Mycobacterium tuberculosis resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli
Monica Dallmann-Sauer, … , Nelita Du Plessis, Erwin Schurr
Monica Dallmann-Sauer, … , Nelita Du Plessis, Erwin Schurr
Published January 21, 2025
Citation Information: J Clin Invest. 2025;135(7):e188016. https://doi.org/10.1172/JCI188016.
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Clinical Research and Public Health Infectious disease

Mycobacterium tuberculosis resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli

Abstract

BACKGROUND Natural resistance to Mycobacterium tuberculosis (Mtb) infection in some people with HIV (PWH) is unexplained.METHODS We performed single cell RNA-sequencing of bronchoalveolar lavage cells, unstimulated or ex vivo stimulated with Mtb, for 7 PWH who were tuberculin skin test (TST) and IFN-γ release assay (IGRA) positive (called LTBI) and 6 who were persistently TST and IGRA negative (called resisters).RESULTS Alveolar macrophages (AM) from resisters displayed a baseline M1 macrophage phenotype while AM from LTBI did not. Resisters displayed alveolar lymphocytosis, with enrichment of all T cell subpopulations including IFNG-expressing cells. In both groups, mycobactericidal granulysin was expressed almost exclusively by a T cell subtype that coexpressed granzyme B, perforin and NK cell receptors. These poly-cytotoxic T lymphocytes (poly-CTL) overexpressed activating NK cell receptors and were increased in resister BAL. Following challenge with Mtb, only intraepithelial lymphocyte-like cells from LTBI participants responded with increased transcription of IFNG. AM from resisters responded with a stronger TNF signature at 6 hours after infection while at 24 hours after infection, AM from LTBI displayed a stronger IFN-γ signature. Conversely, at 24 hours after infection, only AM from resisters displayed an upregulation of MHC class I polypeptide–related sequence A (MICA) transcripts, which encode an activating ligand for poly-CTL.CONCLUSION These results suggest that poly-CTL and M1-like pre-activated AM mediate the resister phenotype in PWH.FUNDING National Institutes of Health. Canadian Institutes of Health Research. Digital Research Alliance of Canada. French National Research Agency. French National Agency for Research on AIDS and Viral Hepatitis. St. Giles Foundation. General Atlantic Foundation. South African Medical Research Council Centre for Tuberculosis Research.

Authors

Monica Dallmann-Sauer, Vinicius M. Fava, Stephanus T. Malherbe, Candice E. MacDonald, Marianna Orlova, Elouise E. Kroon, Aurélie Cobat, Stéphanie Boisson-Dupuis, Eileen G. Hoal, Laurent Abel, Marlo Möller, Jean-Laurent Casanova, Gerhard Walzl, Nelita Du Plessis, Erwin Schurr

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Figure 3

Gene-expression differences in the absence of Mtb between resister and LTBI myeloid cell subpopulations in the absence of Mtb.

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Gene-expression differences in the absence of Mtb between resister and L...
(A) Volcano plot for differences in gene expression between resister and LTBI samples for subpopulation AM.0. Volcano plots of remaining clusters are shown in Supplemental Figure 3. Dashed lines correspond to the log2FC thresholds of –0.2 and 0.2. Total numbers of DEG higher (red) or lower (blue) expressed in resister samples are indicated in the top corners. (B) Numbers of DEG across all myeloid cell subpopulations. Purple and light blue indicate DEG with higher or lower expression in cells from resisters. (C) Selected Hallmark pathways enriched for genes with higher expression in resister compared with LTBI cells. (D) Differential TF activity in resister and LTBI BAL samples for 6-hour noninfected cells. The heatmap shows the top 10 TF displaying the largest mean differential activity per myeloid cell subpopulation, except for clusters with less than 10 significant TF. The mean TF activity scores for cells in each cluster are shown for the LTBI and resister cells. Positive and negative scores indicate stronger or weaker/inactive TF activity, respectively. Nonsignificant (FDR > 0.01) or not tested TFs are shown in gray. (E) Gene expression of selected M1 genes IL6, CCL3, and IL1B, and the M2 gene CD163 in 6-hour noninfected cells. Color and size correspond to the scaled expression and the percentage of cells expressing the gene by cluster, respectively.