SIV-induced Translocation of Bacterial Products in the Liver Mobilizes Myeloid Dendritic and Natural Killer Cells Associated With Liver Damage

Abstract

Disruption of the mucosal epithelium during lentivirus infections permits translocation of microbial products into circulation, causing immune activation and driving disease. Although the liver directly filters blood from the intestine and is the first line of defense against gut-derived antigens, the effects of microbial products on the liver are unclear. In livers of normal macaques, minute levels of bacterial products were detectable, but increased 20-fold in simian immunodeficiency virus (SIV)-infected animals. Increased microbial products in the liver induced production of the chemoattractant CXCL16 by myeloid dendritic cells (mDCs), causing subsequent recruitment of hypercytotoxic natural killer (NK) cells expressing the CXCL16 receptor, CXCR6. Microbial accumulation, mDC activation, and cytotoxic NK cell frequencies were significantly correlated with markers of liver damage, and SIV-infected animals consistently had evidence of hepatitis and fibrosis. Collectively, these data indicate that SIV-associated accumulation of microbial products in the liver initiates a cascade of innate immune activation, resulting in liver damage.

Enhancement of Microbiota in Healthy Macaques Results in Beneficial Modulation of Mucosal and Systemic Immune Function

“…To determine if the increased Tfh cells were associated with increased LN follicles, we assessed LN morphology via H&E staining, as previously described (33). We quantified the number of follicles and found a trend towards increased overall follicles in the LN after PBio therapy (average follicle number pre-PBio was 17.6±5.03; post-PBio was 30.2±15.3; p =0.1130, data not shown; representative IHC, Supplemental Figure 1).…”

HIV-hepatitis B virus coinfection

“…Recent studies in SIV-infected rhesus macaques suggest that increased microbial load in the liver can also trigger chemokine production and an increased infiltrate of CXCR6+ activated NK cells, which may contribute to liver fibrosis [167] . We have also demonstrated that the chemokine CXCL-10, ligand for CXCR3 which is expressed on activated T-cells, is associated with elevations in liver enzymes in HIV-HBV co-infection and may contribute to liver disease via migration of activated T-cells to the liver [163] .…”

Laparoscopic Technique for Serial Collection of Liver and Mesenteric Lymph Nodes in Macaques

“…These samples provide a useful route to evaluate key immunological, virological, and microbiological processes that take place in the MLN and liver, which are separate and unique from systemic immunity. Similarly, liver biopsies are critical for the long-term evaluation of the effects of HIV/SIV, drug therapies, and translocated microbes, which often combine to induce significant liver damage 16 . Further, because the MLN and liver are immune organs exposed to GI microbiota, the ability to evaluate immunity in these organs across time provides an excellent platform for understanding the role that the microbiome plays in maintaining host immune homeostasis.…”

“…These processes are associated with local and systemic immune activation, and increased morbidity and mortality in HIV infected individuals 14 . In SIV infection, translocated bacteria have been observed in the MLN 15 , whereas accumulation of microbial products in the liver has been shown to result in inflammation and damage to the organ 16 . Thus, in the context of HIV and SIV infections, the MLN and liver can be highly informative for understanding the inflammatory processes driven by GI-resident bacteria.…”