BACKGROUND: Maintenance of gut homeostasis is critical to efficient immune responses and is dependent on a population of lamina propria (LP) resident macrophages (Mø) expressing the fractalkine receptor CX3CR1, which play a pivotal role in the maintenance of the intestinal epithelial barrier, microbial translocation and the host response to microbiota changes.
Humans exposed to HIV-1 and Cynomolgus macaques (CMs) exposed to SIV show highly persistent immune activation and inflammation in their gut, which are strong predictors of disease progression and are prevalent despite antiretroviral therapy. Moreover, people diagnosed with COVID-19 also presented with symptoms of gastrointestinal (GI) disruption like diarrhea, vomiting and nausea; along with detectable rectal viral load and various long-term sequela like intestinal dysbiosis. Thus, understanding the immune response to SIV and SARS CoV-2 in the GI tract is cruicial to develop strategies targeted towards improving host outcomes.
METHODS: Hypothesizing that the loss of intestinal CX3CR1+ Mø homeostasis contributes to the sustained immune activation seen during SIV or SARS CoV-2 exposure, we analyzed the frequency, phenotype and functionality of colonic Møs expressing CX3CR1 in the following cohorts of CMs: 12 controls, 12 chronically SIV_mac251-exposed (SIV+), and 11 animals examined either at acute (7-9 days, n=5) or at the resolved phase (43 days, n=6) post exposure to SARS CoV-2.
RESULTS: The control colons had a predominant population of mature tissue-resident CD64+CD14-CD11c-CX3CR1^high Mø. In SIV+ CMs, we observed a significant accumulation of CD14+, CD11c+, CX3CR1^low pro-inflammatory Mø, along with the upregulation of soluble inflammation markers like calprotectin and fractalkine. Meanwhile, in CMs exposed to SARS CoV-2, colonic CX3CR1^low Møs accumulated in the acute phase and correlated with an increase in the intestinal fatty acid binding protein (iFABP) levels, with a concomitant reversal to the CX3CR1^high Mø population observed in the resolved phase. However, this reversal seems to be defective with a significant reduction in total Mø frequency at resolution, accompanied by high levels of soluble CD14, fractalkine and calprotectin.
CONCLUSIONS: Our results suggest that the maintenance of macrophage homeostasis is vital to the preservation of the GI barrier and the short and long-term response to viral exposures, be it with HIV-1 or SARS CoV-2.

Download the e-Poster (PDF)