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 non-Typhoid Salmonella (NTS) during and after a malaria infection but, in mice, malarial hemolysis impairs resistance to NTS 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 weeks 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.

Monocyte dysregulation and systemic inflammation during pediatric falciparum malaria

“…This notion is supported by recent work by Martins et al, in which they demonstrate that heme inhibits phagocyte function directly by disrupting the actin cytoskeleton via interactions with DOCK8 and Cdc42 (50). In addition, increasingly impaired neutrophil phagocytosis of Salmonella was associated with increasingly severe hemolysis during malaria in Gambian children (51).…”

“…A general impairment in monocyte phagocytosis may contribute to increased susceptibility to invasive bacterial infections, a known complication of malaria in children (67)(68)(69). Impairment in neutrophil killing of nontyphoidal Salmonella has been observed following uncomplicated falciparum malaria in African children (51), but this impairment is related to defects in oxidative killing due to malaria-induced changes in heme-oxygenase 1 expression during myeloid cell development and not to phagocytosis.…”

Impairment of neutrophil oxidative burst in children with sickle cell disease is associated with heme oxygenase-1

“…Neutrophil oxidative burst and degranulation assays were performed, as described previously 19 with the following antibodies: Brilliant Violet-421 conjugated anti-CD11b (Biolegend) and allophycocyanin conjugated anti-CD15 (eBioscience). Samples were analyzed using a BD LSRFortessa flow cytometer and FlowJo v. X.07 (Tree Star).…”

“…A similar defect in neutrophil oxidative burst activity, which correlated with the extent of hemolysis, was demonstrated in children with malaria. 19 The extent of hemolysis and HO-1 induction in SCD can be greater than that seen in malaria, 20 and so we hypothesized that hemolysis-related neutrophil dysfunction might occur in SCD. 18 If this is the case, it may provide an additional explanation for susceptibility to infection.…”

Parasite virulence, co-infections and cytokine balance in malaria

“…60,61 Human malaria can increase the susceptibility to concurrent bacteremia by inducing neutrophil dysfunction, with reduced chemotaxis and oxidative burst. 49,62 Induction of heme oxygenase-1 (HO-1)…”