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Microbiome-T Cell Immunology

Lavanya Visvabharathy, PhD

Visvabharathy Lab | VIM Surgery Lab | University of Chicago Department of Surgery

Investigating how intestinal microbes and their metabolites shape viral persistence, CD8 T-cell exhaustion, and durable immune control.

Program 01 Viral Persistence

Understanding How the Colon Provides Camouflage for Viral Persistence: Regulation of Microbiome-T Cell Interactions in the Intestinal Epithelium

The human intestine is known to be a unique environment for sustaining microbial growth. Commensal bacteria, or the microbiome, are essential for maintaining gut homeostasis and general health, while infections can occur in conjunction with microbiome disruption, or dysbiosis. Dysbiosis is linked with gut reservoirs of viral infections including HIV, norovirus, and importantly, SARS-CoV-2, which causes COVID-19.

Though the pandemic phase of COVID-19 seems to have passed, debilitating effects can linger if there is viral persistence. We and others have found viral RNA and protein in the colon of patients with a prior history of COVID-19 within four years. Viral persistence is linked with a characteristic dysbiosis signature that shifts the bile acid composition of the lower gastrointestinal tract, promoting CD8 T-cell exhaustion.

  • Aim 1 Determine whether patients with viral RNA in the colon have a prolonged, active infection.
  • Aim 2 Determine whether the resulting bile acid signature promotes viral persistence in the gut epithelium.
  • Aim 3 Define how bile acids regulate CD8 T-cell exhaustion.
  • Aim 4 Determine how we might change the microbial metabolite environment of the T cell to reverse exhaustion and promote viral clearance.

We study these questions using primary human tissues, including colon biopsies and peripheral blood mononuclear cells, as well as human colon organoid-autologous T-cell co-culture systems.

Multichannel fluorescence microscopy image associated with the intestinal viral persistence project
Multichannel fluorescence microscopy image of intestinal tissue associated with the viral persistence project
Program 02 Adaptive Microbiome Design

Collaborating Lab: Raman Lab, Duchossois Family Institute, University of Chicago

Molecular Cooperation: Leveraging Designed Microbial Communities to Reverse T-Cell Exhaustion

T-cell exhaustion is an adaptive state. Excessive activation leads to pathological inflammation that can damage tissues, and T-cell exhaustion serves to restrain hyperactive effector functions during chronic stimulation, as in the case of autoimmunity. However, T-cell exhaustion is also frequently responsible for the inability to control chronic viral infections or tumor growth.

Indeed, attempting to reverse T-cell exhaustion using immune checkpoint inhibitors is a major focus of cancer treatment trials. Methods to reverse exhaustion to date have been "static"; that is, a drug with one biological action, such as antibody blockade of PD-1 or PD-L1, is deployed to restore T-cell effector functions. While such methods have resulted in moderate success, many cancers become resistant to immunotherapy over time, potentially due to redundancies in T-cell exhaustion pathways that are not targeted by individual antibody treatments.

Cancers and chronic infections adapt and evolve to maximize their survival in the host. We therefore propose that durable reversal of T-cell exhaustion requires an equally adaptive approach to transcriptionally reprogram the cell. Microbiome design is one such approach.

In collaboration with Arjun Raman at the University of Chicago's Duchossois Family Institute, we are using a variety of in vitro systems and multi-omics approaches to systematically define methods to reverse T-cell exhaustion using microbially derived metabolites. Ultimately, we want to build a framework to generate novel, adaptive precision-medicine strategies for complex diseases centered on microbiome control of T-cell immunity.

Schema of the CD8 T-cell exhaustion model and designed microbial community metabolite screening workflow

Related Publication

Read the related PLOS Pathogens paper