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Mtb-induced Monocyte Transcriptional Responses Associate with Resistance to TST/IGRA Conversion in PLWH.

AIDS 2023 September 12
OBJECTIVE: To determine whether Mycobacterium tuberculosis (Mtb)-induced monocyte transcriptional responses differ in people living with HIV (PLWH) who do (RSTR) or do not (LTBI) resist TST/IGRA conversion after exposure.

DESIGN: We compared ex vivo Mtb-induced monocyte transcriptional responses in a Ugandan tuberculosis (TB) household contact study of RSTR and LTBI individuals among PLWH.

METHODS: Monocytes were isolated from peripheral blood mononuclear cells from 19 household contacts of pulmonary TB patients, and their transcriptional profiles were measured with RNA-Seq after a 6-hour infection with Mtb (H37Rv) or media. Differentially expressed genes (DEGs) were identified by a linear mixed effects model and pathways by gene set enrichment analysis that compared RSTR and LTBI phenotypes with and without Mtb stimulation.

RESULTS: Among PLWH, we identified 8,341 DEGs that were dependent on Mtb stimulation (false discovery rate [FDR] < 0.01). Of these, 350 were not significant (FDR > 0.2) in individuals without HIV. Additionally, we found 26 genes that were differentially expressed between RSTR and LTBI monocytes in PLWH, including 20 which were Mtb-dependent (FDR < 0.2). In unstimulated monocytes, several gene sets (TGF-β signaling, TNF-α signaling via NF-κB, NOTCH signaling, coagulation, and epithelial mesenchymal transition) were enriched in RSTR relative to LTBI monocytes (FDR < 0.1). These patterns were not observed in individuals without HIV.

CONCLUSIONS: RSTR monocytes in PLWH show different gene expression in response to Mtb infection when compared to those with LTBI and RSTR without HIV. These differential expression patterns are enriched in inflammatory pathways.

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