Sensitivity of malaria parasites to nitric oxide at low oxygen tensions

Taylor‐Robinson, Andrew W.; Looker, Martin

doi:10.1016/s0140-6736(05)77685-6

Cited by 35 publications

(13 citation statements)

References 5 publications

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“…However, larger post mortem studies of human falciparum malaria have failed to demonstrate massive adherence of monocytes or macrophages, which would explain drastically lower peripheral monocyte counts in patients with severe and complicated disease than in patients with uncomplicated disease (25,27). Our findings are in agreement with previous findings from both human and animal studies which favor the protective role of NO in falciparum malaria (4,21,22,26,(34)(35)(36)(37).…”

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confidence: 93%

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High Levels of Inducible Nitric Oxide Synthase mRNA Are Associated with Increased Monocyte Counts in Blood and Have a Beneficial Role inPlasmodium falciparumMalaria

2000

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To date, there have been conflicting reports concerning the clinical significance of nitric oxide (NO) in Plasmodium falciparum malaria. Some authors have proposed that NO contributes to the development of severe and complicated malaria, while others have argued that NO has a protective role. To investigate these apparently contradictory reports, reverse transcription-coupled PCR was used to study inducible NO synthase (iNOS) in whole-blood RNA samples from patients with severe and complicated malaria or uncomplicated malaria and from healthy donors. This work produced three principal findings. First, samples of patients with severe and complicated malaria were variably positive, with weak to moderate intensity. Markedly higher iNOS RNA levels were observed in samples of patients with uncomplicated malaria than in patients with severe and complicated malaria. Samples of healthy donors were uniformly negative. Second, since we initially demonstrated iNOS expression in whole-blood RNA samples, we extended our investigations to individual blood cells such as monocytes, lymphocytes, neutrophils, and platelets to identify the cellular source of iNOS. We found that iNOS was expressed predominantly in monocytes. Third, retrospective statistical analysis of monocyte counts clearly demonstrated that patients with uncomplicated malaria had higher monocyte counts at the time of presentation than patients with severe and complicated malaria. Taken together, our findings give room to the interpretation that NO may have a beneficial rather than a deleterious role in falciparum malaria.

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confidence: 93%

“…Some authors have associated NO with severe and complicated malaria, particularly cerebral malaria (1,3,6,9,10,12,13,29), whereas other authors have argued that NO has a protective role (2,4,21,22,26,(34)(35)(36)(37)). An interesting contradiction concerning the role of NO in malaria emerged from two recent studies.…”

mentioning

confidence: 99%

High Levels of Inducible Nitric Oxide Synthase mRNA Are Associated with Increased Monocyte Counts in Blood and Have a Beneficial Role inPlasmodium falciparumMalaria

2000

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“…The lower the oxygen tension, the greater the efficacy of NO against P. falciparum in vitro, suggesting that superoxides are scavenging NO (39). In addition, the lack of exacerbation of P. chabaudi malaria in the absence of NO does not directly address whether NO can be induced to function in killing malarial parasites.…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Is Neither Necessary Nor Sufficient for Resolution ofPlasmodium chabaudiMalaria in Mice

Heyde

Zhang

et al. 2000

The Journal of Immunology

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Malaria is a life-threatening re-emerging disease, yet it is still not clear how bloodstage malarial parasites are killed. Nitric oxide (NO), which has potent anti-microbial activity, may represent an important killing mechanism. The production of NO during descending Plasmodium chabaudi parasitemia, a period when parasites are killed by the immune response, supports this concept. However, NOS20/0 and NOS30/0 mice as well as mice treated with NO synthase 2 (NOS2) inhibitors do not develop exacerbated malaria, indicating that NO production is not necessary for the suppression of P. chabaudi parasitemia. It is possible due to the plasticity in the immune response during malaria that Ab-mediated immunity is enhanced in the absence of NO, thereby explaining the lack of exacerbated malaria in NOS-deficient mice even though NO may function in protection. However, NOS2- and B cell-deficient mice, which cannot use Ab-mediated immunity, suppress their parasitemia with a similar time course as B cell-deficient controls. C57BL/6 mice treated with Propionibacterium acnes to elicit high levels of macrophage-derived NO have a similar time course of P. chabaudi parasitemia as P. acnes-treated NOS20/0 mice, which do not produce NO; this indicates that NO is not sufficient for parasite killing. Collectively, these results indicate that NO is not necessary or sufficient to resolve P. chabaudi malaria.

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“…NO donors in vitro have dose-dependent antiplasmodial activity, with cytostatic effects occurring at low concentrations and enhanced cytotoxicity at high concentrations (Taylor-Robinson, 1997a). NO-related cytotoxicity increases with decreasing oxygen tension (Taylor-Robinson and Looker, 1998). Later parasite stages, i.e., trophozoites and schizonts, are more susceptible than the earlier ring stages to NO donors (Taylor-Robinson, 1997a).…”

Section: In Vitro Studiesmentioning

confidence: 99%