Immune correlates of early clearance of Mycobacterium tuberculosis among tuberculosis household contacts in Indonesia

Todia P. Setiabudiawan, Lika Apriani, Ayesha J. Verrall, Fitria Utami, Marion Schneider, Agnes R. Indrati, Pauline P. Halim, Paulina Kaplonek, Hadar Malca, Jessica Shih-Lu Lee, Simone J. C. F. M. Moorlag, L. Charlotte J. Bree, Vera P. Mourits, Leo A. B. Joosten, Mihai G. Netea, Bachti Alisjahbana, Ryan P. McNamara, Galit Alter, Arjan Laarhoven, James E. Ussher, Katrina Sharples, Valerie A. C. M. Koeken, Philip C. Hill and Reinout Crevel ()
Additional contact information
Todia P. Setiabudiawan: Radboud University Medical Center
Lika Apriani: Universitas Padjadjaran
Ayesha J. Verrall: University of Otago
Fitria Utami: Universitas Padjadjaran
Marion Schneider: University of Otago
Agnes R. Indrati: Universitas Padjadjaran
Pauline P. Halim: Universitas Indonesia
Paulina Kaplonek: and Harvard
Hadar Malca: and Harvard
Jessica Shih-Lu Lee: and Harvard
Simone J. C. F. M. Moorlag: Radboud University Medical Center
L. Charlotte J. Bree: Radboud University Medical Center
Vera P. Mourits: Radboud University Medical Center
Leo A. B. Joosten: Radboud University Medical Center
Mihai G. Netea: Radboud University Medical Center
Bachti Alisjahbana: Universitas Padjadjaran
Ryan P. McNamara: and Harvard
Galit Alter: and Harvard
Arjan Laarhoven: Radboud University Medical Center
James E. Ussher: University of Otago
Katrina Sharples: University of Otago
Valerie A. C. M. Koeken: Radboud University Medical Center
Philip C. Hill: University of Otago
Reinout Crevel: Radboud University Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Some individuals, even when heavily exposed to an infectious tuberculosis patient, do not develop a specific T-cell response as measured by interferon-gamma release assay (IGRA). This could be explained by an IFN-γ-independent adaptive immune response, or an effective innate host response clearing Mycobacterium tuberculosis (Mtb) without adaptive immunity. In heavily exposed Indonesian tuberculosis household contacts (n = 1347), a persistently IGRA negative status was associated with presence of a BCG scar, and - especially among those with a BCG scar - with altered innate immune cells dynamics, higher heterologous (Escherichia coli-induced) proinflammatory cytokine production, and higher inflammatory proteins in the IGRA mitogen tube. Neither circulating concentrations of Mtb-specific antibodies nor functional antibody activity associated with IGRA status at baseline or follow-up. In a cohort of adults in a low tuberculosis incidence setting, BCG vaccination induced heterologous innate cytokine production, but only marginally affected Mtb-specific antibody profiles. Our findings suggest that a more efficient host innate immune response, rather than a humoral response, mediates early clearance of Mtb. The protective effect of BCG vaccination against Mtb infection may be linked to innate immune priming, also termed ‘trained immunity’.

Date: 2025
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DOI: 10.1038/s41467-024-55501-6

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