Research Summary

Investigating the effect of viral infections on zinc homeostasis as a cause of permeability barrier disruption in polarized epithelial and endothelial cells

A large number of childhood infections are caused by viruses, which cannot be prevented by vaccines or treated by antivirals. Therefore, developing strategies that reduce susceptibility to infections and severity of disease are highly desirable. The link between zinc and immunity is well established and as majority of children in India are zinc-deficient, it is plausible that this makes them vulnerable to frequent infections. Indeed, a number of clinical trials have demonstrated the beneficial effect of zinc supplementation in reducing the incidence and severity of diarrhea but the same had a not so convincing impact on other conditions such as pneumonia or malaria. The knowledge gap in understanding these discrepancies lies in the lack of information on interaction between infections and zinc homeostasis. Disruption of epithelial barrier and/or endothelial dysfunction is a hallmark of severe viral infections such as dengue, respiratory syncytial virus and rotavirus. Zinc depletion also leads to compromised barrier integrity of endothelial and epithelial cells. Zinc acts as an acute phase reactant during infections and serum zinc levels correlate negatively with severity of infection. Therefore, virus infections serve as an excellent model system to understand the deregulation in zinc metabolism either at the level of absorption, distribution or efflux of intracellular zinc during infections. My proposal is intended to provide a basic understanding of this modulation and its relation with the permeability barriers of epithelial and endothelial cells during virus infections. This would further help us in devising disease-specific and personalized strategies for zinc supplementation.

Figure Legend: Tripartite interactions between viral infection – zinc homeostasis – permeability barrier. Both viral infections and zinc levels are known to affect permeability barrier functions by mechanisms which are not well characterized. The link between viral infections on zinc homeostasis and its effect, if any, on the regulation of permeability barrier will be investigated in the current proposal. Staining of tight junction protein ZO-1 (green) in Caco-2 cells is shown. Nuclei is stained with DAPI (blue).