Shresta Lab

Shresta Lab

"Infectious diseases have no geographic boundaries. It doesn’t matter whether a country is rich or poor, developed or developing, these diseases can still arrive." — Sujan Shresta, Ph.D. // Associate Professor
Center for Infectious Disease

Overview

Sujan Shresta, Ph.D., and her team study the immunology and virology of mosquito-borne human pathogens such as dengue virus (DENV) and Zika virus (ZIKV). DENV causes a spectrum of clinical disease ranging from dengue fever, a self-limited febrile illness, to a life-threatening syndrome called severe dengue or dengue hemorrhagic fever/dengue shock syndrome. ZIKV has been proven to cause serious birth defects, and is also associated with other neurological conditions including Guillain-Barré Syndrome and meningoencephalitis.

Studies suggest that the host’s immune system plays a dual role in protection and pathogenesis; however, how the immune response to DENV and ZIKV protects against or contributes to severe disease remains unclear and controversial. Using mouse models, primary human cell culture models, and patient samples, Dr. Shresta and her team dissect the protective versus pathogenic mechanisms of the immune system in response to these viral infections. As mosquito-borne viruses are increasingly spreading from tropical to temperate zones worldwide, the team has also begun to investigate the emergence of DENV and ZIKV in Nepal. A better understanding of the virus-host interactions is critical for developing much-needed antivirals and vaccines against DENV and ZIKV.

From The Lab

Nov 14, 2018 // Cell Host & Microbe

Maternally-acquired Zika immunity can increase dengue disease severity in mouse pups

Nov 14, 2018 // NOVA PBS

How Zika and Dengue Exploit the Mother-Child Relationship

Aug 2, 2018 // Nature Communications

Maternal dengue immunity protects against fetal damage in mice following Zika virus infection

Nov 13, 2017 // Nature Communications

Dengue immunity can protect against Zika virus

Mar 13, 2017

Pre-existing immunity to dengue virus shapes Zika-specific T cell response

Shresta Lab

Publications

PLoS Negl Trop Dis

A longitudinal systems immunologic investigation of acute Zika virus infection in an individual infected while traveling to Caracas, Venezuela

2018-12
Cell Host Microbe

Maternally Acquired Zika Antibodies Enhance Dengue Disease Severity in Mice

2018-11
Antiviral Res

Synergism between the tyrosine kinase inhibitor sunitinib and Anti-TNF antibody protects against lethal dengue infection

2018-10
Branche E, Tang WW, Viramontes KM, Young MP, Sheets N, Joo Y, Nguyen AT, Shresta S
Proc Natl Acad Sci USA

Deconvolution of pro- and antiviral genomic responses in Zika virus-infected and bystander macrophages

2018-09
Annu Rev Immunol

Immune response to dengue and zika

2018-04
Ngono AE, Shresta S
Sci Rep

Blocking zika virus vertical transmission

2018-01
Vaccines (Basel)

Development of zika virus vaccines

2018-01
Sci Rep

Repurposing of the anti-malaria drug chloroquine for zika virus treatment and prophylaxis

2017-11
Shiryaev SA, Mesci P, Pinto A, Fernandes I, Sheets N, Shresta S, Farhy C, Huang CT, Strongin AY, Muotri AR, Terskikh AV
Nat Commun

Dengue virus-reactive CD8+ T cells mediate cross-protection against subsequent zika virus challenge

2017-11
Wen J, Elong Ngono A, Regla-Nava JA, Kim K, Gorman MJ, Diamond MS, Shresta S
Cell Rep

An IRF-3-, IRF-5-, and IRF-7-independent pathway of dengue viral resistance utilizes IRF-1 to stimulate type I and II interferon responses

2017-11
Carlin AF, Plummer EM, Vizcarra EA, Sheets N, Joo Y, Tang W, Day J, Greenbaum J, Glass CK, Diamond MS, Shresta S
J Interferon Cytokine Res

T cell immunity to zika and dengue viral infections

2017-11
Wen J, Shresta S
Antiviral Res

Characterization of the Zika virus two-component NS2B-NS3 protease and structure-assisted identification of allosteric small-molecule antagonists

2017-07
Shiryaev SA, Farhy C, Pinto A, Huang CT, Simonetti N, Ngono AE, Dewing A, Shresta S, Pinkerton AB, Cieplak P, Strongin…
Cell Host Microbe

ADE-ing and abetting Zika

2017-05
Wen J, Shresta S
Nat Microbiol

Identification of Zika virus epitopes reveals immunodominant and protective roles for dengue virus cross-reactive CD8+ T cells

2017-03
Wen J, Tang WW, Sheets N, Ellison J, Sette A, Kim K, Shresta S
Cell

Modified mRNA vaccines protect against zika virus infection

2017-03
Richner JM, Himansu S, Dowd KA, Butler SL, Salazar V, Fox JM, Julander JG, Tang WW, Shresta S, Pierson TC, Ciaramella…
Cell Host Microbe

Mapping and role of the CD8+ T cell response during primary zika virus infection in mice

2017-01
Elong Ngono A, Vizcarra EA, Tang WW, Sheets N, Joo Y, Kim K, Gorman MJ, Diamond MS, Shresta S
Expert Opin Drug Discov

Novel strategies for discovering inhibitors of dengue and zika fever

2016-10
Makhluf H, Kim K, Shresta S
EBioMedicine

Protective role of cross-reactive CD8 T cells against dengue virus infection

2016-10
Elong Ngono A, Chen HW, Tang WW, Joo Y, King K, Weiskopf D, Sidney J, Sette A, Shresta S
Cell Stem Cell

Zika virus infects neural progenitors in the adult mouse brain and alters proliferation

2016-08
Li H, Saucedo-Cuevas L, Regla-Nava JA, Chai G, Sheets N, Tang W, Terskikh AV, Shresta S, Gleeson JG
Trends Microbiol

Neuroterartogenic viruses and lessons for zika virus models

2016-08
Kim K, Shresta S
Antiviral Res

Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by th eiminosugar UV-4

2016-05
Warfield KL, Plummer EM, Sayce AC, Alonzi DS, Tang W, Tyrrell BE, Hill ML, Caputo AT, Killingbeck SS, Beatty PR, Harris…
mBio

Defining new therapeutics using a more immunocompetent mouse model of antibody-enhanced dengue virus infection

2015-09
Pinto AK, Brien JD, Lam CY, Johnson S, Chiang C, Hiscott J, Sarathy VV, Barrett AD, Shresta S, Diamond MS
Current Opinion in Virology

Influence of antibodies and T cells on dengue disease outcome: insights from interferon receptor-deficient mouse models

2015-08
Tang WW, Grewal R, Shresta S
Critical Reviews in Immunology

Innate antiviral immunity against dengue virus

2015-07
Makhluf H, Shresta S
Journal of Immunology

Different STAT transcription complexes drive early and delayed responses to type I IFNs

2015-07
Abdul-Sater AA, Majoros A, Plumlee CR, Perry S, Gu AD, Lee C, Shresta S, Decker T, Schindler C
Scientific Reports

Protection against dengue disease by synthetic nucleic acid antibody prophylaxis/immunotherapy

2015-07
Flingai S, Plummer EM, Patel A, Shresta S, Mendoza JM, Broderick KE, Sardesai NY, Muthumani K, Weiner DB
Journal of Virology

CD8+ T cells can mediate short-term protection against heterotypic dengue reinfection in mice

2015-06
Zellweger RM, Tang WW, Eddy WE, King K, Sanchez MC, Shresta S
Journal of Virology

Dengue viral evolution under a hose-targeted antiviral

2015-05
Plummer E, Buck MD, Sanchez M, Greenbaum JA, Turner J, Frewal R, Klose B, Sampath A, Warfield KL, Peters B, Ramstedt U,…
Viruses

A novel iminosugar UV-12 with activity against the diverse viruses influenza and dengue (novel iminosugar antiviral for influenza and dengue)

2015-05
Warfield KL, Plummer E, Alonzi DS, Wolfe GW, Sampath A, Nguyen T, Butters TD, Enterlein SG, Stavale EJ, Shresta S,…
Journal of Virology

Immunodominance changes as a function of the infecting dengue virus serotype and primary versus secondard infection

2014-10
Weiskopf D, Angelo MA, Sidney J, Peters B, Shresta S, Sette A
Journal of Immunology

CD8+ T cells prevent antigen-induced antibody-dependent enhancement of dengue disease in mice

2014-10
Zelleweger RM, Eddy WE, Tang WW, Miller R, Shresta S
Journal of Immunological Methods

Mouse models for dengue vaccines and antivirals

2014-08
Plummer EM, Shresta S
Frontiers in Immunology

Mouse models to study dengue virus immunology and pathogenesis

2014-04
Zellweger RM, Shresta S
Advances in Virus Research

Dengue virus vaccine development

2014-01
Yauch LE, Shresta S
Journal of Immunology

The roles of IRF-3 and IRF-7 in innate antiviral immunity against dengue virus

2013-10
Chen HW, King K, Tu J, Sanchez M, Luster AD, Shresta S
PLoS Pathogens

Role of humoral versus cellular responses induced by a protective dengue vaccine candidate

2013-10
Zellerger RM, Miller R, Eddy WE, White LJ, Johnston RE, Shresta S
Antiviral Research

Inhibitory and combinatorial effect of diphyllin, a v-ATPase blocker, on influenza viruses

2013-09
Chen HW, Cheng JX, Liu MT, King K, Peng JY, Zhang XQ, Wang CH, Shresta S, Schooley RT, Liu YT
Proceedings of the National Academy of Sciences of the United States of America

Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8+ T cells

2013-05
Weiskopf D, Angelo MA, de Azeredo EL, Sidney J, Greenbaum JA, Fernando AN, Broadwater A, Kolla RA, De Silva AD, de…
Antiviral Research

An iminosugar with potent inhibition of dengue virus infection in vivio

2013-04
Perry ST, Buck MD, Plummer EM, Penmasta RA, Batra H, Stavale EJ, Warfield KL, Dwek RA, Butters TD, Alonzi DS, Lada SM,…
PLoS One

Tracking the evolution of dengue virus strains D2S10 and D2S20 by 454 pyrosequencing

2013-01
Makhluf H, Buck MD, King K, Perry ST, Henn MR, Shresta S
Journal of Virology

Gamma interferon (IFN-γ) receptor restricts systemic dengue virus replication and prevents paralysis in IFN-α/β receptor-deficient mice

2012-12
Prestwood TR, Morar MM, Zellweger RM, Miller R, May MM, Yauche LE, Lada SM, Shresta S
Journal of Virology

Trafficking and replication patterns reveal splenic macrophages as major targets of dengue virus in mice

2012-11
Prestwood TR, May MM, Plummer EM, Morar MM, Yauch LE, Shresta S
mBio

Role of complement in dengue virus infection: protection or pathogenesis?

2012-02
Shresta S
Journal of Immunology

Insights into HLA-restricted T cell responses in a novel mouse model of dengue virus infection point toward new implications for vaccine design

2011-10
Weiskopf D, Yauch LE, Angelo MA, John DV, Greenbaum JA, Sidney J, Kolla RV, De Silva AD, de Silva AM, Grey H, Peters B,…
Journal of Virology

Inhibition of dengue virus infections in cell cultures and in AG129 mice by a small interfering RNA targeting a high conserved sequence

2011-10
Stein DA, Perty ST, Buck MD, Oehmen CS, Fischer MA, Poore E, Smith JL, Lancaster AM, Hirsch AJ, Slifka MK, Nelson JA,…
Expert Review of Anti-infective Therapy

Better late than never: antivirals for dengue

2011-07
Perry ST, Buck MD, Shresta S
Antiviral Chemistry & Chemotherapy

Important advances in the field of anti-dengue virus research

2011-02
Julander JG, Perry ST, Shresta S
PLoS Pathogens

STAT2 mediates innate immunity to Dengue virus in the absence of STAT1 via the type I interferon receptor

2011-02
Perry ST, Buck MD, Lada SM, Schindler C, Shresta S
Methods in Molecular Biology

Animal models in dengue

2019-06
Plummer E, Shresta S

Principal Investigator

Sujan Shresta, Ph.D.

Associate Professor

Sujan Shresta joined LIAI in 2005 as an Assistant Professor in the Inflammation Biology Division and was promoted to Associate Professor in the Division of Inflammation Biology in 2011. Dr. Shresta’s research focuses on the interface between immunology and virology, with particular interest in viral immunopathogenesis.

Dr. Shresta obtained her B.A. in Biological Sciences from Smith College and Ph.D. in Immunology from Washington University in St. Louis. She completed her post-doctoral training in Virology at the University of California, Berkeley. She received a Research Scholar Development award from the NIAID in 2005.

Lab Members

Emilie Branche

Postdoctoral Fellow

Biosketch:
I obtained my Bachelor’s and Master’s of Science in Genetics and Cell Biology in 2007 and 2009, respectively, from Université Claude Bernard, Lyon, France. I completed my Ph.D. in Biology in October 2015 from Université de Genève, Switzerland after researching the effects of proteins that modulating lipid droplet biogenesis on hepatitis C virus life cycle. I joined Dr. Sujan Shresta’s laboratory in November 2016 as a postdoctoral fellow.

Research Focus:
My projects are focused on understanding virus-host interactions during infection of human macrophages and dendritic cells with dengue and Zika viruses using a systems immunology approach, and testing novel therapeutics against dengue and Zika using mouse models.

Career Goals:
I am very interested in developing treatments for emerging infectious diseases.

Jan Crames

Visiting Graduate Student

Joan Valls Cuevas

Intern

Andrew Gonzalez

Intern

Summer Khan

Intern

Kenneth Kim, Ph.D.

Visiting Scientist

Jamie Kwak

Intern

Melanie McCauley

Research Fellow

I obtained an M.D. from Baylor College of Medicine in 2012 with a focus in International Health. I completed a residency in Internal Medicine at the University of Mississippi before joining the University of California, San Diego in the Division of Infectious Diseases and Global Public Health as a clinical fellow in 2015. In partnership with UC San Diego, I joined Dr. Sujan Shresta’s lab in 2016 to study Zika virus and dengue virus. By obtaining a Fulbright Specialist award, I was able to travel to Nepal in the fall of 2017 to work on a capacity-building project studying the recent spread of dengue virus in the area. In 2018 I was a recipient of the SPARK award which allowed me to further my capacity building work, including expanding patient study enrollment and purchasing some important research equipment for the lab in Nepal!

Research Focus:
I am currently working both on capacity building in Nepal as well as the human immune response to Zika virus and dengue virus.

Career Goals:
I plan to pursue an academic medical career in infectious diseases and international health; my passion lies with working with people from developing countries at risk for neglected tropical diseases. I also hope to continue care as a clinical HIV provider.

Jose Regla Nava

Postdoctoral Fellow

Biosketch:
I graduated from Universidad de Guadalajara, Mexico in 2006 with a B.Sc. degree in Chemistry Pharmaceutical and Biology. I then obtained my M.Sc. in Molecular and Cellular Biology in 2010 and my Ph.D. in Biochemistry, Molecular Biology, Biomedicine and Biotechnology (Molecular Bioscience) in 2015 both degrees from the Universidad Autonoma de Madrid, Spain. I obtained my PhD in the laboratory of Professor Luis Enjuanes at the Spanish National Biotechnology Centre (CNB-CSIC). My PhD work focused on the study of the identification of the Mechanisms Causing Reversion to Virulence in an Attenuated SARS-CoV for the Design of a Genetically Stable Vaccine. I began working as a postdoc in the Sujan Shresta’s laboratory at the La Jolla Institute for Immunology in March 2016.

Research Focus:
My research projects are focused on the Dengue and Zika viruses.

Career Goals:
I plan to pursue a career in scientific research focused on design and development of a new vaccines for protection against infectious diseases.

Annie Elong Ngono, Ph.D.

Postdoctoral Fellow

Biosketch:
I obtained my PhD from the University of Nantes (France) in Immunology, Molecular and Cellular Biology in 2013. I worked on the roles of myelin-specific T and B cells in multiple sclerosis. In January 2015, I began working as a postdoctoral fellow at LIAI studying virus-host cells interactions in animal models and human cells. My current projects focus on understanding the molecular mechanisms of the balance between protective and pathogenic T cell responses to flaviviruses, including Dengue and Zika.

Career Goals:
I am developing expertise in infectious diseases and plan to work in infectious disease public health, particularly to improve health systems in developing, low-income countries.

Kruti Patel

Intern

Mercylia Susantono

Intern

Thasneem Syed

Intern

Yutaka Terada

Postdoctoral Fellow

Yutaka Terada

Postdoc Fellow (0 year)

Julia Timis

Visiting Graduate Student

Teodora Vozdolska

Intern

Ying-Ting Wang

Visiting Scientist

Shresta Lab

Research Projects

Innate immune response to DENV and ZIKV

The IFN system is a major mechanism by which many viruses evade the cellular antiviral response. DENV and ZIKV can suppress Type I IFN signaling, but the exact mechanisms remain to be fully understood. Moreover, emerging literature indicates that the type I IFN system mediates antiviral immunity in a highly context-specific manner depending on the virus, cell type, and host species. Therefore, we have been using our mouse models to understand the mechanisms by which type I IFN contributes to antiviral immunity during DENV and ZIKV infection. We have previously determined that type I IFN production is regulated by two signaling pathways: the STAT1-dependent and the STAT1-independent pathways. We have defined the latter mechanism of protection against DENV infection to be the type I IFN receptor-STAT2 pathway, and revealed that the type I IFN receptor-STAT2 pathway, in the absence of STAT1, modulates type I IFN production and interferon-stimulated gene (ISG) response in a delayed manner. Studies are underway to define the particular interferon regulatory factor and ISG mechanisms through which both the STAT1-dependent and STAT2-independent pathways contribute to protection vs. pathogenesis using both mouse models and human cell culture models.

Adaptive immune response to DENV and ZIKV

Vaccine development for DENV is challenging in that the vaccine must induce long-lasting immunity against all four DENV serotypes (DENV1-4), as pre-existing immunity against a heterologous serotype may contribute to severe dengue disease (DHF/DSS). In particular, DENV-specific antibody responses may mediate antibody-dependent enhancement (ADE) of DENV infection under certain conditions. In 2010, we formally demonstrated ADE by developing a mouse mode of ADE-mediated disease, and we began to dissect the contribution of humoral vs. cellular immune components in dengue vaccine-mediated protection using model vaccine candidates as tools to probe the mechanisms by which the vaccine-induced immune responses in mice contribute to protection vs. ADE. Our studies have revealed a critical role for CD8 T-cell responses in dengue vaccine-mediated protection, and showed that the vaccine-induced antibody response can mediate ADE. Thus, contrary to the dogma that emphasizes the importance of humoral immunity alone, our findings imply that a DENV vaccine should induce both humoral and cellular responses to maximize efficacy and safety. In support of this assertion, our recent studies exploring the role of T cells in DENV reinfection and ADE settings have revealed that CD8 T-cells can actually abrogate ADE, suggesting a DENV vaccine that does not elicit CD8 T-cell responses may be dangerous. Since DENV and ZIKV are closely related and cross-reactive in many immunologic assays, it is currently uknown whether a first infection with one virus might protect or worsen a subsequent infection with the other virus. We are currently investigating the role of various T-cell costimulatory pathways in regulating the humoral and cellular responses to and between DENV and ZIKV, and are defining the particular pathways that should be targeted to maximize safety and efficacy of vaccines.

Development of vaccines against DENV and ZIKV

Emergence of mosquito-borne viruses such as DENV and ZIKV in Nepal