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 dengue virus (DENV) and Zika virus (ZIKV), both globally important mosquito-borne human pathogens. DENV causes a spectrum of clinical disease ranging from Dengue Fever (DF), a self-limited febrile illness, to a life-threatening syndrome called Dengue Hemorrhagic Fever/Dengue Shock Syndrome (DHF/DSS). ZIKV has been proven to cause serious birth defects, and is also being investigated for associations with other neurological conditions including Guillain-Barré Syndrome (GBS) and meningoencephalitis.

Studies suggest that the host’s immune system plays 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 and human cell culture models, Dr. Shresta and her team dissect the protective versus pathogenic mechanisms of the immune system in response to these viral infections. Using gene-targeted mice and human cells that lack specific components of the immune system, a better understanding of the immune response to DENV and ZIKV is critical for developing much-needed vaccines and antivirals.

A second line of research involves the identification of viral components that modulate the severity of DENV and ZIKV infection in infants. Dr. Shresta and her team have isolated new DENV and ZIKV strains in mice by adapting viral isolates from humans and mosquitoes into peripheral tissues of mice. Using a reverse-genetics system, in which specific viral sequences are manipulated within the context of a full-length infectious clone of the virus, they have been defining the roles of particular viral components in influencing DENV and ZIKV infection in mice and human cells. As both DENV and ZIKV are increasingly spreading from tropical to temperate zones worldwide, the team has also begun to investigate DENV evolution in Nepal and ZIKV sexual transmission. Knowledge of the viral determinants of severe dengue and Zika disease, climatic zone shifts, and viral genetic variation may provide novel avenues for developing DENV- and ZIKV-specific therapeutics.

From The Lab

Jan 12, 2017

T cells join the fight against Zika

Dec 20, 2016

LJI researchers strengthen the case for sexual transmission of Zika virus

Oct 12, 2016 // Miami Herald

Zika dangers could threaten more than just infants, scientists say

Sep 21, 2016 // Mother Jones

Zika may be a threat to the adult brain, too

Sep 2, 2016 // The Independent

Zika may cause brain damage in adults too

Shresta Lab

Publications

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…
Antiviral Res

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

2016-03
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
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
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,…
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
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
Critical Reviews in Immunology

Innate antiviral immunity against dengue virus

2005-07
Makhluf H, Shresta S
Trends Microbiol

Neuroterartogenic viruses and lessons for zika virus models

2016-07
Kim K, Shresta S
Methods in Molecular Biology

Animal models in dengue

2017-02
Plummer E, Shresta S
Advances in Virus Research

Dengue virus vaccine development

2017-02
Yauch LE, Shresta S
PLoS One

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

2017-02
Makhluf H, Buck MD, King K, Perry ST, Henn MR, Shresta S
Antiviral Chemistry & Chemotherapy

Important advances in the field of anti-dengue virus research

2017-02
Julander JG, Perry ST, Shresta S

Principal Investigator

shresta

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

MaxBunz

Max Bunz

Graduate Student

Biosketch:
I graduated from University of Tuebingen, Germany in 2015 with a B.Sc. degree in biochemistry. At the moment I am enrolled in the biochemistry master program in Tuebingen. In this regard, I worked in different labs on various immunological fields and do a 6-month internship in Dr. Shresta’s lab since January 2017.

Julia Ellison

Intern

Lily Foley

Intern

AngelaFowler

Angela Fowler

Postdoctoral Fellow

Biosketch:
I obtained my Bachelor’s of Science degree, majoring in Biology and minoring in Chemistry, from Pittsburg State University in Pittsburg, KS. I completed my Ph.D. in Microbiology in November 2016 from the University of Kansas after researching host cell-viral interactions of HSV-1 in cell culture models.

Research Focus:
I joined Dr. Sujan Shresta’s lab in December 2016 after obtaining a T32 postdoctoral fellowship. I am currently working with Zika virus and how it affects the T cell response and T cell signaling through tumor necrosis receptor (TNFR) signaling components OX40, 4-1BB, and CD27 in specific mouse model systems.

Career Goals:
I want to increase the knowledge of what is known about viruses and the immune response to them so that better treatments and immunizations can be made, thus contributing to less severe diseases worldwide.

Birendra Prasad Gupta

Visiting Scientist

Anh-Thy Huynh

Intern

KennethKim

Kenneth Kim, DVM DACVP

Visiting Scientist

Biosketch:
As a comparative anatomic pathologist, my interests range from mouse models of flaviviral infection to diagnostic pathology in several species. Prior to becoming a pathologist I practiced small animal medicine and surgery for 10 years with a focus in emergency gastroenteric surgery.

Career goals:
At the Shresta lab, I evaluate mouse models histopathologically and localize antigen in tissue using several methods.

HudaMakhluf

Huda Makhluf

Visiting Scientist

Biosketch:
Dr. Huda Makhluf is a visiting scientist in Dr. Shresta’s lab. She was previously a Scientific BioCurator in the Department of Vaccine Development at LJI. Currently, she is an Associate Professor and Chair of the Department of Mathematics and Natural Sciences at National University in La Jolla. Dr. Makhluf earned her Ph.D. in Microbiology and Immunology from the Medical University of South Carolina. She conducted her post-doctoral training at Harvard.

AnilaMamidi

Anila Mamidi

Lab Assistant

Biosketch:
Anila Mamidi currently attends the University of California, San Diego as a Biochemistry and Cellular Biology major. She is an active member of the Biological Sciences Student Association (BSSA) at UCSD. In November 2015, she joined the Shresta laboratory at the La Jolla Institute for Allergy and Immunology. In her free time, she works on her sketching skills and also enjoys running.

Career Goals:

In the future, she looks forward to pursuing a career in medical research after she graduates from UCSD in 2018.

KrishnaDasManandhar

Krishna Das Manandhar

Fulbright Senior Research Scholar

History:
I graduated from Tribhuvan University (TU), Kathmandu, Nepal in 1988 and did Ph.D. from Banaras Hindu University, Varanasi, India in 2008. I have been teaching since 1992. I was promoted to Professor in 2013 at the Central Department of Biotechnology, TU. I have worked on different projects on infectious and parasitic diseases like visceral leishmaniasis, dengue, neurocystocercosis etc.

Research focus:

The research project I am focused on is Immuno-Epidemiology of Dengue virus in Nepal.

Career Goals:

Continue research with infectious disease and the immunological response in viral infections and establish a reference laboratory at my Department.

Melanie McCauley

Visiting Scientist

AnnieElong

Annie Elong Ngono

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.

Arishma Rajkarnikar-Singh

Intern

JoseRegla

Jose Angel Regla

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 Allergy and 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.

NickSheets

Nicholas Sheets

Research Tech II/Lab Manager

History:
I graduated from National University in 2015 with a B.S. degree in Biological Science. I started working in Dr. Shresta’s laboratory in March of 2013 as an internship and was offered a position as a laboratory assistant in September 2013. Following this position I began being more involved in multiple projects and was promoted to laboratory manager in October 2015.

Research focus:
The research projects I am focused on are concerned molecular pathways and conducting in vivo experiments of infection of Dengue, Zika virus, and other Flavivirus.

Career Goals:
Continue research with infectious disease and the immunological pathways involved in viral infections.

Vivian Shing

Intern

WilliamTang

William Tang

Research Tech I/Lab Manager

Biosketch:
I graduated from University of California – San Diego with a B.S. degree in Biochemistry and Cell Biology. I began working as a lab assistant in the Shresta laboratory at the La Jolla Institute for Allergy and Immunology in 2012, and became a research technician in 2013.

Research Focus:

My research projects have been focused on various molecular mechanisms and aspects of adaptive immunity involving dengue and zika viruses. I am interested in understanding how these viruses affect host pathogenesis, and ultimately how these findings translate into the medical field or potential therapeutics.

Career Goals:
I plan to pursue a career in medicine and scientific research focused on translational medicine to serve and to address the basic health care needs of neglected communities, either domestically in low-income neighborhoods or in developing countries.

Karla Viramontes

Intern

EdwardVizcarra

Edwards Vizcarra, B.S.

Research Technician I

Biosketch:
I graduated from University of California, San Diego in 2014 with a B.S. in Biochemistry and Cell Biology. When I graduated, I began working at LJI as a lab technician in Dr. Sujan Shresta’s lab. Currently, my work consists of dissecting the molecular mechanisms that are involved in both Dengue and Zika viral infection. Our lab uses modern day techniques such as the CRISPR/Cas9 system and next generation sequencing to help us elucidate these mechanisms.

Career Goals:
I plan to pursue a PhD in Biomedical Science with an emphasis on molecular biology or microbiology. One of my main career goals is to become a professor at either a community college or at a four year university.

JinshengWen

Jinsheng Wen, Ph.D.

Professor

Biosketch:
I graduated from Xinxiang Medical College in 2001 with a B.S. degree in Clinic Medicine. I then obtained my Ph.D. in Microbiology from Sun-yat Sen University in 2007. I began working as a teacher in the department of Microbiology and Immunology at Wenzhou Medical University in August 2007 and was promoted to the full professor position in September 2015.

Research Focus:
My research projects are focused on the roles of T-cell epitopes in Arboviruses. I am interested in understanding how dengue virus and zika virus-specific T-cell responses can mediate protective immunity or disease pathogenesis, and in defining new protective T-cell epitopes for immunotherapeutic reagents or novel vaccine development.

Career Goals:
I plan to pursue a career in scientific research focused on Arboviruses involved in human disease.

Matthew Young

Laboratory Assistant

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.