Mycobacterial growth inhibition is associated with trained innate immunity
Simone A. Joosten, … , Mihai G. Netea, Tom H.M. Ottenhoff
Simone A. Joosten, … , Mihai G. Netea, Tom H.M. Ottenhoff
Published February 20, 2018
Citation Information: J Clin Invest. 2018;128(5):1837-1851. https://doi.org/10.1172/JCI97508.
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Research Article Immunology Infectious disease

Mycobacterial growth inhibition is associated with trained innate immunity

Abstract

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.

Authors

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

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Figure 1

Mycobacterial growth control is associated with recent TB exposure.

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Mycobacterial growth control is associated with recent TB exposure. PBMC...
PBMCs were infected with live BCG, rotated 4 days, and incubated in MGIT tubes in the BACTEC machine. Horizontal lines indicate medians. “Δ median” indicates the difference in medians between groups. (A) PBMCs collected before BCG vaccination, 4, 8, and 12 weeks after vaccination, and 1 year after vaccination. Left plot indicates donors with the strongest reduction in BCG growth at week 4 (n = 8), middle plot at week 8 (n = 2), and right plot at week 12 (n = 6). (B) For each individual from A, the time point with maximal MGIA control was compared with the prevaccination sample using the Wilcoxon paired-rank test. (C–G) All groups in C–G were compared with a common group of 30 controls — 16 individuals prior to BCG vaccination and 14 blood bank donors — using the Kruskal-Wallis test. (C) Patients with active TB disease (n = 19). (D) Individuals with latent TB infection (LTBI; n = 22). (E) Individuals with long-term LTBI (lt-LTBI; n = 20). An age-matched control group (lt-LTBI ctr; n = 10) was included. (F) Three independent cohorts of recently TB-exposed individuals collected during contact investigations: 35 at a soccer club, 11 in a supermarket, and 39 immigrants with recent exposure to active TB. (G) Combined analysis of all groups tested: BCG (n = 16 at peak response); recently exposed (F: n = 85); LTBI (from D and E: n = 42); active TB (from C). Data were compared using the Kruskal-Wallis test. Dashed lines indicate the lower limit of the CI of the median of the controls, and the 1 log reduction compared with this median. Samples above the CI of median lacked control of mycobacterial outgrowth and samples with more than 1 log reduction had good control.