Autophagy in the chiaroscuro of human viral diseases Illuminating mechanisms of mucosal immunity using intestinal organoid-based models

Viruses rely on host cellular pathways to replicate and spread. Among these, the autophagy pathway emerges as both guardian and accomplice in viral infection. This thesis explores how autophagy and endosomal trafficking shape infection dynamics of three major human viruses: SARS-CoV-2, dengue virus, and HIV-1. Using primary human immune cells and advanced human intestinal organoid models, this work studied how these viruses interact with autophagy and intracellular trafficking at mucosal surfaces.
We show that SARS-CoV-2 utilizes late stages of autophagy and endosomal acidification in intestinal epithelial cells, and that carefully blocking or boosting different stages of autophagy can strongly reduce infection. Dengue virus instead uses early autophagy in dendritic cells while blocking degradation, likely diverting autophagosomes into secretory routes that release infectious extracellular vesicles.
Host genetics further influence these outcomes: an autophagy-enhancing variant in the autophagy protein ATG16L1 protects against intestinal SARS-CoV-2 but increases dengue virus infection in dendritic cells and is linked to improved HIV-1 outcomes, underscoring that the same host factor can have virus-specific effects.
Finally, we develop human intestinal immuno-organoid co-culture systems with dendritic cells and CD4⁺ T-cells to study how HIV-1 crosses intact epithelial barriers and infects underlying immune cells, and to test both classic antiretrovirals and novel host-directed drugs. Together, these studies highlight autophagy as a central regulator of viral disease and support host-targeted, precision antiviral strategies.