Myeloperoxidase Selectively Binds and Selectively Kills Microbes

ABSTRACTMembers of the heme peroxidase family play an important role in host defense. Myeloperoxidase (MPO) is expressed in phagocytes and is the only animal heme peroxidase previously reported to be capable of using chloride ion as a substrate to form the highly microbicidal species hypochlorous acid (HOCl) at neutral pH. Despite the potent bacterial killing activity of HOCl, individuals who fail to express MPO typically show only a modest increase in some fungal infections. This may point to the existence of redundant host defense mechanisms. Vascular peroxidase 1 (VPO1) is newly discovered member of the heme peroxidase family. VPO1 is expressed in cells of the cardiovascular system and is secreted into the bloodstream. In the present study, we investigate whether VPO1 is capable of generating HOCl and its role in host defense. Like MPO, VPO1 in the presence of H2O2and chloride generates HOCl. VPO1-dependent HOCl generation was demonstrated by chlorination of taurine and tyrosine using mass spectrometry. In addition, the VPO1/H2O2/Cl−system can cause the chlorination of monochlorodimedone and the oxidation of 5-thio-2-nitrobenzoic acid. Purified VPO1 and VPO1 in plasma mediate bacterial killing that is dependent on chloride and H2O2; killing is inhibited by peroxidase inhibitors and by the H2O2scavenger catalase. In the presence of erythrocytes, bacterial killing by VPO1 is slightly reduced. Thus, VPO1, in addition to MPO, is the second member of the heme peroxidase family capable of generating HOCl under physiological conditions. VPO1 is likely to participate in host defense, with bactericidal activity mediated through the generation of HOCl.

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“…RBCs displayed only a slight inhibition of VPO1-and MPO-mediated E. coli killing (Fig. 5Eb), which is consistent with a previous report (1).…”

Section: Vpo1supporting

confidence: 81%

“…It was reported that the selective binding of MPO to bacteria benefited the bacterial killing and decreased damage of RBCs (1). Although there is no predicted structure motif in MPO binding to bacteria, there may be electrostatic binding.…”

Section: Discussionmentioning

confidence: 99%

Microbicidal Activity of Vascular Peroxidase 1 in Human Plasma via Generation of Hypochlorous Acid

Cao

Moore

et al. 2012

Infect Immun

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“…To our knowledge, this has not been described before. This finding was surprising, because we anticipated from existing evidence in bacterial (20) and fungal (16) infections that high MPO levels would contribute to parasite elimination. As mentioned before, high MPO plasma levels had been shown in patients with P. falciparum infection (26)(27)(28).…”

Section: Discussioncontrasting

confidence: 40%

“…NETs are extracellular structures of chromatin and antimicrobial proteins that are released from activated neutrophils and can bind to the pathogen (17). These antimicrobial features enable MPO to participate directly in the defense of fungal (16,18) and various bacterial infections (17,19,20). In addition, MPO further activates neutrophils (21) and promotes their recruitment (22), leading to an enhanced proinflammatory immune response.…”

mentioning

confidence: 99%

Myeloperoxidase Attenuates Pathogen Clearance during Plasmodium yoelii Nonlethal Infection

et al. 2017

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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

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“…These 29 proteins ( Figure 3B, Table 1) included archetypal antimicrobial proteins and peptides and fell into two categories: those proteins with known bacteriostatic (such as mucin-1, fibronectin, and CD14) or bactericidal (e.g., lysozyme C, calprotectin [S100A8/A9], and dermcidin) roles and those proteins that function as microbial receptors or bind to bacterial surface molecules. [28][29][30][31][32][33] Importantly, 28 of 29 immune proteins have known expression in kidney (Table 1). We confirmed the presence and exosomal residency of a representative group of these innate immune exosomal proteins, including lysozyme C, dermcidin, mucin-1, calprotectin, and myeloperoxidase, by Western blot and immunogold EM ( Figure 3C, Supplemental Figure 9).…”

Section: Resultsmentioning

confidence: 99%

Human Urinary Exosomes as Innate Immune Effectors

Hiemstra¹,

Charles

Gracia

et al. 2014

Journal of the American Society of Nephrology

141

121

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Exosomes are small extracellular vesicles, approximately 50 nm in diameter, derived from the endocytic pathway and released by a variety of cell types. Recent data indicate a spectrum of exosomal functions, including RNA transfer, antigen presentation, modulation of apoptosis, and shedding of obsolete protein.Exosomes derived from all nephron segments are also present in human urine, where their function is unknown. Although one report suggested in vitro uptake of exosomes by renal cortical collecting duct cells, most studies of human urinary exosomes have focused on biomarker discovery rather than exosome function. Here, we report results from in-depth proteomic analyses and EM showing that normal human urinary exosomes are significantly enriched for innate immune proteins that include antimicrobial proteins and peptides and bacterial and viral receptors. Urinary exosomes, but not the prevalent soluble urinary protein uromodulin (Tamm-Horsfall protein), potently inhibited growth of pathogenic and commensal Escherichia coli and induced bacterial lysis. Bacterial killing depended on exosome structural integrity and occurred optimally at the acidic pH typical of urine from omnivorous humans. Thus, exosomes are innate immune effectors that contribute to host defense within the urinary tract.

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Myeloperoxidase Selectively Binds and Selectively Kills Microbes

Cited by 50 publications

References 31 publications

Microbicidal Activity of Vascular Peroxidase 1 in Human Plasma via Generation of Hypochlorous Acid

Microbicidal Activity of Vascular Peroxidase 1 in Human Plasma via Generation of Hypochlorous Acid

Myeloperoxidase Attenuates Pathogen Clearance during Plasmodium yoelii Nonlethal Infection

Human Urinary Exosomes as Innate Immune Effectors

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