Early Clearance of Mycobacterium tuberculosis Is Associated With Increased Innate Immune Responses

• Published in: The Journal of infectious diseases Vol. 221; no. 8; pp. 1342 - 1350
• Main Authors: Verrall, Ayesha J, Schneider, Marion, Alisjahbana, Bachti, Apriani, Lika, van Laarhoven, Arjan, Koeken, Valerie A C M, van Dorp, Suszanne, Diadani, Emira, Utama, Fitri, Hannaway, Rachel F, Indrati, Agnes, Netea, Mihai G, Sharples, Katrina, Hill, Philip C, Ussher, James E, van Crevel, Reinout
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 28.03.2020
• Subjects: Adult; Cytokines; Diagnostic Tests, Routine - methods; Female; Flow cytometry; Flow Cytometry - methods; Humans; Immune clearance; Immune response; Immunity, Innate - immunology; Indonesia; Inflammation; Innate immunity; Interferon-gamma Release Tests - methods; Male; Middle Aged; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; Streptococcus infections; Tuberculosis; Tuberculosis - immunology; Tuberculosis - microbiology; γ-Interferon; Indonesia; monocytes; infection; trained innate immunity; BCG vaccine; early clearance; Mycobacterium; tuberculosis infection
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiz147

Abstract Background A proportion of tuberculosis (TB) case contacts do not become infected, even when heavily exposed. We studied the innate immune responses of TB case contacts to understand their role in protection against infection with Mycobacterium tuberculosis, termed “early clearance.” Methods Indonesian household contacts of TB cases were tested for interferon-γ release assay (IGRA) conversion between baseline and 14 weeks post recruitment. Blood cell populations and ex vivo innate whole blood cytokine responses were measured at baseline and, in a subgroup, flow cytometry was performed at weeks 2 and 14. Immunological characteristics were measured for early clearers, defined as a persistently negative IGRA at 3 months, and converters, whose IGRA converted from negative to positive. Results Among 1347 case contacts, 317 were early clearers and 116 were converters. Flow cytometry showed a resolving innate cellular response from 2 to 14 weeks in persistently IGRA-negative contacts but not converters. There were no differences in cytokine responses to mycobacterial stimuli, but compared to converters, persistently IGRA-negative contacts produced more proinflammatory cytokines following heterologous stimulation with Escherichia coli and Streptococcus pneumoniae. Conclusions Early clearance of M. tuberculosis is associated with enhanced heterologous innate immune responses similar to those activated during induction of trained immunity. In household tuberculosis case contacts from Indonesia, a persistently negative interferon-γ release assay was associated with resolving innate immune cell response over time. Stronger heterologous cytokine responses were also seen, similar to those activated during induction of trained innate immunity.