Human neutrophil lipocalin: a specific marker for neutrophil activation in severe Plasmodium falciparum malaria
Introduction
Plasmodium falciparum malaria remains one of the leading causes of morbidity and mortality in the tropical and subtropical regions of the world. There are an estimated 300–500 million malaria infections each year and in Africa alone, more than one million children die from the disease. Severe and complicated malaria, including cerebral malaria and severe anemia, are the major causes of death (Marsh et al., 1995).
The patho-physiology of severe malaria is not yet fully understood. The hallmark of the pathology in human cerebral malaria is the sequestration of parasitized erythrocytes in cerebral blood vessels (Turner, 1997, Warrell, 1997). The adhesion of the parasitized erythrocytes to endothelial cells, their binding to non-infected erythrocytes (rosetting) and their agglutination (auto-agglutination) are mainly mediated by P. falciparum erythrocyte membrane protein-1 (PfEMP-1) expressed on the surface of the infected erythrocytes (Wahlgren et al., 1999). Excessive production of tumor necrosis factor-alpha (TNF-α) by monocytes/macrophages plays a key role in the pathogenesis of both human and experimental cerebral malaria (Kwiatkowski and Perlmann, 1999). In the P. berghei mouse model for cerebral malaria, although neutrophils are not sequestered in the brain, depletion of neutrophils decreased the expression of TNF-α, IFN-γ and IL-12 in the brain. Therefore, it was suggested that neutrophils may play a role in the pathogenesis of experimental cerebral malaria by enhancing pro-inflammatory cytokines in the brain (Chen et al., 2000).
Involvement of neutrophils in parasite neutralizing immune responses is indicated from the observation of phagocytosis of P. falciparum merozoites by neutrophils in infected individuals (Kumaratilake et al., 1992). Studies have shown that the process of merozoite phagocytosis requires the presence of cytokines (e.g. TNF-α) and opsonizing antibodies (Kumaratilake et al., 1990, Kumaratilake et al., 1996). Neutrophils might be stimulated either directly by the parasites or by cytokines or other mediators produced during the malaria attack. Ligation of TNF-α to its receptors on neutrophils primes the cells for increased release of granule secretory products upon activation, including lysosomal enzymes/proteins (Klebanoff et al., 1986, Shalaby et al., 1987).
A role for neutrophil activation in the patho-physiology of severe malaria was indicated in our previous report by the presence of elevated levels of myeloperoxidase (MPO) and lysozyme, both acting as markers for neutrophil activation (Mohamed et al., 1996). However, both MPO and lysozyme are produced also by monocytes/macrophages. In this report we confirm our previous findings on neutrophil activation in severe malaria patients by measuring human neutrophil lipocalin (HNL) as a specific marker for neutrophil activation (Xu et al., 1994a).
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Study area and subjects
The study was conducted at the Gedarif Hospital in the eastern part of Sudan, 380 km from the capital (Khartoum). Malaria in the area is markedly seasonal, and follows the annual June–September rains, with a peak of transmission during October and November. P. falciparum is the main parasite species, accounting for more than 96% of infections, while 3% are attributed to P. vivax.
An out-patient clinic was established in the hospital during the season of 1996 to serve patients suspected of having
Results
In this study, the plasma levels of HNL, MPO and lysozyme were evaluated for their clinical significance in patients with severe malaria (group III) as compared with those with mild malaria (group II) or with negative blood film for malaria parasite (group I). The mean age of the 65 subjects enrolled in the study was 24 years (range 7–80) and there was no significant difference between the three study groups.
Table 1 shows the mean plasma concentrations of HNL, MPO and lysozyme. The severe
Discussion
The present study confirms and extends previous reports on the activation of neutrophils as a clinical parameter in severe malaria. We previously indicated neutrophil activation in severe malaria by the elevated levels of MPO and lysozyme in this patient group as compared with patients with mild malaria (Mohamed et al., 1996). However, as both MPO and lysozyme are also present in monocytes/macrophages, these cells may have contributed to the elevated levels of these proteins observed in plasma
Acknowledgements
This study was supported by grants from the Swedish Medical Research Council, the Medical Faculty of Uppsala University, Sweden and Department of Biochemistry, Faculty of Medicine, University of Khartoum, Sudan. Authors Abdelrahim O. Mohammed and Gehad Elghazali contributed equally to this work.
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