BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner
Valerie A.C.M. Koeken, … , Reinout van Crevel, Mihai G. Netea
Valerie A.C.M. Koeken, … , Reinout van Crevel, Mihai G. Netea
Published July 21, 2020
Citation Information: J Clin Invest. 2020;130(10):5591-5602. https://doi.org/10.1172/JCI133935.
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Clinical Research and Public Health Immunology

BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner

Abstract

BACKGROUND Induction of innate immune memory, also termed trained immunity, by the antituberculosis vaccine bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known; while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases.METHODS We investigated the impact of BCG (BCG-Bulgaria, InterVax) vaccination on systemic inflammation in a cohort of 303 healthy volunteers, as well as the effect of the inflammatory status on the response to vaccination. A targeted proteome platform was used to measure circulating inflammatory proteins before and after BCG vaccination, while ex vivo Mycobacterium tuberculosis– and Staphylococcus aureus–induced cytokine responses in peripheral blood mononuclear cells were used to assess trained immunity.RESULTS While BCG vaccination enhanced cytokine responses to restimulation, it reduced systemic inflammation. This effect was validated in 3 smaller cohorts, and was much stronger in men than in women. In addition, baseline circulating inflammatory markers were associated with ex vivo cytokine responses (trained immunity) after BCG vaccination.CONCLUSION The capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation should be further explored for potential therapeutic applications.FUNDING Netherlands Organization for Scientific Research, European Research Council, and the Danish National Research Foundation.

Authors

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 S. Benn, Reinout van Crevel, Mihai G. Netea

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Figure 6

Sex-specific effect of BCG vaccination on systemic inflammation.

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Sex-specific effect of BCG vaccination on systemic inflammation. (A) Com...
(A) Comparison of baseline circulating inflammatory proteins plotted as fold changes between males (n = 132) and females (n = 171). Significant changes between sexes are depicted in red (FDR < 0.05). (B) Comparison of inflammatory proteins between males and females from the discovery cohort (300BCG) were plotted against the comparison between males (n = 215) and females (n = 278) from the validation cohort (500FG). Proteins that were only significantly different in the 300BCG cohort are depicted in green (n = 9), those that were only significant in the 500FG cohort are depicted in blue (n = 3), and the proteins significantly different between males and females in both cohorts are depicted in red (n = 34) and are labeled with their name (FDR < 0.05). Fold changes of circulating inflammatory markers on day 14 versus baseline (C) and day 90 versus baseline (D) in the male-only (n = 132) versus the female-only (n = 171) subset. Significant changes compared with baseline in the male-only subset are depicted in red (FDR < 0.05), and proteins that did not significantly change after BCG vaccination in either the male-only or the female-only subset are depicted in gray. There were no proteins significantly different in the female-only subset.