Transcriptional profile of Mycobacterium tuberculosis infection in people living with HIV. iScience
Tepekule et al. investigated whether changes in the immune system induced by Mycobacterium tuberculosis (MTB), as predicted from epidemiological observations, can be detected in peripheral blood in people with HIV (PWH). The authors hypothesized that exposure to MTB does not only induce an antigen specific T-cell response but also impacts the activation state of the innate immune system analogous to the trained immunity phenotype described after BCG vaccination.
To investigate the impact of MTB infection on the transcriptome of PWH, the authors conducted a detailed analysis using peripheral blood mononuclear cells (PBMC). 78% of samples coinciding with the TB testing date. Total follow up was median 78.5 months after MTB testing (range 9.7–244.5 months). They focused PWH with a suppressed viral load to adjust for the potential effects of a replicating HIV-1 infection on the transcriptome. The algorithm matched 22 PWH in pairs based on their CD4 cell count, ethnicity, and sex to minimize further confounding variables.
The analysis of PBMC transcriptomic profiles in PWH revealed distinct clustering in MTB-infected individuals. Functional annotation identified alterations in IL-6, TNF, and KRAS pathways. Notably, MTB related genes displayed an inverse correlation with HIV-1 viremia, at both individual and signature score levels.
In conclusion, this study shows that MTB-specific T cell responses correlate with systemic transcriptional changes in PWH, independently of HIV-1 viral load. These MTB-associated transcriptional changes were inversely correlated with HIV-1 viremia, suggesting a potential causal link between MTB infection and improved control of HIV-1 replication. The consistent upregulation of TNF alpha signalling via NF-kB and the IL6-JAK-STAT3 pathway in MTB infection irrespective of HIV-1 viremia indicates a sustained inflammatory response. These data seamlessly align with the evolving idea of MTB infection as a spectrum of diseases, wherein stages of MTB infection differently influence the innate immune system.