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: 4.92). 10/2012; 189(11). DOI: 10.4049/jimmunol.1201028
Source: PubMed


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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Available from: Aubrey J Cunnington,
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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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    ABSTRACT: Increased susceptibility to co-infection with enteric Gram-negative bacteria, particularly non-typhoidal Salmonella, is reported in malaria and Oroya fever (Bartonella bacilliformis infection), and can lead to increased mortality. Accumulating epidemiological evidence indicates a causal association with risk of bacterial co-infection, rather than just co-incidence of common risk factors. Both malaria and Oroya fever are characterized by hemolysis, and observations in humans and animal models suggest that hemolysis causes the susceptibility to bacterial co-infection. Evidence from animal models implicates hemolysis in the impairment of a variety of host defense mechanisms, including macrophage dysfunction, neutrophil dysfunction, and impairment of adaptive immune responses. One mechanism supported by evidence from animal models and human data, is the induction of heme oxygenase-1 in bone marrow, which impairs the ability of developing neutrophils to mount a competent oxidative burst. As a result, dysfunctional neutrophils become a new niche for replication of intracellular bacteria. Here we critically appraise and summarize the key evidence for mechanisms which may contribute to these very specific combinations of co-infections, and propose interventions to ameliorate this risk.
    Frontiers in Microbiology 06/2015; 6:666. DOI:10.3389/fmicb.2015.00666 · 3.99 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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    ABSTRACT: Heme oxygenase-1 (HO-1) is a highly inducible and ubiquitous cellular enzyme that sub-serves cytoprotective responses to toxic insults, including inflammation and oxidative stress. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, brain HO-1 expression is increased, presumably reflecting an endogenous neuroprotective response against ongoing cellular injury. In contrast,we have found in human immunodeficiency virus (HIV) infection of the brain, which is also associated with inflammation, oxidative stress, and neurodegeneration, HO-1 expression is decreased, likely reflecting a unique role for HO-1 deficiency in neurodegeneration pathways activated by HIV infection. We have also shown that HO-1 expression is markedly suppressed by HIV replication in cultured macrophages, which represent the primary cellular reservoir for HIV in the brain. HO-1 deficiency is associated with release of neurotoxic levels of glutamate from both HIV-infected and immune-activated macrophages; this glutamate mediated neurotoxicity is suppressed by pharmacological induction of HO-1 expression in the macrophages.Thus, HO-1 induction could be a therapeutic strategy for neuroprotection against HIV infection and other neuroinflammatory brain diseases. Here, we review various stimuli and signaling pathways regulating HO-1 expression in macrophages, which could promote neuronal survival through HO-1-modulation ofendogenous antioxidant and immune modulatory pathways, thus limiting the oxidative stress that can promote HIV disease progression in the CNS. The use of pharmacological inducers of endogenous HO-1 expression as potential adjunctive neuroprotective therapeutics in HIV infection is also discussed.
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    • "On the other hand, Hp2-2 has been proposed to have a protective function against malaria [23, 24]. A recent study demonstrates a link between hemolysis-induced activation of the HO-1 and neutrophil dysfunction which may be affected by the Hp concentration and phenotype [25]. However, it should be noted that other malaria studies have not confirmed significant association of Hp genotype on disease outcome [26–28]. "
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    ABSTRACT: The haptoglobin- (Hp-) CD163-heme oxygenase-1 (HO-1) pathway is an efficient captor-receptor-enzyme system to circumvent the hemoglobin (Hb)/heme-induced toxicity during physiological and pathological hemolyses. In this pathway, Hb tightly binds to Hp leading to CD163-mediated uptake of the complex in macrophages followed by lysosomal Hp-Hb breakdown and HO-1-catalyzed conversion of heme into the metabolites carbon monoxide (CO), biliverdin, and iron. The plasma concentration of Hp is a limiting factor as evident during accelerated hemolysis, where the Hp depletion may cause serious Hb-induced toxicity and put pressure on backup protecting systems such as the hemopexin-CD91-HO pathway. The Hp-CD163-HO-1 pathway proteins are regulated by the acute phase mediator interleukin-6 (IL-6), but other regulatory factors indicate that this upregulation is a counteracting anti-inflammatory response during inflammation. The heme metabolites including bilirubin converted from biliverdin have overall an anti-inflammatory effect and thus reinforce the anti-inflammatory efficacy of the Hp-CD163-HO-1 pathway. Future studies of animal models of inflammation should further define the importance of the pathway in the anti-inflammatory response.
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