Identification, Characterization, and Transcriptional Reprogramming of Epithelial Stem Cells and Intestinal Enteroids in Simian Immunodeficiency Virus Infected Rhesus Macaques

Nongthombam Boby,Monica N Shroyer,Arpita Das,Edith Porter,Peter J Didier,Qiuying Sha,Xuewei Cao,Alyssa Ransom,Barcley T Pace,Bapi Pahar,Sudesh K Srivastav,Christopher Mabee

doi:10.3389/fimmu.2021.769990

Nongthombam Boby, Monica N Shroyer + Show 10 more

Open Access

https://doi.org/10.3389/fimmu.2021.769990

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Abstract

Epithelial cell injury and impaired epithelial regeneration are considered key features in HIV pathogenesis and contribute to HIV-induced generalized immune activation. Understanding the molecular mechanisms underlying the disrupted epithelial regeneration might provide an alternative approach for the treatment of HIV-mediated enteropathy and immune activation. We have observed a significant increased presence of α defensin5+ (HD5) Paneth cells and proliferating Ki67+ epithelial cells as well as decreased expression of E-cadherin expression in epithelial cells during SIV infection. SIV infection did not significantly influence the frequency of LGR5+ stem cells, but the frequency of HD5+ cells was significantly higher compared to uninfected controls in jejunum. Our global transcriptomics analysis of enteroids provided novel information about highly significant changes in several important pathways like metabolic, TCA cycle, and oxidative phosphorylation, where the majority of the differentially expressed genes were downregulated in enteroids grown from chronically SIV-infected macaques compared to the SIV-uninfected controls. Despite the lack of significant reduction in LGR5+ stem cell population, the dysregulation of several intestinal stem cell niche factors including Notch, mTOR, AMPK and Wnt pathways as well as persistence of inflammatory cytokines and chemokines and loss of epithelial barrier function in enteroids further supports that SIV infection impacts on epithelial cell proliferation and intestinal homeostasis.

Highlights

Human immunodeficiency virus (HIV) continues to be a cause of major global life-threatening disease, with 37.7 million people are living with HIV/AIDS worldwide in 2020
Understanding the molecular mechanisms underlying the disrupted intestinal epithelial cell (iEC) regeneration during simian immunodeficiency virus (SIV) infection might lead to an alternative approach for the treatment of HIV-mediated enteropathy
We observed no significant reduction in LGR5+ intestinal stem cells (ISCs) in the small intestine during SIV infection compared to normal uninfected macaques

Summary

Introduction

Human immunodeficiency virus (HIV) continues to be a cause of major global life-threatening disease, with 37.7 million people are living with HIV/AIDS worldwide in 2020. Loss of intestinal barrier function and subsequent translocation of luminal bacteria are thought to be the major cause of the chronic systemic immune activation that perpetuates HIV replication and progression to AIDS [2,3,4]. The simian immunodeficiency virus (SIV) infected Rhesus Macaque (RhM) model is a well-accepted model for the study of HIV-associated enteropathy [5, 6], and we have discovered that intestinal epithelial cell (iEC) apoptosis and loss of tight junction (TJ) proteins occur soon after SIV infection [7, 8]. The repair process encompasses epithelial cell restitution, proliferation, and differentiation. ISCs proliferate and differentiate to replenish the decreased cell population and to reinstate the epithelial cell functions, respectively. The study of ISCs has been greatly advanced through the introduction of enteroids, which were first derived from mouse intestine [20, 21]

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