Exposure-Dependent Control of Malaria-Induced Inflammation in Children

PLoS Pathogens

Silvia Portugal¹  Jeff Skinner¹  Jacqueline Moebius¹  Shanping Li¹  Peter D. Crompton¹  Safiatou Doumbo²  Boubacar Traore²  Seydou Dia²  Younoussou Kone²  Kassoum Kayentao²  Ogobara K. Doumbo²  Didier Doumtabe²  Aissata Ongoiba²  Stephen F. Porcella³  Kishore Kanakabandi³  Daniel E. Sturdevant³  Kimmo Virtaneva³ 

[1] Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America;Mali International Center of Excellence in Research, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali;Rocky Mountain Laboratory Research Technologies Section, Genomics Unit, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America

关键词: Malaria;    Malarial parasites;    Plasmodium;    Parasitic diseases;    T cells;    Cytokines;    Inflammation;    Parasite replication;   

DOI  :  10.1371/journal.ppat.1004079

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

In malaria-naïve individuals, Plasmodium falciparum infection results in high levels of parasite-infected red blood cells (iRBCs) that trigger systemic inflammation and fever. Conversely, individuals in endemic areas who are repeatedly infected are often asymptomatic and have low levels of iRBCs, even young children. We hypothesized that febrile malaria alters the immune system such that P. falciparum re-exposure results in reduced production of pro-inflammatory cytokines/chemokines and enhanced anti-parasite effector responses compared to responses induced before malaria. To test this hypothesis we used a systems biology approach to analyze PBMCs sampled from healthy children before the six-month malaria season and the same children seven days after treatment of their first febrile malaria episode of the ensuing season. PBMCs were stimulated with iRBC in vitro and various immune parameters were measured. Before the malaria season, children's immune cells responded to iRBCs by producing pro-inflammatory mediators such as IL-1β, IL-6 and IL-8. Following malaria there was a marked shift in the response to iRBCs with the same children's immune cells producing lower levels of pro-inflammatory cytokines and higher levels of anti-inflammatory cytokines (IL-10, TGF-β). In addition, molecules involved in phagocytosis and activation of adaptive immunity were upregulated after malaria as compared to before. This shift was accompanied by an increase in P. falciparum-specific CD4+Foxp3− T cells that co-produce IL-10, IFN-γ and TNF; however, after the subsequent six-month dry season, a period of markedly reduced malaria transmission, P. falciparum–inducible IL-10 production remained partially upregulated only in children with persistent asymptomatic infections. These findings suggest that in the face of P. falciparum re-exposure, children acquire exposure-dependent P. falciparum–specific immunoregulatory responses that dampen pathogenic inflammation while enhancing anti-parasite effector mechanisms. These data provide mechanistic insight into the observation that P. falciparum–infected children in endemic areas are often afebrile and tend to control parasite replication.

【 授权许可】

CC BY