Enhanced Intestinal TGF-β/SMAD-Dependent Signaling in Simian Immunodeficiency Virus Infected Rhesus Macaques

Abstract

Transforming growth factor-β signaling (TGF-β) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either SMAD2/3 and SMAD7 (SMAD-dependent) or SMAD-independent signaling pathways under normal conditions. Increased production of TGF-β promotes immunosuppression in Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection. However, the cellular source and downstream events of increased TGF-β production that attributes to its pathological manifestations remain unknown. Here, we have shown increased production of TGF-β in a majority of intestinal CD3−CD20−CD68+ cells from acute and chronically SIV infected rhesus macaques, which negatively correlated with the frequency of jejunum CD4+ T cells. No significant changes in intestinal TGF-β receptor II expression were observed but increased production of the pSMAD2/3 protein and SMAD3 gene expression in jejunum tissues that were accompanied by a downregulation of SMAD7 protein and gene expression. Enhanced TGF-β production by intestinal CD3−CD20−CD68+ cells and increased TGF-β/SMAD-dependent signaling might be due to a disruption of a negative feedback loop mediated by SMAD7. This suggests that SIV infection impacts the SMAD-dependent signaling pathway of TGF-β and provides a potential framework for further study to understand the role of viral factor(s) in modulating TGF-β production and downregulating SMAD7 expression in SIV. Regulation of mucosal TGF-β expression by therapeutic TGF-β blockers may help to create effective antiviral mucosal immune responses.

Simian Immunodeficiency Virus Infection Mediated Changes in Jejunum and Peripheral SARS-CoV-2 Receptor ACE2 and Associated Proteins or Genes in Rhesus Macaques

“…Due to infeasibility of sample collection, lung tissues representing each cohort of infection were obtained from different animals, and thus could not be used for the longitudinal study. In our earlier studies we did not detect any association between viral dosage, CD4 depletion, and viral loads in RMs (25,(39)(40)(41).…”

“…The jejunum LPL was isolated by collagenase treatment followed by Percoll (Sigma-Aldrich, USA) density gradient centrifugation as described earlier (25,39,42). Briefly, a jejunum section of 2-4 cm length was collected, washed with chilled sterile PBS, and minced into small pieces.…”

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

“…However, the stable presence of LGR+ cells during chronic infection was not sufficient to restore E-cadherin expression, suggesting a prolonged failure of intestinal barrier function. We have recently shown an increased production of intestinal TGF-β during SIV infection ( 9 ), and this increased TGF-β production may have some direct inhibitory effect on E-cadherin expression. A direct in vivo and in vitro interaction between TGF-β and E-cadherin+ dendritic cells has been documented ( 66 ).…”

“…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 ). Internalization of IL-10R with the resultant impact on IL-10 signaling and dysregulation of the IL-10 and TGF-β-mediated anti-inflammatory responses also play a crucial role in iEC damage and subsequent SIV-mediated pathology ( 7 , 9 ) and may contribute to diminished iEC regeneration. Each intestinal villus in the small intestine is encircled by at least six crypts of Lieberkühn, which provide populations of stem cells that self-renew and give rise to the various differentiated iECs ( 10 ).…”

New Insights in the Fight against HIV

“…The group of Serrano-Rísquez shows how genetic variants in CD46, which protects the host from potentially deleterious effects of complement activation, are associated with resistance to HIV-1 infection [ 4 ]. However, a fine balance between pro- and anti-inflammatory stimuli is necessary to maintain immunological homeostasis at tissue sites of virus replication, as demonstrated by Boby and coworkers [ 5 ]. In a non-human primate model of HIV infection, the authors identified a dysregulated expression of the immunosuppressive molecule transforming growth factor (TGF) β, along with its cellular source, as a correlate of HIV pathogenesis in the intestine, one of the major sites supporting HIV replication and harboring latently infected cells.…”