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Sujan Shresta

Associate professor

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.





Key Words:

ANG2, antibody, antibody-dependent enhancement ADE, B cell, bispecific antibody, congenital infection, dengue, dengvaxia, human, infant, mosquito-borne, mouse, pathogens, synthetic genomics, T cell, TNF, vaccine, virus, Zika.

Dr. Shresta is an immunologist. Her team focus on studying the immunology of virology of Dengue and Zika virus, which are globally important mosquito borne human pathogens. Currently, no FDA approved Zika vaccine is available and those under development elicit primarily antibody (B cell) rather than T cell responses. Recently, a Philippine government agency sued Sanofi for its anti-dengue vaccine Dengvaxia. Vaccines can induce or exacerbate disease, mainly by virus bound antibodies that can facilitate viral entry in certain cells rather than block infection. Studies conducted by Dr. Shresta’s group indicate that both antibody and T cell responses together may be required for protection against Dengue and Zika. The team showed that maternally acquired anti-zika antibodies in infants whose mothers were previously exposed to zika virus could increase the severity of dengue disease. Whereas, mothers with no prior immunity of zika virus got milder disease. Shresta developed a mouse model of this. When mouse pups of Zika immune mothers were infected with Zika, the pups were protected. But when the mothers were immune to Dengue and then were infected with Zika, the disease was severe. Shresta showed that this requirtes antibodies; it is called antibody dependent enhancement (ADE). ADE can be fatal when a distinct but structurally similar flavivirus infects the mice. This result is particularly critical in the light of vaccine development where all the vaccines under development generate antibody responses, which may not protect completely. It seems like a T cell response is required for the vaccine to be fully effective. Immune responses evoked by T cells are effective in preventing pathogenic effects of antibodies.

Dr. Shresta actively collaborates with local companies including Synthetic Genomics to develop an mRNA platform based vaccine (antibody and T cell-targeted, pentavalent vaccine). At present the studies are performed only in mouse models. There are plans to advance to more evolved animal models. Shresta is also working on various T cell costimulatory ligands to enhance immunity. An anti-TNF antibody works but is expensive. Another target is vascular permeability, which is the problem that can make these infections lethal. Possible targets are TNF and ANG2. Dr. Shresta would like to develop bispecific antibodies that targets TNF and ANG-2.

Gaps in research: don’t know how to develop the bispecific antibodies. Dr. Shresta recommends faculty meeting annually/periodically to learn more faculty research work at LJI.

Michael Diamond at Wash U, Ralph Bareck at UNC Chapel Hill, UT M Galveston--Collaborators in Nepal including Universities for clinical studies/ epidemiology studies.