Controlled Human Malaria Infection Induces Long-Term Functional Changes in Monocytes.

Jona Walk,Robert W Sauerwein,Hendrik G Stunnenberg,Bas Blok,Mihai G Netea,Rob J W Arts,Farid Keramati,L Charlotte J De Bree

doi:10.3389/fmolb.2020.604553

Abstract

Innate immune memory responses (also termed “trained immunity”) have been described in monocytes after BCG vaccination and after stimulation in vitro with microbial and endogenous ligands such as LPS, β-glucan, oxidized LDL, and monosodium urate crystals. However, whether clinical infections are also capable of inducing a trained immunity phenotype remained uncertain. We evaluated whether Plasmodium falciparum infection can induce innate immune memory by measuring monocyte-derived cytokine production from five volunteers undergoing Controlled Human Malaria Infection. Monocyte responses followed a biphasic pattern: during acute infection, monocytes produced lower amounts of inflammatory cytokines upon secondary stimulation, but 36 days after malaria infection they produced significantly more IL-6 and TNF-α in response to various stimuli. Furthermore, transcriptomic and epigenomic data analysis revealed a clear reprogramming of monocytes at both timepoints, with long-term changes of H3K4me3 at the promoter regions of inflammatory genes that remain present for several weeks after parasite clearance. These findings demonstrate an epigenetic basis of trained immunity induced by human malaria in vivo.

Highlights

Throughout our life, the immune system continually encounters a wide array of microorganisms and other danger signals
36 days after infection, more than 3 weeks after parasite clearance, IL-6 and TNF-α production was significantly increased upon stimulation with LPS, C. albicans and S. aureus compared to baseline (Figures 2A,B). 7 months after infection, IL-6 production returned to baseline, though TNF-α and IL-1β production remained increased compared to baseline
We detect a marked increase in monocyte pro-inflammatory cytokine production to heterologous stimuli 5 weeks after a Controlled Human Malaria Infection in previously malaria-naïve volunteers

Summary

Introduction

Throughout our life, the immune system continually encounters a wide array of microorganisms and other danger signals. Epigenetic reprogramming of monocytes (Cheng et al, 2014; Saeed et al, 2014; Arts et al, 2016) can result in long-lasting changes in the innate immune compartment after exposure to various microorganisms (Kleinnijenhuis et al, 2012; Quintin et al, 2012). Epigenetic reprogramming underlies these effects (Cheng et al, 2014; Saeed et al, 2014; Arts et al, 2016). Trained immunity is thought to underlie some clinical observations of heterologous protective effects after vaccination, including the observed reduction in all cause infant mortality after BCG and measles vaccination (de Bree et al, 2018)

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Results

Conclusion