Abstract
BACKGROUND: Coronary artery disease (CAD), tuberculosis (TB), and HIV are major global health concerns. Individuals affected by one or more of these conditions often exhibit chronic inflammation and immune dysregulation, with monocytes playing a central role. Monocyte subsets are known to expand in individuals with HIV, TB, or CAD, but the mechanisms by which these cells contribute to inflammation and immune responses remain poorly understood. METHODS: We employed high-dimensional mass cytometry to characterize monocyte heterogeneity in 61 Ugandan adults with varying combinations of HIV, TB, and subclinical or overt CAD. An integrative approach was used, combining manual gating, unsupervised clustering, and machine learning to identify distinct monocyte phenotypes associated with CAD and TB. Monocyte activation markers soluble CD14 (sCD14) and sCD163 were measured in plasma. CAD was diagnosed by coronary computed tomography angiography. TB was determined by a questionnaire and interferon-gamma release assay (IGRA) testing. RESULTS: Participants' demographics and clinical characteristics were similar by CAD or HIV/TB status. Median age was 61 years; 37.7% were female. People living with HIV and latent TB or prior active TB had higher sCD14 plasma levels compared with HIV/TB-negative individuals. Individuals with CAD showed reduced surface expression of the scavenger receptor CD163 on non-classical monocytes. Unsupervised clustering further revealed 2 distinct non-classical monocyte subsets associated with disease states: A CD86dim CX3CR1dim CD45RA+ GPR56+ CXCR3+ subset significantly depleted in individuals with CAD, and a CD86+ CX3CR1++ CD45RA++ GPR56- CD38- CXCR3- subset enriched in individuals with latent TB. CONCLUSIONS: These findings underscore the complexity of the monocyte landscape in CAD progression, particularly in regions where HIV and TB are co-endemic. Our study reveals distinct alterations within 2 non-classical monocyte subpopulations associated with CAD and with HIV/TB, offering mechanistic insights that may support the development of precision biomarkers and immune-targeted therapies across these disease contexts.