Exposure-dependent control of malaria-induced inflammation in children.
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, ev...
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oai:doaj.org-article:e4e9b922a4e742aba4bc1050044c01c32021-11-18T06:06:41ZExposure-dependent control of malaria-induced inflammation in children.1553-73661553-737410.1371/journal.ppat.1004079https://doaj.org/article/e4e9b922a4e742aba4bc1050044c01c32014-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24743880/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374In 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.Silvia PortugalJacqueline MoebiusJeff SkinnerSafiatou DoumboDidier DoumtabeYounoussou KoneSeydou DiaKishore KanakabandiDaniel E SturdevantKimmo VirtanevaStephen F PorcellaShanping LiOgobara K DoumboKassoum KayentaoAissata OngoibaBoubacar TraorePeter D CromptonPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 10, Iss 4, p e1004079 (2014) |
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| collection |
DOAJ |
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| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Silvia Portugal Jacqueline Moebius Jeff Skinner Safiatou Doumbo Didier Doumtabe Younoussou Kone Seydou Dia Kishore Kanakabandi Daniel E Sturdevant Kimmo Virtaneva Stephen F Porcella Shanping Li Ogobara K Doumbo Kassoum Kayentao Aissata Ongoiba Boubacar Traore Peter D Crompton Exposure-dependent control of malaria-induced inflammation in children. |
| description |
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. |
| format |
article |
| author |
Silvia Portugal Jacqueline Moebius Jeff Skinner Safiatou Doumbo Didier Doumtabe Younoussou Kone Seydou Dia Kishore Kanakabandi Daniel E Sturdevant Kimmo Virtaneva Stephen F Porcella Shanping Li Ogobara K Doumbo Kassoum Kayentao Aissata Ongoiba Boubacar Traore Peter D Crompton |
| author_facet |
Silvia Portugal Jacqueline Moebius Jeff Skinner Safiatou Doumbo Didier Doumtabe Younoussou Kone Seydou Dia Kishore Kanakabandi Daniel E Sturdevant Kimmo Virtaneva Stephen F Porcella Shanping Li Ogobara K Doumbo Kassoum Kayentao Aissata Ongoiba Boubacar Traore Peter D Crompton |
| author_sort |
Silvia Portugal |
| title |
Exposure-dependent control of malaria-induced inflammation in children. |
| title_short |
Exposure-dependent control of malaria-induced inflammation in children. |
| title_full |
Exposure-dependent control of malaria-induced inflammation in children. |
| title_fullStr |
Exposure-dependent control of malaria-induced inflammation in children. |
| title_full_unstemmed |
Exposure-dependent control of malaria-induced inflammation in children. |
| title_sort |
exposure-dependent control of malaria-induced inflammation in children. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/e4e9b922a4e742aba4bc1050044c01c3 |
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