Gut immune dysfunction through impaired innate pattern recognition receptor expression and gut microbiota dysbiosis in chronic SIV infection

Abstract

HIV targets the gut mucosa early in infection, causing immune and epithelial barrier dysfunction and disease progression. However, gut mucosal sensing and innate immune signaling through mucosal pattern recognition receptors (PRR) during HIV infection and disease progression are not well defined. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model of AIDS, we found a robust increase in PRR and inflammatory cytokine gene expression during the acute SIV infection in both peripheral blood and gut mucosa, coinciding with viral replication. PRR expression remained elevated in peripheral blood following the transition to chronic SIV infection. In contrast, massive dampening of PRR expression was detected in the gut mucosa, despite the presence of detectable viral loads. Exceptionally, expression of TLR4 and 8 was down modulated and diverged from expression patterns for most other TLRs in the gut. Decreased mucosal PRR expression was associated with increased abundance of several pathogenic bacterial taxa, including Pasteurellaceae members, Aggregatibacter and Actinobacillus, and Mycoplasmataceae family. Early anti-retroviral therapy led to viral suppression, but only partial maintenance of gut PRR and cytokine gene expression. In summary, SIV infection dampens mucosal innate immunity through PRR dysregulation and may promote immune activation, gut microbiota changes and ineffective viral clearance.

The HIV-Associated Enteric Microbiome Has Gone Viral

“…The observation of little to no bacterial microbiome differences in the absence of severe disease in SIV-infected macaques reported here by Handley et al was consistent with these previous studies of macaques (although it may be important to note that more pronounced bacterial microbiome changes have also been observed in macaques in the acute phase of infection (Glavan et al, 2015), which was not evaluated by Handley et al .). Although the results of human and macaque studies may be more consistent than had been previously thought in terms of a lack of a very pronounced phenotype, it is also important to note that all of these studies have used feces to evaluate microbiome composition.…”

Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study

“…The largest increase was detected for Aggregatibacter , a bacterial taxon associated with a decrease in mucosal pattern-recognition receptors. 22 The greatest decrease was noted for Roseburia, including butyrate-producing bacteria that promote the epithelial barrier. 23 Distinct taxa were in turn associated with progression to complications, suggesting a role in modulation of host biology.…”

The gut microbiome and HIV-1 pathogenesis

“…However, decreased diversity, depletion of Firmicutes, and a transient increase in Proteobacteria have been observed in fecal [93, 94] and jejunal mucosa[95] samples during acute SIV infection. Moreover, decreased abundances of Firmicutes in jejunum tissue samples[95] and decreased fecal abundance of Lactobacillus spp. persisted into chronic SIV infection[93, 94].…”

“…persisted into chronic SIV infection[93, 94]. Alterations in the mucosa-associated microbiome during acute infection correlated with changes in cytokine gene expression and with expression of genes important in innate recognition of microbes in both the mucosa and mesenteric lymph node (MLN)[95, 96]. Depletion of stool Lactobacillus was associated with increased indoleamine 2,3-dioxygenase1 (IDO1) enzyme activity and loss of blood Th17 cells suggesting a role for Lactobacillus in the control of the IDO pathway and SIV pathogenesis[94].…”