The Interface between Metabolism and Immunity within a Virus Microenvironment
Ileana M. Cristea, Ph.D.
Henry L. Hillman Professor of Molecular Biology
Princeton University
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.
Towards this goal, she has promoted the integration of virology with proteomics and bioinformatics. She has developed methods for studying spatial and temporal virus-host protein interactions, bridging developments in mass spectrometry to important findings in virology. For example, her laboratory has contributed to the emergence of the research field of nuclear DNA sensing in immune response, to uncovering mechanisms underlying organelle remodeling and organelle structure-function relationships during infections, and has discovered sirtuins as broad-spectrum antiviral factors.
Dr. Cristea is the Past-President of the American Human Proteome Organization (US HUPO), the chair of the Biology/Disease-driven Human Proteome Project (B/D-HPP) of HUPO, and the co-chair of the Infectious Disease team of HUPO B/D-HPP. She has taught the summer Proteomics Course at Cold Spring Harbor Laboratory for over ten years, and is Senior Editor for mSystems, Associate Editor for the Journal of Proteome Research and on the Editorial Boards of Molecular Systems Biology and Molecular & Cellular Proteomics. She was recognized with the Bordoli Prize from the British Mass Spectrometry Society (2001), NIDA Avant-Garde Award for HIV/AIDS Research (2008), Human Frontiers Science Program Young Investigator Award (2009), Early Career Award in Mass Spectrometry from ACS (2011), ASMS Research Award (2012), Molecular Cellular Proteomics Lectureship (2013), Mallinckrodt Scholar Award (2015), Discovery Award in Proteomic Sciences at HUPO (2017), and the Princeton University Graduate Mentoring Award (2020).
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.
Learning Objectives:
- Remodeling of organelle-organelle contacts underlies the protection of fragmented mitochondria from mitophagy and enhanced bioenergetics during HCMV infection.
- Infection-induced lactate production promotes virus spread by driving lactylation of host immune factors and suppressing cytokine expression.
- Within a virus microenvironment, proximity to HCMV infected cells increases the susceptibility of uninfected neighboring cells to infection with HCMV, HSV-1 or Influenza A.
https://videocast.nih.gov/watch=55036
This page was last updated on Wednesday, April 16, 2025