Article

Prolonged Neutrophil Dysfunction after Plasmodium falciparum Malaria Is Related to Hemolysis and Heme Oxygenase-1 Induction

Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom
The Journal of Immunology (Impact Factor: 5.36). 10/2012; 189(11). DOI: 10.4049/jimmunol.1201028
Source: PubMed

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.

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    • "Presumably ROS produced from neutrophils would exacerbate this toxicity , and reducing production of ROS would be expected to be beneficial . Impairment of the neutrophil oxidative burst , related to upregulation of HO - 1 , has subsequently been demonstrated in Gambian children with malaria ( Cunnington et al . , 2012 ) . Impaired neutrophil oxidative burst has also been observed in sickle cell disease ( Qari and Zaki , 2011 ) , which is characterized by severe hemolysis and dramatically increased susceptibility to NTS infection ( in contrast to SCT ) , indicating this mechanism may be a general consequence of hemolysis ."
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    Frontiers in Microbiology 06/2015; 6:666. DOI:10.3389/fmicb.2015.00666 · 3.94 Impact Factor
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    • "In contrast, higher HO-1 expression is associated with increased susceptibility to malaria (Plasmodium falciparum) infection [193] [194] [195] [196]. This may be due to the heme overload from malaria-induced hemolysis, from which increased HO- 1 activity would lead to an overload of free iron [197]. "
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