Mechanism of cell-to-cell transmission of flaviviruses

This proposal will investigate the mechanism of cell-to-cell transmission and spread of flaviviruses using Dengue and Zika as model systems. We will therefore address a longstanding debate on how they exit from infected cells, and preferentially spread into specific cell types. Dengue and Zika are the two most prevalent flaviviruses worldwide, sharing significant overlap in their genome architecture and biology. Dengue infects >50 million people annually, causing severe pathologies. Zika too has emerged as a global threat with recent outbreaks linked to serious neuro-developmental complications in children and Guillain Barré syndrome in adults. No vaccines or therapeutics exist for these viruses, and our current understanding on mechanisms of their transmission and spread is severely limited. Viral infections spread by overcoming multiple barriers to move from cell to cell. Viral progenies can move across extracellular space either as free particles via fluid phase diffusion, within vesicles, or by cell-cell contacts. To understand transmission, we will therefore address: (i) characteristics of the extracellular virus populations, (ii) whether multiple transmission routes exist (iii) whether the viral envelope is the primary determinant of transmissibility. This proposal builds on our previously published and ongoing studies on viral manipulation of autophagy for assembly and spread.