title: Prolonged neutrophil dysfunction after Plasmodium falciparum malaria is related to hemolysis and heme oxygenase-1 induction.
abstract: It is not known why people are more susceptible to bacterial infections such as nontyphoid Salmonella during and after a malaria infection, but in mice, malarial hemolysis impairs resistance to nontyphoid Salmonella by impairing the neutrophil oxidative burst. This acquired neutrophil dysfunction is a consequence of induction of the cytoprotective, heme-degrading enzyme heme oxygenase-1 (HO-1) in neutrophil progenitors in bone marrow. In this study, we assessed whether neutrophil dysfunction occurs in humans with malaria and how this relates to hemolysis. We evaluated neutrophil function in 58 Gambian children with Plasmodium falciparum malaria [55 (95%) with uncomplicated disease] and examined associations with erythrocyte count, haptoglobin, hemopexin, plasma heme, expression of receptors for heme uptake, and HO-1 induction. Malaria caused the appearance of a dominant population of neutrophils with reduced oxidative burst activity, which gradually normalized over 8 wk of follow-up. The degree of neutrophil impairment correlated significantly with markers of hemolysis and HO-1 induction. HO-1 expression was increased in blood during acute malaria, but at a cellular level HO-1 expression was modulated by changes in surface expression of the haptoglobin receptor (CD163). These findings demonstrate that neutrophil dysfunction occurs in P. falciparum malaria and support the relevance of the mechanistic studies in mice. Furthermore, they suggest the presence of a regulatory pathway to limit HO-1 induction by hemolysis in the context of infection and indicate new targets for therapeutic intervention to abrogate the susceptibility to bacterial infection in the context of hemolysis in humans.
authors.affiliation: Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom. aubrey.cunnington@lshtm.ac.uk
authors.forename: Aubrey J
authors.initials: AJ
authors.lastname: Cunnington
authors.forename: Madi
authors.initials: M
authors.lastname: Njie
authors.forename: Simon
authors.initials: S
authors.lastname: Correa
authors.forename: Ebako N
authors.initials: EN
authors.lastname: Takem
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Riley
authors.forename: Michael
authors.initials: M
authors.lastname: Walther
mesh_terms: D000208:Acute Disease; D015703:Antigens, CD / Q000097:blood; D015214:Antigens, Differentiation, Myelomonocytic / Q000097:blood; D002648:Child; D002675:Child, Preschool; D060085:Coinfection; D004906:Erythrocyte Count; D005260:Female; D015870:Gene Expression; D006242:Haptoglobins / Q000032:analysis; D006418:Heme / Q000032:analysis; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000276:immunology*; D006461:Hemolysis / Q000276:immunology*; D006466:Hemopexin / Q000032:analysis; D006801:Humans; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010963:Plasmodium falciparum / Q000276:immunology; D011956:Receptors, Cell Surface / Q000097:blood; D016897:Respiratory Burst / Q000276:immunology; D012475:Salmonella / Q000276:immunology; D012480:Salmonella Infections / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D015854:Up-Regulation; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D006242:Haptoglobins; D011956:Receptors, Cell Surface; D006418:Heme; D006466:Hemopexin; D051547:Heme Oxygenase-1