binding and envelopment. Nevertheless, the ubiquitin signaling that governs NS2 ubiquitination remained unknown. Here, we map the NS2 interactome with the ubiquitin proteasome system (UPS) via mammalian cell-based screens. NS2 interacts with E3 ligases, deubiquitinases, and ligase regulators, some of which are candidate proviral or antiviral factors. MARCH8, a RING-finger E3 ligase, catalyzes K63-linked NS2 polyubiquitination in vitro and in HCV-infected cells. MARCH8 is required for infection with HCV, dengue, and Zika viruses and specifically mediates HCV envelopment. Our data reveal regulation of HCV envelopment via ubiquitin signaling and both a viral protein substrate and a ubiquitin K63-linkage of the understudied MARCH8, with potential implications for cell biology, virology, and host-targeted antiviral design.
View details for PubMedID 30759391
Virus-inclusive single-cell RNA sequencing reveals the molecular signature of progression to severe dengue.
Proceedings of the National Academy of Sciences of the United States of America
Zanini, F., Robinson, M. L., Croote, D., Sahoo, M. K., Sanz, A. M., Ortiz-Lasso, E., Albornoz, L. L., Rosso, F., Montoya, J. G., Goo, L., Pinsky, B. A., Quake, S. R., Einav, S.
Dengue virus (DENV) infection can result in severe complications. However, the understanding of the molecular correlates of severity is limited, partly due to difficulties in defining the peripheral blood mononuclear cells (PBMCs) that contain DENV RNA in vivo. Accordingly, there are currently no biomarkers predictive of progression to severe dengue (SD). Bulk transcriptomics data are difficult to interpret because blood consists of multiple cell types that may react differently to infection. Here, we applied virus-inclusive single-cell RNA-seq approach (viscRNA-Seq) to profile transcriptomes of thousands of single PBMCs derived early in the course of disease from six dengue patients and four healthy controls and to characterize distinct leukocyte subtypes that harbor viral RNA (vRNA). Multiple IFN response genes, particularly MX2 in naive B cells and CD163 in CD14+ CD16+ monocytes, were up-regulated in a cell-specific manner before progression to SD. The majority of vRNA-containing cells in the blood of two patients who progressed to SD were naive IgM B cells expressing the CD69 and CXCR4 receptors and various antiviral genes, followed by monocytes. Bystander, non-vRNA-containing B cells also demonstrated immune activation, and IgG1 plasmablasts from two patients exhibited clonal expansions. Lastly, assembly of the DENV genome sequence revealed diversity at unexpected sites. This study presents a multifaceted molecular elucidation of natural dengue infection in humans with implications for any tissue and viral infection and proposes candidate biomarkers for prediction of SD.
View details for PubMedID 30530648
Cyclin G-associated kinase (GAK) affinity and antiviral activity studies of a series of 3-C-substituted isothiazolo[4,3-b]pyridines.
European journal of medicinal chemistry
Wouters, R., Pu, S., Froeyen, M., Lescrinier, E., Einav, S., Herdewijn, P., De Jonghe, S.
2018; 163: 256–65
Cyclin G-associated kinase (GAK) is a cellular regulator of the clathrin-associated host adaptor proteins AP-1 and AP-2, which regulates intracellular trafficking of dengue virus during early and late stages of the viral lifecycle. Previously, the discovery of isothiazolo[4,3-b]pyridines as potent and selective GAK inhibitors with promising antiviral activity was reported. In this manuscript, the synthesis of isothiazolo[4,3-b]pyridines with a carbon-linked substituent at position 3 is described by the application of regioselective Suzuki and Sonogashira coupling reactions. A derivative with a 3,4-dimethoxyphenyl residue at position 3 demonstrates low nanomolar binding affinity for GAK and antiviral activity against dengue virus. These findings reveal that appropriate substitution of a phenyl moiety at position 3 of the scaffold can improve GAK binding affinity.
View details for PubMedID 30529544
Viral journeys on the intracellular highways.
Cellular and molecular life sciences : CMLS
Robinson, M., Schor, S., Barouch-Bentov, R., Einav, S.
Viruses are obligate intracellular pathogens that are dependent on cellular machineries for their replication. Recent technological breakthroughs have facilitated reliable identification of host factors required for viral infections and better characterization of the virus-host interplay. While these studies have revealed cellular machineries that are uniquely required by individual viruses, accumulating data also indicate the presence of broadly required mechanisms. Among these overlapping cellular functions are components of intracellular membrane trafficking pathways. Here, we review recent discoveries focused on how viruses exploit intracellular membrane trafficking pathways to promote various stages of their life cycle, with an emphasis on cellular factors that are usurped by a broad range of viruses. We describe broadly required components of the endocytic and secretory pathways, the Endosomal Sorting Complexes Required for Transport pathway, and the autophagy pathway. Identification of such overlapping host functions offers new opportunities to develop broad-spectrum host-targeted antiviral strategies.
View details for PubMedID 30043139
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.
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.
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.
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.