The majority of Jessica's thesis work was recently accepted at JCI Insight!
To understand the effect of HIV on cellular dynamics in Mtb granulomas, we used an NHP model of HIV/Mtb co-infection, using SIV as a surrogate for HIV, that was previously published. Co-infected animals were infected with pathogenic SIV with or without daily, suppressive ART starting at day 3 post-infection followed by low-dose Mtb challenge 16 weeks later (SIV/Mtb and SIV/ART/Mtb groups). A control group of animals was infected with Mtb only. Granulomas from untreated SIV/Mtb animals 1) had higher bacterial burden (colony-forming units, CFU) than Mtb only or SIV/ART/Mtb animals and 2) often had high SIV RNA levels.
Using Nanostring's GeoMx spatial transcriptomics platform, Jessica looked at differentially expressed genes in myeloid cells (like macrophages) and T lymphocytes throughout multiple granulomas from animals in each group.
T cells from co-infected granulomas had significantly reduced activation and signaling genes compared to Mtb only or ART-treated SIV/Mtb granulomas. But, myeloid cells from SIV/Mtb granulomas had higher pro-inflammatory, IFN-I signaling, and chemokine production pathway genes than Mtb only granulomas.
Granulomas are highly structured and Jessica saw myeloid and T cell gene expression that was spatially distinct in the inner core vs outer rim of Mtb only granulomas. This spatial distinction was lost in SIV/Mtb coinfected granulomas! And early ART did not restore this disrupted gene expression!
Macrophage-T cell communication was examined based on expression of ligand-receptor pairs in different regions of the granulomas. Communication strength was decreased in SIV/Mtb granulomas compared to Mtb only granulomas and ART did not restore this and led to higher bacterial dissemination/burden.
Taken together, our results suggest that SIV infection disregulates spatially organized myeloid-T cell immune responses in lung granulomas, correlating with increased extrapulmonary disease. Surprisingly, very early suppressive ART did not restore this disregulation!
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