Viruses remain one of the most serious threats to human health, a reality dramatically illustrated by recent global pandemics. Viral infection is initiated by a sequence of finely regulated events—viral landing on the cell surface, engagement with host receptors, and subsequent entry into the cell—that ultimately determine viral tropism, infectivity, and disease outcome. Despite decades of research, these very first steps of infection remain poorly understood at the molecular and mechanical levels. A major limitation comes from the experimental systems traditionally used to study virus–host interactions: most rely on 2D cancer-derived cell lines that fail to capture the structural complexity, polarity, and cell-to-cell heterogeneity of human epithelial tissues. As a result, crucial regulatory mechanisms occurring in realistic physiological environments remain unexplored.
This project proposes to overcome these limitations by establishing a new paradigm for investigating viral entry under near-physiological 3D conditions. By combining advanced nanobiophysical methods (single-virus atomic force microscopy (AFM) and optical tweezers), we aim to quantify, in real time, the molecular forces, dynamics, and mechanical checkpoints that govern the earliest stages of infection. Using epithelial models of increasing complexity, from monolayers to organoids and engineered tissues, we will decipher how tissue organization, differentiation, and heterogeneity influence the pathways through which viruses attach and penetrate host cells.
The overarching objective is to build an integrative and mechanistic picture of viral entry as it occurs in vivo, and to identify new physical and molecular vulnerabilities that could be exploited for antiviral intervention.
