Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression.

Abstract

SummaryNitric oxide (NO)-related activity has been shown to be protective against Plasmodium fakiparum in vitro. It has been hypothesized, however, that excess NO production contributes to the pathogenesis of cerebral malaria. The purpose of this study was to compare markers of NO production [urinary and plasma nitrate + nitrite (NO~)], leukocyte-inducible nitric oxide synthase type 2 (NOS2), and plasma TNF-c~ and IL-10 levels with disease severity in 191 Tanzanian children with and without malaria. Urine NO• excretion and plasma NOx levels (corrected for renal impairment) were inversely related to disease severity, with levels highest in subclinical infection and lowest in fatal cerebral malaria. Results could not be explained by differences in dietary nitrate ingestion among the groups. Plasma levels of IL-10, a cytokine known to suppress NO synthesis, increased with disease severity. Leukocyte NOS2 antigen was detectable in all control children tested and in all those with subclinical infection, but was undetectable in all but one subject with cerebral malaria. This suppression of NO synthesis in cerebral malaria may contribute to pathogenesis. In contrast, high fasting NO x levels and leukocyte NOS2 in healthy controls and asymptomatic infection suggest that increased NO synthesis might protect against clinical disease. NO appears to have a protective rather than pathological role in African children with malaria.

Low levels of mammalian TGF-β1 are protective against malaria parasite infection, a paradox clarified in the mosquito host

“…Most studies to date have associated inducible NO production in the mammalian host with anti-parasitic effects (Rockett et al, 1991, Naotunne et al, 1993, Mellouk et al, 1994, Anstey et al, 1996, Pino et al, 2004, Sharma et al, 2004 as well as with increased inflammatory pathology to the host Cowden, 2003 andRiley et al, 2006). In contrast, two studies have concluded that higher levels of NO in humans (Hobbs et al, 2002) and in mice (Gramaglia et al, 2006) were associated with less severe malaria but no differences in parasitemia levels.…”

“…Nitric oxide has also been linked to the development of cerebral malaria, the most severe form of human infection, with most studies reporting a positive association between high NO levels and increased pathology in late stage disease (Clark and Cowden 2003). In contrast, Anstey et al, (1996) documented that high NO levels were associated with reduced malaria severity and low parasite density and Hobbs et al, (2002) showed that higher NO production was associated with less severe malaria but with no differences in parasitemia levels. As such, studies of NO levels in human malaria have revealed both protective and pathological effects.…”

Human genetic factors related to susceptibility to mild malaria in Gabon

“…38 However, increased expression of NOS2 in PBMC, and particularly in monocytes, 39 leading to increased NOS2-derived NO synthesis, is associated with protection against clinical disease. 40 It seems therefore too early to establish a definitive causal association between NOS2 polymorphisms and malaria susceptibility.…”

Malaria Parasites in the Asymptomatic: Looking for the Hay in the Haystack

“…Nitric oxide (NO), which has been shown to be produced at higher levels by mononuclear cells in asymptomatic children [96], can suppress the pathogenesis of severe malaria through induction of heme oxygenase-1 (HO-1), CO production, and inhibition of T cell activation [97]. However, conflicting results have questioned the role for NO in mediating tolerance [98].…”