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Crosstalk Between Nitric and Carbon Monoxide in Suppressing the Pathogenesis of Cerebral Malaria

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Gases team up as defence against cerebral malaria

An EU-funded project completed research into a potential therapy targeting cerebral malaria.

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Malaria can lead to the development of cerebral malaria, a severe type of malaria that affects the brain and central nervous system. If not treated immediately this rapidly developing brain disease can prove fatal in 24 to 72 hours. Cerebral malaria occurs when infected and non-infected red blood cells collect in the tiny capillaries that supply blood to the brain. This can cause damage to these blood vessels and disrupt the supply of blood, oxygen and nutrients to the brain. The 'Crosstalk between nitric and carbon monoxide in suppressing the pathogenesis of cerebral Malaria' (Gasmalaria) project studied the effects of gasotransmitters, gas molecules produced in the body, on the pathogenesis of cerebral malaria. In particular, the functional interaction of nitric oxide (NO) and carbon monoxide (CO) were investigated as NO can induce the expression of haeme oxygenase-1 (HO-1), an enzyme that produces CO through haeme catabolism. This has been shown to suppress cerebral malaria in mice. Researchers demonstrated that both CO and NO can provide host tolerance against Plasmodium infection. Malaria is caused by the Plasmodium parasite that is transmitted by the female Anopheles mosquito. This means that whilst not reducing the parasite burden in the infected individual, the gasotransmitters confer a survival advantage. The ability of NO to act as a protective agent depends on the production of HO-1. This haeme enzyme is produced after activation of the transcription factor nuclear factor erythroid 2-related factor (Nrf2). Incidentally, the same protective mechanism is present in sickle cell anaemia. Here the production of HO-1 is strongly induced by the presence of sickle haemoglobin to confer natural protection against malaria as a result of evolution in areas affected by the parasite. Gasmalaria uncovered details of how the host can become tolerant to the parasite and offered an exciting new avenue in the wake of emerging gene therapies based on naturally occurring genes.

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