Myeloperoxidase Attenuates Pathogen Clearance during Plasmodium yoelii Nonlethal Infection

Abstract

Myeloperoxidase (MPO), a leukocyte-derived enzyme mainly secreted by activated neutrophils, is known to be involved in the immune response during bacterial and fungal infection and inflammatory diseases. Nevertheless, the role of MPO in a parasitic disease like malaria is unknown. We hypothesized that MPO contributes to parasite clearance. To address this hypothesis, we used Plasmodium yoelii nonlethal infection in wild-type and MPO-deficient mice as a murine malaria model. We detected high MPO plasma levels in wild-type mice with Plasmodium yoelii infection. Unexpectedly, infected MPO-deficient mice did not show increased parasite loads but were able to clear the infection more rapidly than wild-type mice. Additionally, the presence of neutrophils at the onset of infection seemed not to be essential for the control of the parasitemia. The effect of decreased parasite levels in MPO-deficient mice was absent from animals lacking mature T and B cells, indicating that this effect is most likely dependent on adaptive immune response mechanisms. Indeed, we observed increased gamma interferon and tumor necrosis factor alpha production by T cells in infected MPO-deficient mice. Together, these results suggest that MPO modulates the adaptive immune response during malaria infection, leading to an attenuated parasite clearance.KEYWORDS peroxidase, Plasmodium, neutrophils, malaria, immunology, cytokines, animal disease model, knockout mice, T-lymphocytes, T-cell immunity, innate immunity P lasmodium falciparum infection is still one of the major tropical infectious diseases. The control of the symptomatic blood-stage infection by the host requires the innate and the adaptive immune systems (1, 2). Using mouse models, it was shown that macrophages (3), CD4 ϩ T cells (4-6), and B cells (7,8) are essential for effective parasite clearance. However, an effective immune activation and regulation is necessary for rapid parasite control and for the prevention of host pathology (5, 9). Myeloperoxidase (MPO), a heme protein secreted mainly by neutrophils, could be an important mediator in both antiparasitic defense and host pathology. Being 5% of the total protein, MPO is the most abundant protein in neutrophils (10). During infections and inflammatory diseases, MPO is increasingly released from azurophilic granules of activated neutrophils into the phagocytic vacuoles and extracellular space (11). MPO has also been found in monocytes, where it represents about 1% of the total protein (12). Monocytes later lose their ability to secret MPO during their differentiation toward macrophages. Macrophages, however, are able to take up MPO by neutrophils or MPO alone (13). The most prominent feature of MPO is its ability to catalyze the oxidation of halogenides and various substrates together with its cofactor, hydrogen peroxide (14, 15). Besides

Circulating Neutrophil Extracellular Traps and Neutrophil Activation Are Increased in Proportion to Disease Severity in Human Malaria

“…Neutrophil elastase and PR3 were increased in malaria from each Plasmodium species and across disease severity, and they are known mediators of acute lung injury in murine malaria models [19] and vascular damage in vitro [33]. Myeloperoxidase, which was elevated only in severe falciparum malaria, has been linked to impaired parasite clearance [34]. Uncontrolled malarial neutrophil activation impairs function [35–37], reduces chemotaxis [9], compromises endothelial integrity [13, 38, 39], and has been associated with cerebral vasculopathy in children with cerebral malaria [14] and liver damage in vivax malaria [15].…”

Myeloperoxidase and Other Markers of Neutrophil Activation Associate With Malaria and Malaria/HIV Coinfection in the Human Placenta

“…Placental levels of MPO, MMP9, and PRTN3 all positively correlate with placental parasitemia as well as placental hemozoin bearing WBCs, suggesting that production is enhanced by chronic infection. Since MPO attenuates pathogen clearance during P. yoelii nonlethal infection ( 85 ), it is tempting to speculate that this enzyme may inhibit parasite clearance in PM as well. In an initial pilot study, we found placental blood MPO levels to be increased significantly with chronic, inflammatory PM in primigravidae.…”

Soluble markers of neutrophil, T-cell and monocyte activation are associated with disease severity and parasitemia in falciparum malaria

“…MPO and neutrophils have been implicated in the pathogenesis of falciparum malaria. A recent study of Plasmodium yoelii non-lethal infection in wild-type and MPO deficient mice as a murine malaria model, suggested that MPO could contribute to a protective anti-parasite response [24]. However, very few studies have analyzed MPO levels in human falciparum malaria.…”