Altered Ex-Vivo Cytokine Responses in Children With Asymptomatic Plasmodium falciparum Infection in Burkina Faso: An Additional Argument to Treat Asymptomatic Malaria?

Annelies Post,André Van Der Ven,Halidou Tinto,Leo A B Joosten,Quirijn De Mast,Salou Diallo,Mihai G Netea,Jan Jacobs,Mike Berendsen,Ousmane Traore,Rob J W Arts,Berenger Kaboré

doi:10.3389/fimmu.2021.614817

Abstract

IntroductionPatients with clinical malaria have an increased risk for bacterial bloodstream infections. We hypothesized that asymptomatic malaria parasitemia increases susceptibility for bacterial infections through an effect on the innate immune system. We measured circulating cytokine levels and ex-vivo cytokine production capacity in asymptomatic malaria and compared with controls.MethodsData were collected from asymptomatic participants <5 years old with and without positive malaria microscopy, as well as from hospitalized patients <5 years old with clinical malaria, bacteremia, or malaria/bacteremia co-infections in a malaria endemic region of Burkina Faso. Circulating cytokines (TNF-α, IFN-γ, IL-6, IL-10) were measured using multiplex assays. Whole blood from asymptomatic participants with and without positive malaria microscopy were ex-vivo stimulated with S. aureus, E. coli LPS and Salmonella Typhimurium; cytokine concentrations (TNF-α, IFN-γ, IL-1β, IL-6, IL-10) were measured on supernatants using ELISA.ResultsIncluded were children with clinical malaria (n=118), bacteremia (n=22), malaria and bacteremia co-infection (n=9), asymptomatic malaria (n=125), and asymptomatic controls (n=237). Children with either clinical or asymptomatic malaria had higher plasma cytokine concentrations than controls. Cytokine concentrations correlated positively with malaria parasite density with the strongest correlation for IL-10 in both asymptomatic (r=0.63) and clinical malaria (r=0.53). Patients with bacteremia had lower circulating IL-10, TNF-α and IFN-γ and higher IL-6 concentrations, compared to clinical malaria. Ex-vivo whole blood cytokine production to LPS and S. aureus was significantly lower in asymptomatic malaria compared to controls. Whole blood IFN-γ and IL-10 production in response to Salmonella was also lower in asymptomatic malaria.InterpretationIn children with asymptomatic malaria, cytokine responses upon ex-vivo bacterial stimulation are downregulated. Further studies are needed to explore if the suggested impaired innate immune response to bacterial pathogens also translates into impaired control of pathogens such as Salmonella spp.

Highlights

Patients with clinical malaria have an increased risk for bacterial bloodstream infections
In total 171 of them were eligible for inclusion in the current study: 171 patients had clinical malaria, 30 patients had bacteremia (Salmonella spp n=18, streptococci n=5, Escherichia coli n=3, Haemophilus influenzae n=2, Neisseria meningitidis n=1 and one double infection) and 9 patients had a co-infection (Salmonella spp. n=6, and one of each Streptococcus pneumoniae, Neisseria meningitidis and Acinetobacter baumannii)
IL-6, IL-10 and IL-1b in samples exposed to Salmonella Typhimurium did not significantly correlate with parasite densities, which corresponds to the ex-vivo cytokine stimulation results. These results suggest that asymptomatic malaria downregulates the cytokine production capacity of circulating immune cells after stimulation with LPS and heat killed S. aureus, while Salmonella Typhimurium downregulates the mostly lymphocyte-derived IFN-g but had limited effect on monocyte-derived cytokines

Summary

Introduction

Patients with clinical malaria have an increased risk for bacterial bloodstream infections. We hypothesized that asymptomatic malaria parasitemia increases susceptibility for bacterial infections through an effect on the innate immune system. Non-typhoidal Salmonellae are among the most commonly found isolates in blood cultures among children in sub-Saharan Africa (SSA) [3,4,5], both among patients with and without co-occurring malaria infection. The case fatality rate of invasive non-Typhoidal Salmonella (iNTS) bloodstream infection is estimated at 20% [6]. Different mechanisms may underlie the epidemiologic association between malaria and iNTS infections [9]. Malaria is reported to cause temporary neutrophil [10] and macrophage dysfunction, and influences the cytokine production capacity of immune cells which could alter susceptibility to iNTS [11]. Changes in iron homeostasis with increased storage of iron within macrophages contributes to a suitable growing environment for Salmonella infection [12]

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