Human neutrophil lipocalin: a specific marker for neutrophil activation in severe Plasmodium falciparum malaria

Mohammed, Abdelrahim O; ElGhazali, Gehad; Mohammed, Hassabo B.; Elbashir, Mustafa I.; Xu, Shaoyuan; Berzins, Klavs; Venge, Per

doi:10.1016/s0001-706x(03)00116-5

Cited by 25 publications

(27 citation statements)

References 19 publications

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“…It is upregulated and secreted by immune cells after Toll-like receptor recognition of bacteria, with a bacteriostatic effect (12). The association of this transcript with severe malaria is consistent with a study in the Sudan that found plasma concentrations of HNL to be significantly elevated in patients with severe malaria compared to levels in patients with mild malaria (21). These results may lead to the identification of peripheral blood-based biomarkers of severe disease.…”

Section: Discussionsupporting

confidence: 85%

Mild Plasmodium falciparum Malaria following an Episode of Severe Malaria Is Associated with Induction of the Interferon Pathway in Malawian Children

et al. 2012

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Infection with Plasmodium falciparum can lead to a range of severe to minimal symptoms, occasionally resulting in death in young children or nonimmune adults. In areas of high transmission, older children and adults generally suffer only mild or asymptomatic malaria infections and rarely develop severe disease. The immune features underlying this apparent immunity to severe disease remain elusive. To gain insight into host responses associated with severe and mild malaria, we conducted a longitudinal study of five children who first presented with severe malaria and, 1 month later, with mild malaria. Employing peripheral blood whole-genome profiling, we identified 68 genes that were associated with mild malaria compared to their expression in the severe malaria episode (paired Students t test, P < 0.05). These genes reflect the interferon (IFN) pathway and T cell biology and include IFN-induced protein transcripts 1 to 3, oligoadenylate synthetases 1 and 3, and the T cell markers cathepsin W and perforin. Gene set enrichment analysis identified Gene Ontology (GO) pathways associated with mild malaria to include the type I interferon-mediated signaling pathway (GO 0060337), T cell activation (GO 0042110), and other GO pathways representing many aspects of immune activation. In contrast, only six genes were associated with severe malaria, including thymidine kinase 1, which was recently found to be a biomarker of cerebral malaria susceptibility in the murine model, and carbonic anhydrase, reflecting the blood's abnormal acid base environment during severe disease. These data may provide potential insights to inform pathogenesis models and the development of therapeutics to reduce severe disease outcomes due to P. falciparum infection.

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Section: Discussionsupporting

confidence: 85%

Mild Plasmodium falciparum Malaria following an Episode of Severe Malaria Is Associated with Induction of the Interferon Pathway in Malawian Children

et al. 2012

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“…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). Correspondingly, in the P. yoelii 17NL model applied here, MPO plasma levels were also significantly increased during infection.…”

Section: Discussionsupporting

confidence: 80%

“…The high plasma levels of MPO, which result mainly from MPO secretion by neutrophils (10), may play an important role in immune regulation. In human malaria, increased neutrophil counts (30)(31)(32) as well as activation (27) during the acute phase of infection have been observed and, arguably, contribute to increased MPO plasma levels. Neutrophils are the first line of defense of the innate immune system against microbes (33).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, leukocyte-derived ROS (25) may contribute to parasite killing. Moreover, patients with P. falciparum malaria have increased MPO plasma levels (26)(27)(28), which are higher than levels observed in patients with cardiovascular disease or sepsis (28,29), for which MPO has been intensively studied in recent years. Based on these findings, we hypothesized that increased MPO production would lead to increased ROS levels, which would contribute to accelerated Plasmodium parasite clearance.…”

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confidence: 99%

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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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“…20 Interestingly, neutropenia is commonly observed during malaria and is more common in infection with P vivax than P falciparum, 29,30 and there is clinical and experimental evidence that neutrophils contribute to the adverse outcomes after malarial infection. [31][32][33][34][35] Furthermore, a genomewide analysis of the host response to malaria also implicates neutrophilmediated pathways in underlying malarial pathogenesis. 36 Hence, one possibility is that the protection against neutrophil-mediated inflammation during infection by a lethal ancestral form of malaria may have also promoted the selection of the Duffy-null trait.…”

Section: Discussionmentioning

confidence: 99%

The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry

Kulkarni

Marconi

et al. 2009

Blood

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Persons of African ancestry, on average, have lower white blood cell (WBC) counts than those of European descent (ethnic leukopenia), but whether this impacts negatively on HIV-1 disease course remains unknown. Here, in a large natural history cohort of HIV-infected subjects, we show that, although leukopenia (< 4000 WBC/mm 3 during infection) was associated with an accelerated HIV disease course, this effect was more prominent in leukopenic subjects of European than African ancestry. The Africanspecific ؊46C/C genotype of Duffy Antigen Receptor for Chemokines (DARC) confers the malaria-resisting, Duffy-null phenotype, and we found that the recently described association of this genotype with ethnic leukopenia extends to HIV-infected African Americans (AAs). The association of Duffy-null status with HIV disease course differed according to WBC but not CD4 ؉ T-cell counts, such that leukopenic but not nonleukopenic HIV ؉ AAs with DARC ؊46C/C had a survival advantage compared with all Duffypositive subjects. This survival advantage became increasingly pronounced in those with progressively lower WBC counts. These data highlight that the interaction between DARC genotype and the cellular milieu defined by WBC counts may influence HIV disease course, and this may provide a partial explanation of why ethnic leukopenia remains benign in HIVinfected AAs, despite immunodeficiency.

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Human neutrophil lipocalin: a specific marker for neutrophil activation in severe Plasmodium falciparum malaria

Cited by 25 publications

References 19 publications

Mild Plasmodium falciparum Malaria following an Episode of Severe Malaria Is Associated with Induction of the Interferon Pathway in Malawian Children

Mild Plasmodium falciparum Malaria following an Episode of Severe Malaria Is Associated with Induction of the Interferon Pathway in Malawian Children

Myeloperoxidase Attenuates Pathogen Clearance during Plasmodium yoelii Nonlethal Infection

The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry

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