Research Projects

The proposal originates from the vital role of innate immune system during infection caused by mosquito- and tick-borne encephalitic Orthoflaviviruses like Zika virus (ZIKV) and Kyasanur Forest Disease Virus (KFDV). These viruses employ multifaceted strategies to evade the immune system for survival and pathogenesis in host resulting in high mortality rate, and viral pathogenesis causing neurological and autoimmune implications. Therefore, it is important to study the causes of pathogenesis in the context of innate immune system. There is extensive research available on Dengue virus (DENV) pathogenesis. However, there is dearth of literature on encephalitic virus (ZIKA and KFDV) pathogenesis in terms of innate immunity. The serious manifestations of ZIKV and KFDV encompass every age group from neonates to the elderly. The disease burden due to seasonal outbreaks of KFDV and ongoing endemics of ZIKV in across the world including in India raises concern (1,2). ZIKV causes birth defects like microcephaly in neonates and clinical implications like hemorrhagic fever in KFDV raise an urgency to deal with these viruses to prevent virus survival and pathogenesis alongside help the innate immune system (3,4). The current proposal aims to investigate the dysregulated innate immunity and the consequent effects in response to envelope (E) protein of the ZIKV and KFDV. The most abundant white blood cells, neutrophils are crucial for fighting viral infections and developing innate immunity. Viruses modulate neutrophil responses causing innate immune dysfunction to assist viral infection. Recent studies have shown that the DENV E protein present on surface of the virus mediates innate immune dysfunction that leads to inflammation and contributes to DENV pathogenesis (5,6,7). The existing literature highlights the role of NS1 protein in inducing innate immune evasion (8). The NS1-induced effects typically correspond to high viral titers, indicating an ongoing infection. However, we hypothesize that E protein of the virus helps evading neutrophil-mediated antiviral innate immune response in the early phase of infection to allow virus propagation, which augments NS1 production and severe pathogenesis. The exact mechanism and the neutrophilic receptor for E protein-induced activation is unknown. The encephalitic viral infections are marked with NETosing neutrophils, activated macrophages and cytokine storm leading to immunopathogenesis, neuroinflammation, vascular leakage, and hemorrhagic fever (9). NETosis is an innate immune response where neutrophils divulge-out their cellular DNA to create a trap to capture the infectious agent called Neutrophil Extracellular Traps (NETs). In viral infection, NETs have been implicated in promoting inflammation and tissue damage. The gap in the available literature is the unknown mechanism and the neutrophil receptor that interacts with E protein and induces innate immune dysfunction. Studying this in details will help design strategies to treat associated viral pathogeneses. The study proposes to investigate the mechanism, neutrophilic receptors interacting with E protein leading to NETosis and dysfunction of innate immunity in ZIKA and KFDV in comparison to DENV. The chemical profile of E protein-exposed neutrophils and secretome-induced effect on macrophages, endothelial and neuronal cells will be investigated. The viral interactions with the host receptors will be mapped to study the pathways involved. The study offers to decipher novel players in immune cell response along with the mechanistic insights into the interactions between host receptors and E protein. The study involves cutting-edge molecular techniques to investigate factors responsible for severe clinical manifestations. The study will validate the identified crucial interactions in vitro & in vivo and restoration of dysregulated cytokine profiles by using available and/or computationally designed antiviral proteins against E protein.