Preprint
Single-cell immune profiling at time of M. tuberculosis exposure reveals antigen-reactive programs that predict progression to active disease
medRxiv
Cold Spring Harbor Laboratory Press, 1.1
30/04/2025
PMID: 40343021
Abstract
Early delineation of host immune responses at the moment of Mycobacterium tuberculosis (Mtb) exposure and infection is critical to identify individuals at risk of progressing to active tuberculosis (TB). We performed single-cell transcriptional profiling of over 500,000 peripheral blood mononuclear cells from 57 HIV-negative close contacts of TB cases in Brazil, including 25 individuals who developed active disease within two years (progressors) and 32 matched controls who remained disease-free (non-progressors). Cells were stimulated separately with the MTB300 peptide pool or irradiated Mtb (gRV), enabling resolution of antigen-reactive states across adaptive (CD4⁺ T-cells expressing abundant cytokines including IFNG, TNF, and IL17F) and trained-innate lineages, such as NK cells (producing GM-CSF, IFNG, CCL3, CCL4) and monocytes (GM-CSF, IL12B, IL36G). Progressors exhibited early hyper-metabolic CD4⁺ T-cell programs and proliferative NK cell signatures, whereas non-progressors preferentially upregulated complement activation and CCL3/4-driven chemokine signaling in monocytes. Notably, among progressors, gene expression profiles within antigen-reactive CD4⁺ T-cells and monocytes predicted the timing of progression to active TB. Together, these findings reveal high frequencies and functional diversity of antigen-reactive cells in Mtb-exposed individuals and nominate tractable immune correlates for the rational design of next-generation TB vaccines.
Details
- Title
- Single-cell immune profiling at time of M. tuberculosis exposure reveals antigen-reactive programs that predict progression to active disease
- Authors/Creators
- Jonathan Penã Avila - Hospital Israelita Albert EinsteinJoshua Simmons - Vanderbilt University Medical CenterMarina C. Figueiredo - Vanderbilt University Medical CenterMegan Turner - Vanderbilt University Medical CenterMarcelo Cordeiro-Santos - Universidade Nilton LinsValeria C. Rolla - Instituto Nacional de Infectologia Evandro ChagasAfranio L. Kristki - Universidade Federal do Rio de JaneiroRama Gangula - Vanderbilt University Medical CenterCynthia Nochowicz - Vanderbilt University Medical CenterRamesh Ram - Murdoch UniversitySamuel Bailin - Vanderbilt University Medical CenterSimon Mallal - Murdoch UniversitySilvana Gaudieri - School of Human Sciences, University of Western AustraliaEric Alves - School of Human Sciences, University of Western AustraliaBeatriz Barreto Barreto-Duarte - Instituto de Pesquisa Clínica e Translacional (IPCT), Faculdade ZARNSArtur T. L. Queiroz - Fundação Oswaldo CruzHelder I. Nakaya - Hospital Israelita Albert EinsteinBruno B. Andrade - Universidade SalvadorTimothy R. Sterling - Vanderbilt University Medical CenterSpyros A. Kalams - Vanderbilt University Medical CenterRePORT-Brazil Consortium
- Publication Details
- medRxiv
- Publisher
- Cold Spring Harbor Laboratory Press
- Edition
- 1.1
- Number of pages
- 35
- Identifiers
- 991005779233907891
- Murdoch Affiliation
- Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Preprint
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