Ileana Cristea is a Professor in the Department of Molecular Biology at Princeton University. Her laboratory investigates mechanisms of cellular defense during infection with human viruses.

LECTURE SUMMARY: Viral infections spread within complex and dynamic cellular microenvironments that shape the outcome of infection. As such, intra-cellular communication cascades, as well as communication between infected cells and cells in the surrounding tissue create a virus microenvironment. Here, we will describe some of our efforts to characterize communication at the intra- and inter-cellular levels. At the intra-cellular level, we will consider spatiotemporal alterations in organelle-organelle contacts that facilitate the rapid regulation of cellular metabolism and immune responses during infections with several DNA and RNA viruses. Upon infection with human cytomegalovirus (HCMV), we investigate the paradox of infection-induced mitochondria fragmentation concurrent with increased respiration. We integrate live, super-resolution microscopy, cryotomography, proteomics, and molecular assays to show how HCMV infection drive the formation of mitochondrial-ER encapsulation that protect fragmented mitochondria against mitophagy and promote increased mitochondrial bioenergetics. At the interface between this metabolic rewiring and immune signaling, we consider that several prevalent human viruses, including HCMV, induce a Warburg-like effect that results in increased lactate production. We discover virus-induced lactylation of intrinsically disordered regions of host immune factors that suppresses their functions and facilitates virus spread during infections with HCMV and herpes simplex virus 1 (HSV-1). Further investigating communication at the inter-cellular level, we establish an approach to characterize a virus microenvironment, distinguishing cell populations based on their proximity to an infection site. We show that HCMV infection primes uninfected, proximal cells for infections with HCMV, HSV-1, and influenza A. Mechanistic investigations point to the contribution of alterated cell cycle, organelle-organelle contacts, and mitochondrial functions in the increased susceptibility of uninfected, proximal cells to viral infections. Overall, these findings demonstrate how infection reshapes the surrounding microenvironment through intra- and inter-cellular signaling to facilitate viral spread and how spatial proximity to an infection guides cell fate.

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