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Randomized Controlled Trial
. 2019 Aug 16;69(5):820-828.
doi: 10.1093/cid/ciy934.

A Balanced Proinflammatory and Regulatory Cytokine Signature in Young African Children Is Associated With Lower Risk of Clinical Malaria

Carlota Dobaño  1   2   3 , Augusto J Nhabomba  2 , Maria N Manaca  2 , Tamara Berthoud  1 , Ruth Aguilar  1   2   3 , Llorenç Quintó  1   2   3 , Arnoldo Barbosa  1   2 , Mauricio H Rodríguez  1   2 , Alfons Jiménez  1   3 , Penny L Groves  4 , Rebeca Santano  1 , Quique Bassat  1   2   4 , John J Aponte  1   2   3 , Caterina Guinovart  1   2   3 , Denise L Doolan  5 , Pedro L Alonso  1   2   3
Affiliations
Randomized Controlled Trial

A Balanced Proinflammatory and Regulatory Cytokine Signature in Young African Children Is Associated With Lower Risk of Clinical Malaria

Carlota Dobaño et al. Clin Infect Dis. .

Abstract

Background: The effect of timing of exposure to first Plasmodium falciparum infections during early childhood on the induction of innate and adaptive cytokine responses and their contribution to the development of clinical malaria immunity is not well established.

Methods: As part of a double-blind, randomized, placebo-controlled trial in Mozambique using monthly chemoprophylaxis with sulfadoxine-pyrimethamine plus artesunate to selectively control timing of malaria exposure during infancy, peripheral blood mononuclear cells collected from participants at age 2.5, 5.5, 10.5, 15, and 24 months were stimulated ex vivo with parasite schizont and erythrocyte lysates. Cytokine messenger RNA expressed in cell pellets and proteins secreted in supernatants were quantified by reverse-transcription quantitative polymerase chain reaction and multiplex flow cytometry, respectively. Children were followed up for clinical malaria from birth until 4 years of age.

Results: Higher proinflammatory (interleukin [IL] 1, IL-6, tumor necrosis factor) and regulatory (IL-10) cytokine concentrations during the second year of life were associated with reduced incidence of clinical malaria up to 4 years of age, adjusting by chemoprophylaxis and prior malaria exposure. Significantly lower concentrations of antigen-specific T-helper 1 (IL-2, IL-12, interferon-γ) and T-helper 2 (IL-4, IL-5) cytokines by 2 years of age were measured in children undergoing chemoprophylaxis compared to children receiving placebo (P < .03).

Conclusions: Selective chemoprophylaxis altering early natural exposure to malaria blood stage antigens during infancy had a significant effect on T-helper lymphocyte cytokine production >1 year later. Importantly, a balanced proinflammatory and anti-inflammatory cytokine signature, probably by innate cells, around age 2 years was associated with protective clinical immunity during childhood.

Clinical trials registration: NCT00231452.

Keywords: Plasmodium falciparum; age; cytokines; exposure; immunity.

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Figures

Figure 1.
Figure 1.
Weighted scattered plots of Plasmodium falciparum antigen-specific cytokine concentrations (pg/mL) in each study group and at each cross-sectional visit, showing geometric means and 95% confidence intervals. A, T-helper 1 (TH1) cytokines: interleukin (IL) 12, IL-2, interferon-γ. B, T-helper 2 (TH2) cytokines: IL-4, IL-5. C, Proinflammatory and regulatory cytokines: IL-1, IL-6, tumor necrosis factor, IL-8, and IL-10. Tables 1 and 2 show the outcomes of the statistical tests for the comparisons that had significantly different cytokine responses. The area of the symbol is proportional to the number of observations; those with previous or current P. falciparum infections are shown in red. In the case of TH1 and TH2 cytokines at the cross-sectional visit at 24 months, most concentration values were low or undetectable for the late-exposure and early-exposure groups (ie, larger area of red and blue symbols at the bottom). Abbreviations: Ctrol, control; EE, early exposure; IFN, interferon; IL, interleukin; LE, late exposure; TNF, tumor necrosis factor.
Figure 2.
Figure 2.
Heatmaps and scatterplots of the correlations between antibody levels and cytokine concentrations after stimulation with Plasmodium falciparum schizont lysate (log-transformed) at the indicated study visits. A, Antibodies vs T-helper 1 and 2 cytokines at month 24. B, Antibodies vs proinflammatory and regulatory cytokines at month 24. Spearman coefficients and P values: *<.05, **<.01, ***<.001. Abbreviations: AMA1, apical membrane antigen; EBA175, erythrocyte-binding antigen; IFN, interferon; IgG, immunoglobulin G; IgM, immunoglobulin M; IL, interleukin; iRBC, infected red blood cell; MSP1, merozoite surface protein; TH1, T-helper 1; TH2, T-helper 2; TNF, tumor necrosis factor; VSA, variant surface antigen.
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