Mycobacterium tuberculosis resisters despite HIV exhibit activated T cells and macrophages in their pulmonary alveoli
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
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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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 5

AM and DC responses to ex vivo infection with Mtb in resister and LTBI cells.

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AM and DC responses to ex vivo infection with Mtb in resister and LTBI c...
(A) Volcano plots of differential gene expression in response to Mtb challenge by group and time after infection for subpopulation AM.0. Dashed lines correspond to the log2FC thresholds of –0.2 and 0.2. Total numbers of up- and downregulated DEG are indicated in the top corners (FDR < 0.2). (B) Proportions of DEG per cluster in response to Mtb challenge by group and time point. (C) GSEA results for selected Hallmark pathways that display enrichment for genes with changed expression in response to Mtb across clusters. All significant pathways presented in this figure were enriched for upregulated genes. Nonsignificant results (FDR > 0.05) are shown in white. (D) Log2FC of expression for cluster AM.0 genes that respond significantly differently to Mtb in resister (x axis) and LTBI (y axis) cells. The coordinate lines correspond to log2FC = 0. For each section of the plot, the total number of DEG is presented. (E) GSEA for Hallmark pathways based on the significantly differential Mtb response between resisters and LTBI at 6 hours and 24 hours. Genes were ranked according to overresponse in resister samples. Hence, positive and negative NES correspond to enrichment of genes with higher and lower log2FC in resister compared with LTBI cells, respectively. Hallmark pathways as in panel C.