The lack of defined correlates of protection hampers development of vaccines against tuberculosis (TB). In vitro mycobacterial outgrowth assays are thought to better capture the complexity of the human host/Mycobacterium tuberculosis (Mtb) interaction. Here, we used a mycobacterial growth inhibition assay (MGIA) based on peripheral blood mononuclear cells to investigate the capacity to control outgrowth of bacille Calmette-Guérin (BCG). Interestingly, strong control of BCG outgrowth was observed almost exclusively in individuals with recent exposure to Mtb, but not in (long-term) latent TB infection, and only modestly in BCG vaccinees. Mechanistically, control of mycobacterial outgrowth strongly correlated with the presence of a CD14dim monocyte population, but also required the presence of T cells. The nonclassical monocytes produced CXCL10, and CXCR3 receptor blockade inhibited the capacity to control BCG outgrowth. Expression of CXCR3 splice variants was altered in recently Mtb-exposed individuals. Cytokines previously associated with trained immunity were detected in MGIA supernatants, and CXCL9, CXCL10, and CXCL11 represent new markers of trained immunity. These data indicate that CXCR3 ligands are associated with trained immunity and are critical factors in controlling mycobacterial outgrowth. In conclusion, control of mycobacterial outgrowth early after exposure to Mtb is the result of trained immunity mediated by a CXCL10-producing nonclassical CD14dim monocyte subset.
Simone A. Joosten, Krista E. van Meijgaarden, Sandra M. Arend, Corine Prins, Fredrik Oftung, Gro Ellen Korsvold, Sandra V. Kik, Rob J.W. Arts, Reinout van Crevel, Mihai G. Netea, Tom H.M. Ottenhoff
Title and authors | Publication | Year |
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BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner
Valerie A. C. M. Koeken, L. Charlotte J. de Bree, Vera P. Mourits, Simone J.C.F.M. Moorlag, Jona Walk, Branko Cirovic, Rob J.W. Arts, Martin Jaeger, Helga Dijkstra, Heidi Lemmers, Leo A.B. Joosten, Christine Stabell Benn, Reinout van Crevel, Mihai Netea |
Journal of Clinical Investigation | 2020 |
Towards new TB vaccines
B Brazier, H McShane |
Seminars in Immunopathology | 2020 |
Cell-Mediated Immune Responses to in vivo-Expressed and Stage-Specific Mycobacterium tuberculosis Antigens in Latent and Active Tuberculosis Across Different Age Groups
M Coppola, R Villar-Hernández, KE van Meijgaarden, I Latorre, BM Moreno, E Garcia-Garcia, KL Franken, C Prat, Z Stojanovic, ML Galvão, JP Millet, J Sabriá, A Sánchez-Montalva, A Noguera-Julian, A Geluk, J Domínguez, TH Ottenhoff |
Frontiers in immunology | 2020 |
Tools for Assessing the Protective Efficacy of TB Vaccines in Humans: in vitro Mycobacterial Growth Inhibition Predicts Outcome of in vivo Mycobacterial Infection
R Tanner, I Satti, SA Harris, MK O'Shea, D Cizmeci, D O'Connor, A Chomka, M Matsumiya, R Wittenberg, AM Minassian, J Meyer, HA Fletcher, H McShane |
Frontiers in immunology | 2020 |
Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development
ST Pasco, J Anguita |
Cells | 2020 |
Expanding the role of bacterial vaccines into life-course vaccination strategies and prevention of antimicrobial-resistant infections
JT Poolman |
npj Vaccines | 2020 |
Key recent advances in TB vaccine development and understanding of protective immune responses against Mycobacterium tuberculosis
TJ Scriba, MG Netea, AM Ginsberg |
Seminars in Immunology | 2020 |
Perspective for Precision Medicine for Tuberculosis
C Lange, R Aarnoutse, D Chesov, R van Crevel, SH Gillespie, HP Grobbel, B Kalsdorf, I Kontsevaya, A van Laarhoven, T Nishiguchi, A Mandalakas, M Merker, S Niemann, N Köhler, J Heyckendorf, M Reimann, M Ruhwald, P Sanchez-Carballo, D Schwudke, F Waldow, AR DiNardo |
Frontiers in immunology | 2020 |
Prevention of tuberculosis in macaques after intravenous BCG immunization
PA Darrah, JJ Zeppa, P Maiello, JA Hackney, MH Wadsworth, TK Hughes, S Pokkali, PA Swanson, NL Grant, MA Rodgers, M Kamath, CM Causgrove, DJ Laddy, A Bonavia, D Casimiro, PL Lin, E Klein, AG White, CA Scanga, AK Shalek, M Roederer, JA Flynn, RA Seder |
Nature | 2020 |
Neonatal BCG Vaccination Reduces Interferon-γ Responsiveness to Heterologous Pathogens in Infants From a Randomized Controlled Trial
B Freyne, NL Messina, S Donath, S Germano, R Bonnici, K Gardiner, D Casalaz, RM Robins-Browne, MG Netea, KL Flanagan, T Kollmann, N Curtis, V Abruzzo, K Allen, C Morrison, AL Ponsonby, P Vuillermin |
The Journal of Infectious Diseases | 2020 |
BCG vaccination strategy implemented to reduce the impact of COVID-19: Hype or Hope?
K Rajarshi, A Chatterjee, S Ray |
2020 | |
BCG as a game-changer to prevent the infection and severity of COVID-19 pandemic?
AR Sharma, G Batra, M Kumar, A Mishra, R Singla, A Singh, RS Singh, B Medhi |
Allergologia et Immunopathologia | 2020 |
Safety and COVID-19 Symptoms in Individuals Recently Vaccinated with BCG: a Retrospective Cohort Study
SJ Moorlag, RC van Deuren, CH van Werkhoven, M Jaeger, P Debisarun, E Taks, VP Mourits, VA Koeken, LC de Bree, T ten Doesschate, MC Cleophas, S Smeekens, M Oosting, FL van de Veerdonk, LA Joosten, J ten Oever, JW van der Meer, N Curtis, P Aaby, C Stabell-Benn, EJ Giamarellos-Bourboulis, M Bonten, R van Crevel, MG Netea |
Cell reports. Medicine | 2020 |