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

Koeken, Valerie A C M; Bree, L. Charlotte J. de; Mourits, Vera P.; Moorlag, Simone J.C.F.M.; Walk, Jona; Cirovic, Branko; Arts, Rob J. W.; Jaeger, Martin; Dijkstra, Helga; Lemmers, Heidi; Joosten, Leo A. B.; Benn, Christine Stabell; Crevel, Reinout van; Netea, Mihai G.

doi:10.1172/jci133935

Cited by 114 publications

(127 citation statements)

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“…Moreover, BCG had neuroprotective effects in experimental models of neurodegenerative diseases [ 51 , 52 , 53 ] where it induced anti-inflammatory and inflammation-resolving effects by the recruitment of regulatory T cells or inflammation-resolving monocytes to the brain. Together these studies clearly indicate that BCG indeed may protect against inflammatory conditions and are in line with a recent study which shows that BCG vaccination in humans inhibits systemic inflammation [ 54 ]. Excessive inflammatory immune responses during infections with Plasmodium parasites are associated with severe complications such as CM.…”

Section: Discussionsupporting

confidence: 88%

BCG Provides Short-Term Protection from Experimental Cerebral Malaria in Mice

et al. 2020

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Clinical and experimental evidence suggests that the tuberculosis vaccine BCG offers protection against unrelated pathogens including the malaria parasite. Cerebral malaria (CM) is the most severe complication associated with Plasmodium falciparum infection in humans and is responsible for most of the fatalities attributed to malaria. We investigated whether BCG protected C57BL/6 mice from P. berghei ANKA (PbA)-induced experimental CM (ECM). The majority of PbA-infected mice that were immunized with BCG showed prolonged survival without developing clinical symptoms of ECM. However, this protective effect waned over time and was associated with the recovery of viable BCG from liver and spleen. Intriguingly, BCG-mediated protection from ECM was not associated with a reduction in parasite burden, indicating that BCG immunization did not improve anti-parasite effector mechanisms. Instead, we found a significant reduction in pro-inflammatory mediators and CD8+ T cells in brains of BCG-vaccinated mice. Together these data suggest that brain recruitment of immune cells involved in the pathogenesis of ECM decreased after BCG vaccination. Understanding the mechanisms underlying the protective effects of BCG on PbA-induced ECM can provide a rationale for developing effective adjunctive therapies to reduce the risk of death and brain damage in CM.

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Section: Discussionsupporting

confidence: 88%

BCG Provides Short-Term Protection from Experimental Cerebral Malaria in Mice

et al. 2020

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“…This effect was much stronger in men than in women. Hence, the capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation may be clinically relevant for potential therapeutic applications (68).…”

Section: Discussionmentioning

confidence: 99%

Memory-Like Responses of Brain Microglia Are Controlled by Developmental State and Pathogen Dose

et al. 2020

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Microglia, the innate immune cells of the central nervous system, feature adaptive immune memory with implications for brain homeostasis and pathologies. However, factors involved in the emergence and regulation of these opposing responses in microglia have not been fully addressed. Recently, we showed that microglia from the newborn brain display features of trained immunity and immune tolerance after repeated contact with pathogens in a dose-dependent manner. Here, we evaluate the impact of developmental stage on adaptive immune responses of brain microglia after repeated challenge with ultra-low (1 fg/ml) and high (100 ng/ml) doses of the endotoxin LPS in vitro. We find that priming of naïve microglia derived from newborn but not mature and aged murine brain with ultra-low LPS significantly increased levels of pro-inflammatory mediators TNF-α, IL-6, IL-1β, MMP-9, and iNOS as well as neurotrophic factors indicating induction of trained immunity (p < 0.05). In contrast, stimulation with high doses of LPS led to a robust downregulation of pro-inflammatory cytokines and iNOS independent of the developmental state, indicating induced immune tolerance. Furthermore, high-dose priming with LPS upregulated anti-inflammatory mediators IL-10, Arg-1, TGFβ, MSR1, and IL-4 in newborn microglia (p < 0.05). Our data indicate pronounced plasticity of the immune response of neonate microglia compared with microglia derived from mature and aged mouse brain. Induced trained immunity after priming with ultra-low LPS doses may be responsible for enhanced neuro-inflammatory susceptibility of immature brain. In contrast, the immunosuppressed phenotype following high-dose LPS priming might be prone to attenuate excessive damage after recurrent systemic inflammation.

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“…To identify new biomarkers, especially for PB leprosy, the scope can be widened from the broadly studied immune markers to metabolic markers, which contribute to leprosy pathogenesis as well ( Mayboroda et al., 2016 ; Cruz et al., 2008 ; Silva et al., 2017 ). New techniques ( Koeken et al., 2020 ; Mourits et al., 2020 ) to identify disease markers in HCs developing PB leprosy in high throughput fashion are currently explored by us.…”

Section: Discussionmentioning

confidence: 99%