BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity

Arts, Rob J. W.; Moorlag, Simone J.C.F.M.; Novakovic, Boris; Li, Yang; Wang, Shuang-Yin; Oosting, Marije; Kumar, Vinod; Xavier, Ramnik J.; Wijmenga, Cisca; Joosten, Leo A. B.; Reusken, Chantal; Benn, Christine Stabell; Aaby, Péter; Koopmans, Marion; Stunnenberg, Hendrik G.; Crevel, Reinout van; Netea, Mihai G.

doi:10.1016/j.chom.2017.12.010

Cited by 963 publications

(1,090 citation statements)

References 58 publications

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“…Similarly, a randomized control trial of BCG vaccination of low birth weight babies in Guinea‐Bissau suggested a reduction in infant mortality (mortality rate ratio = 83%; 95% CI 0.63–1.08%) driven by fewer cases of neonatal sepsis, respiratory infection and fever in the BCG‐vaccinated group. In a human yellow fever virus vaccine strain challenge study, BCG‐vaccinated volunteers had reduced viremia compared to non‐vaccinated participants . These findings are consistent with a variety of observational studies linking BCG vaccination and reduced risk of non‐mycobacterial infections, allergies, malignancies and all‐cause mortality .…”

Section: Clinical Effectiveness Of Bcgsupporting

confidence: 79%

“…Since innate responses are initiated by recognition of broadly conserved pathogen‐associated molecular patterns, BCG training induces stronger innate cytokine responses to both tuberculosis and other unrelated microorganisms. Consistent with this, the production of IL‐1β was correlated with reduction of yellow fever viremia in BCG‐vaccinated volunteers, whereas specific IFN‐γ production was not . Intriguingly, it was shown in mice that BCG vaccination could drive epigenetic changes in hematopoietic stem cells, potentially explaining how trained innate immunity can be effective over the long term …”

Section: Bcg‐induced Trained Innate Immunitymentioning

confidence: 59%

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Beyond memory T cells: mechanisms of protective immunity to tuberculosis infection

2019

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Tuberculosis (TB) is a serious infectious disease caused by infection with Mycobacterium tuberculosis, and kills more people annually than any other single infectious agent. Although a vaccine is available, it is only moderately effective and an improved vaccine is urgently needed. The ability to develop a more effective vaccine has been thwarted by a lack of understanding of the mechanism of vaccine‐induced immune protection. Over recent decades, many novel TB vaccines have been developed and almost all have aimed to generate memory CD4 T cells. In this review, we critically evaluate evidence in the literature that supports the contention that memory CD4 T cells are the prime mediators of vaccine‐induced protection against TB. Because of the lack of robust evidence supporting memory CD4 T cells in this role, the potential for B‐cell antibody and “trained” innate cells as alternative mediators of protective immunity is explored.

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Section: Clinical Effectiveness Of Bcgsupporting

confidence: 79%

Section: Bcg‐induced Trained Innate Immunitymentioning

confidence: 59%

Beyond memory T cells: mechanisms of protective immunity to tuberculosis infection

2019

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“…22 Blood was drawn before vaccination and 1 month later (see Supplementary material, Fig. Venous blood of healthy volunteers was drawn and genotyped after informed consent (Radboudumc, Nijmegen, the Netherlands).…”

Section: Blood Samplesmentioning

confidence: 99%

The role of Toll‐like receptor 10 in modulation of trained immunity

et al. 2019

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Toll-like receptor 10 (TLR10) is the only member of the human Toll-like receptor family with an inhibitory function on the induction of innate immune responses and inflammation. However, its role in the modulation of trained immunity (innate immune memory) is unknown. In the present study, we assessed whether TLR10 modulates the induction of trained immunity induced by b-glucan or bacillus Calmette-Gu erin (BCG). Interleukin 10 receptor antagonist production was increased upon activation of TLR10 ex vivo after BCG vaccination, and TLR10 protein expression on monocytes was increased after BCG vaccination, whereas anti-TLR10 antibodies did not significantly modulate b-glucan or BCG-induced trained immunity in vitro. A known immunomodulatory TLR10 missense single-nucleotide polymorphism (rs11096957) influenced trained immunity responses by b-glucan or BCG in vitro. However, the in vivo induction of trained immunity by BCG vaccination was not influenced by TLR10 polymorphisms. In conclusion, TLR10 has a limited, non-essential impact on the induction of trained immunity in humans.

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“…Six days after initial training, macrophages were restimulated with LPS. Previously it has been shown BCG‐induced trained immunity results in genome wide epigenetic reprogramming in vivo and up‐regulation of several cytokines. Pro‐inflammatory TNF‐α and IL‐6 and anti‐inflammatory IL‐10 were selected as example cytokines for our primary outcomes based on previous studies .…”

Section: Resultsmentioning

confidence: 99%

The impact of sex hormones on BCG-induced trained immunity

Bree

Janssen

Aaby

et al. 2018

Journal of Leukocyte Biology

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The anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) is a well-known immune modulator that induces nonspecific protective effects against heterologous infections through induction of innate immune memory, also termed "trained immunity." In randomized trials in low weight newborns, BCG vaccination reduced neonatal mortality due to decreased incidence of sepsis and respiratory infections. In many studies, sex-differential nonspecific effects of vaccines have been observed, but the mechanisms behind these differential effects are unknown. We investigated whether the important sex hormones estrogen and dihydrotestosterone (DHT) influence BCG-induced trained immunity in human primary monocytes. Although addition of estradiol and DHT to BCG inhibited the production of proinflammatory cytokines after direct stimulation of human monocytes, they did not influence the induction of trained immunity by BCG. In addition, estradiol or DHT did not induce training or tolerance in monocytes themselves. We conclude that these important sex hormones are unlikely to explain the sex-differential effects after BCG vaccination. Future studies should focus on the investigation of alternative mechanisms as an explanation for sex-differential nonspecific effects of BCG vaccination.

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BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity

Cited by 963 publications

References 58 publications

Beyond memory T cells: mechanisms of protective immunity to tuberculosis infection

Beyond memory T cells: mechanisms of protective immunity to tuberculosis infection

The role of Toll‐like receptor 10 in modulation of trained immunity

The impact of sex hormones on BCG-induced trained immunity

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