Research Projects

Both iron accumulation and macrophage/microglial activation are recognized as pathological hallmarks underlying the progression of viral infection diseases of Japanese encephalitis (JE) viral infection. From recent DBT-Ramalingaswami re-entry project study, we provided in vivo preliminary evidence supporting the importance of the hepcidin-ferroportin in regulating iron content in JE viral infection (Fig; 1). We demonstrated that membrane-bound iron export protein, ferroportin-1 (Fpn-1) decreases significantly post-JE viral infection at both transcription and protein levels, increasing the iron load in brain tissue and macrophages, thus causing NOX2-mediated oxidative stress and cell death. On the other hand, we noted hepcidin level increases in response to JE viral infection. An important question regarding the regulation of iron in macrophage activation and its role in the rise in intracellular JE viral copy number is still unclear and warrants continued effort to clarify this important mechanism in key viral diseases such as encephalitis. Moreover it is also being observed that the use of different antibodies or inhibitors against hepcidin-ferroportin, which are not carefully characterized for their specificity, make a more complex observational scenario and could be one of the reasons for different findings in different studies. Based on this, here we hypothesized that selective regulation of the hepcidin-ferroportin axis, such as by reducing/controlling hepcidin levels, may lead to restoration of iron-efflux from the cells and can reduce microglia/macrophage activation and neuronal cell death following JE viral infection. Thus, we propose to develop a novel class of hepcidin regulating biologics (antibodies) that can reduce the hepcidin levels and/or block hepcidin binding to ferroportin receptor. Our specific aim includes clearing excess hepcidin from the circulation by a novel recombinant ferroportin-Fc fusion protein (Seldeg-Fc) and anti-hepcidin monoclonal antibodies to block hepcidin-ferroportin interaction. We anticipate the proposed antibody-based approach would be beneficial to regulate the iron load (in brain tissue and macrophage cells) and the neuroinflammation of JE viral infectious disease. Further, in the study, we also propose to investigate the hepcidin-independent pathways by including experimental groups of TLRs regulation (TLR2,4 &6) to determine the solid basis for the downregulation of the ferroportin level after JE viral infection. Project objectives are inferred here based on key observations of pathways in both preclinical models (in vitro cell culture and in vivo mice encephalitis model) and patients' (clinical) findings. These findings will open key therapeutic avenues for many viral diseases.