Immune responses associated with severe disease in patients with primary dengue infection

SUMMARY Dengue is an emerging global public health threat. Decades of extensive research undertaken primarily in dengue-endemic regions has resulted in the prevailing consensus that secondary infections and antibody- dependent enhancement (ADE) are pivotal in the pathogenesis of severe dengue disease. While previous research showed severe outcomes in naïve populations, our understanding of the mechanisms underpinning the pathogenesis of the severe disease during primary dengue infections, and how it diverges from secondary infections, remains limited. Bridging this knowledge gap is vital, given that dengue is spreading to new areas with substantial naïve population, compounded by lack of vaccines that can generate balanced immune response or distinct clinical management protocols for primary versus secondary dengue. Hence, the specific aims outlined below will provide comprehensive studies in India, where we find substantial burden of severe disease by primary infections, to concurrently scrutinize the disease spectrum in primary and secondary dengue, to elucidate pathogenesis. Aim 1, Determine the differences in innate immune responses during severe primary and secondary dengue infection. Aim 2, Evaluate differences in the magnitude, function, and post-translational modification of dengue-specific antibodies during severe primary and secondary dengue infection. Aim 3, Determine how dengue specific CD8+ and CD4+ T cell responses differ between severe primary and secondary dengue infection. The proposed studies encompass in-depth analyses of innate, inflammatory, antibody, and T- cell responses, alongside virological aspects, and their intricate interplay. Leveraging state-of-the-art tools and technologies such as viral inclusive s\cRNA seq, Fc glycosylation, and human monoclonals, the research will be primarily conducted in India utilizing samples from patient cohorts there. The joint ICGEB-Emory Vaccine Center laboratory in New Delhi, that we developed over several years to enhance human immunology research capacity, stands as an invaluable and unique resource for this endeavor.