Many pathogens subvert intestinal immunity to persist within the gastrointestinal tract (GIT); yet, the underlying mechanisms that enable sanctuary specifically in this reservoir are unclear. Using mass cytometry and network analysis, we demonstrate that chronic LCMV infection of the GIT leads to dysregulated microbial composition, a cascade of metabolic alterations, increased susceptibility to GI disease, and a system-wide recalibration of immune composition that defines viral persistence. Chronic infection led to outgrowth of activated Tbet–expressing T reg cell populations unique to the GIT and the rapid erosion of pathogen-specific CD8 tissue-resident memory T cells. Mechanistically, T reg cells and coinhibitory receptors maintained long-term viral sanctuary within the GIT, and their targeting reactivated T cells and eliminated this viral reservoir. Thus, our data provide a high-dimensional definition of the mechanisms of immune regulation that chronic viruses implement to exploit the unique microenvironment of the GIT and identify T reg cells as key modulators of viral persistence in the intestinal tract.
A network of immune and microbial modifications underlies viral persistence in the gastrointestinal tract
Disclosures: The authors declare no competing interests exist.
- Views Icon Views
- Share Icon Share
- Search Site
Bethany L. Macleod, Heidi J. Elsaesser, Laura M. Snell, Russell J. Dickson, Mengdi Guo, Kebria Hezaveh, Wenxi Xu, Akash Kothari, Tracy L. McGaha, Cynthia J. Guidos, David G. Brooks; A network of immune and microbial modifications underlies viral persistence in the gastrointestinal tract. J Exp Med 7 December 2020; 217 (12): e20191473. doi: https://doi.org/10.1084/jem.20191473
Download citation file: