title: Exposure-dependent control of malaria-induced inflammation in children.
abstract: 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.
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Silvia
authors.initials: S
authors.lastname: Portugal
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Moebius
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Jeff
authors.initials: J
authors.lastname: Skinner
authors.affiliation: Mali International Center of Excellence in Research, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Safiatou
authors.initials: S
authors.lastname: Doumbo
authors.affiliation: Mali International Center of Excellence in Research, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Didier
authors.initials: D
authors.lastname: Doumtabe
authors.affiliation: Mali International Center of Excellence in Research, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Younoussou
authors.initials: Y
authors.lastname: Kone
authors.affiliation: Mali International Center of Excellence in Research, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Seydou
authors.initials: S
authors.lastname: Dia
authors.affiliation: 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.
authors.forename: Kishore
authors.initials: K
authors.lastname: Kanakabandi
authors.affiliation: 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.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Sturdevant
authors.affiliation: 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.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Virtaneva
authors.affiliation: 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.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Porcella
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Shanping
authors.initials: S
authors.lastname: Li
authors.affiliation: Mali International Center of Excellence in Research, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.affiliation: Mali International Center of Excellence in Research, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Kassoum
authors.initials: K
authors.lastname: Kayentao
authors.affiliation: Mali International Center of Excellence in Research, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Aissata
authors.initials: A
authors.lastname: Ongoiba
authors.affiliation: Mali International Center of Excellence in Research, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali.
authors.forename: Boubacar
authors.initials: B
authors.lastname: Traore
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Crompton
mesh_terms: D056704:Adaptive Immunity; D000293:Adolescent; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000469:parasitology; D016778:Malaria, Falciparum / Q000097:blood / Q000453:epidemiology / Q000276:immunology*; D008297:Male; D010963:Plasmodium falciparum / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines
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