Intestinal Epithelial Barrier Disruption through Altered Mucosal MicroRNA Expression in Human Immunodeficiency Virus and Simian Immunodeficiency Virus Infections

Abstract

Epithelial barrier dysfunction during human immunodeficiency virus (HIV) infection has largely been attributed to the rapid and severe depletion of CD4؉ T cells in the gastrointestinal (GI) tract. Although it is known that changes in mucosal gene expression contribute to intestinal enteropathy, the role of small noncoding RNAs, specifically microRNA (miRNA), has not been investigated. Using the simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV pathogenesis, we investigated the effect of viral infection on miRNA expression in intestinal mucosa. SIV infection led to a striking decrease in the expression of mucosal miRNA compared to that in uninfected controls. This decrease coincided with an increase in 5=-3=-exoribonuclease 2 protein and alterations in DICER1 and Argonaute 2 expression. Targets of depleted miRNA belonged to molecular pathways involved in epithelial proliferation, differentiation, and immune response. Decreased expression of several miRNA involved in maintaining epithelial homeostasis in the gut was localized to the proliferative crypt region of the intestinal epithelium. Our findings suggest that SIV-induced decreased expression of miRNA involved in epithelial homeostasis, disrupted expression of miRNA biogenesis machinery, and increased expression of XRN2 are involved in the development of epithelial barrier dysfunction and gastroenteropathy. IMPORTANCEMicroRNA (miRNA) regulate the development and function of intestinal epithelial cells, and many viruses disrupt normal host miRNA expression. In this study, we demonstrate that SIV and HIV disrupt expression of miRNA in the small intestine during infection. The depletion of several key miRNA is localized to the proliferative crypt region of the gut epithelium. These miRNA are known to control expression of genes involved in inflammation, cell death, and epithelial maturation. Our data indicate that this disruption might be caused by altered expression of miRNA biogenesis machinery during infection. These findings suggest that the disruption of miRNA in the small intestine likely plays a role in intestinal enteropathy during HIV infection.

Dysregulation of microRNA biogenesis in the small intestine after ethanol and burn injury

“…Environmental factors (e.g. injury, ethanol, and disease) can impair microRNA expression and biogenesis, which may adversely affect the components of the intestinal barrier (31, 43, 47–50). McKenna et al .…”

Longitudinal Examination of the Intestinal Lamina Propria Cellular Compartment of Simian Immunodeficiency Virus-Infected Rhesus Macaques Provides Broader and Deeper Insights into the Link between Aberrant MicroRNA Expression and Persistent Immune Activation

“…Lately, the enhanced expression of miR-21 (13) and miR-142 (14) was correlated with macrophage activation and encephalitis in the brain of SIV-infected rhesus macaques. Focusing on the GI tract, an important site of CD4 ϩ T-cell depletion and HIV/SIV replication, we (15,16) and others (17) reported significant miRNA dysregulation in intact colon during SIV infection. Unlike our two previous studies that utilized intact intestinal tissue (15,16), in the present study, we focused exclusively on the intestinal lamina propria compartment to obtain a deeper understanding of the link between aberrant miRNA expression and chronic immune activation/inflammation in the intestine.…”

Critical Role for the Adenosine Pathway in Controlling Simian Immunodeficiency Virus-Related Immune Activation and Inflammation in Gut Mucosal Tissues

“…Notably, the vast majority of these studies focused on T cells from peripheral blood. Since progressive HIV/SIV infections are characterized by profound mucosal dysfunction caused by increased cell death associated with high virus replication and inflammatory responses (3,22,(49)(50)(51), we studied the changes in CD39 and CD73 expression on Tregs from the gut of SIV-infected nonhuman primates (NHPs). We also aimed to better understand the role of the ADO pathway in modulating immune activation/inflammation during HIV/SIV infection.…”