Damaged Intestinal Epithelial Integrity Linked to Microbial Translocation in Pathogenic Simian Immunodeficiency Virus Infections

Abstract

The chronic phase of HIV infection is marked by pathological activation of the immune system, the extent of which better predicts disease progression than either plasma viral load or CD4+ T cell count. Recently, translocation of microbial products from the gastrointestinal tract has been proposed as an underlying cause of this immune activation, based on indirect evidence including the detection of microbial products and specific immune responses in the plasma of chronically HIV-infected humans or SIV-infected Asian macaques. We analyzed tissues from SIV-infected rhesus macaques (RMs) to provide direct in situ evidence for translocation of microbial constituents from the lumen of the intestine into the lamina propria and to draining and peripheral lymph nodes and liver, accompanied by local immune responses in affected tissues. In chronically SIV-infected RMs this translocation is associated with breakdown of the integrity of the epithelial barrier of the gastrointestinal (GI) tract and apparent inability of lamina propria macrophages to effectively phagocytose translocated microbial constituents. By contrast, in the chronic phase of SIV infection in sooty mangabeys, we found no evidence of epithelial barrier breakdown, no increased microbial translocation and no pathological immune activation. Because immune activation is characteristic of the chronic phase of progressive HIV/SIV infections, these findings suggest that increased microbial translocation from the GI tract, in excess of capacity to clear the translocated microbial constituents, helps drive pathological immune activation. Novel therapeutic approaches to inhibit microbial translocation and/or attenuate chronic immune activation in HIV-infected individuals may complement treatments aimed at direct suppression of viral replication.

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…coli in the colonic mucosa since the earliest phases of infection, with a progressive increase throughout chronic disease that is associated with epithelial barrier dysfunction, as documented by the multifocal disruption of the epithelial GI barrier via staining of the tight junction protein claudin-3. In that same study, LPS was also identified within systemic lymph nodes and liver, the amount of which positively correlated with colonic LPS, therefore confirming the systemic passage of gutderived microbic elements (63). In addition, the magnitude of epithelial breakdown was correlated with the extent of microbial translocation and intestinal immune activation, as shown by the colocalization of bacterial products and proinflammatory cytokines (IFN-␣ and IL-18) in the colonic lamina propria.…”

“…While reciprocal interactions between immune activation and microbial translocation are most likely to occur during pathogenic HIV/SIV infections, evidence of microbial translocation as a factor driving pathological immune activation in HIV-infected (63). In particular, using immunohistochemistry and confocal fluorescence microscopy, those authors were able to show the presence of LPS/E.…”

Type 3 innate lymphoid cell depletion is mediated by TLRs in lymphoid tissues of simian immunodeficiency virus‐infected macaques

“…These ILC3 cells lack CD4 and typical NK-associated molecules, but they produce considerable levels of IL-17 and IL-22, which are known to contribute to the maintenance of lymphoid tissue structure and mucosal barriers. HIV infection is associated with loss of intestinal barrier function, resulting in bacterial translocation, which drives systemic immune activation and disease progression (21,22), but the early events involved in loss of mucosal barrier function remain uncertain. This study shows that SIV infection results in losses of ILC3 cells in lymphoid tissues, which may be a consequence of microbial products entering mucosal tissues and apoptosis through TLR pathways.…”

“…HIV/simian immunodeficiency virus (SIV)-induced immunodeficiency is characterized by a marked loss of intestinal CD4 + T cells, severe disruption of GALT, and increased intestinal permeability resulting in microbial translocation, which in turn causes systemic immune activation resulting in more rapid disease progression (21,22). Little is known regarding the role of ILCs in HIV/SIV infection in mucosal immunity and microbial translocation.…”

Dietary phenylalanine-improved intestinal barrier health in young grass carp (Ctenopharyngodon idella) is associated with increased immune status and regulated gene expression of cytokines, tight junction proteins, antioxidant enzymes and related signalling molecules

“…These data indicated a possible beneficial effect of Phe on TJs in fish, which warrants study. In addition, intestinal epithelial integrity is important for maintaining the normal function of the physical barriers present in fish [26], but intestinal epithelial cells are sensitive to oxidative damage [27]. To combat oxidative damage, fish are equipped with antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) [28].…”