Characterisation of parasite and host determinants of severe Plasmodium knowlesi malaria

Severe malaria is responsible for unacceptably high mortality and morbidity and is the focus of intensive research aimed to alleviate this health burden. Until recently four species of parasite were associated with malaria in humans only one of these, Plasmodium falciparum, was associated with severe and fatal disease. Research to discover the means by which falciparum parasites kill their host have been hampered by the lack of a representative animal model and a comparative disease in humans. In 2004 a new form of potentially severe malaria in man, caused by P. knowlesi parasites, was reported in Southeast Asia. The large and sustained focus of knowlesi malaria, normally found in monkeys, in the human populations suggests that the natural parasite host relationship is changing and that we should be prepared for more cases. In addition that knowlesi malaria can be fatal provides for the first time a comparative disease by which to measure the disease mechanisms in the much more common severe falciparum malaria. Much is known about severe falciparum malaria, however, extrapolation of this information to severe knowlesi malaria is not possible until severe knowlesi malaria is properly characterised. There are similarities, patients with severe and fatal knowlesi malaria have vital organ dysfunction and large numbers of parasites. However patients with severe knowlesi malaria do not have severe anaemia or obvious signs of cerebral malaria, a common presentation of severe falciaprum malaria. The aims of the study proposed here are to: properly characterise the severe from of knowlesi malaria and to provide a much needed clinical and laboratory case definition for severe knowlesi malaria; measure the pre-treatment host response in patients with and without high parasitaemia to identify immune markers of severe disease; and in the first instance identify parasite genetic markers associated with high parasitaemia. In this way we will accumulate information on severe knowlesi malaria with direct application to patient diagnosis. This information is particularly important in the event of a host switch from non-human to human for this potentially virulent parasite. Of equal importance is the indirect application of the results to the study of pathophysiology of severe falciparum malaria. The importance of this is far reaching because with time the relative impact of particular host and parasite markers of severe knowlesi malaria can be tested in vivo and specific targets for the prevention and control of severe malaria identified.

Knowlesi malaria in humans in Sarawak Malaysian Borneo causes a spectrum of disease including fatal infection. Knolwesi malaria is not restricted to Borneo and the disease in Sarawak is not in decline. Due to persistent human encroachment and destruction of the forest habitat of the natural primate hosts and vectors of Plasmodium knowlesi in Southeast Asia we may well be witnessing a host switch adaptation for this species. Ongoing research in Sarawak supports a largely zoonotic reservoir for knowlesi malaria because of vector restriction, although low-level human to human transmission can not be ruled out. The majority of patients present with parasitaemias less than 100,000/uL blood and respond well to treatment. A subset, not less than 2%, of all PCR confirmed knowlesi cases, present with hyperparasitaemia and severe and fatal malaria. Much is known about severe falciparum malaria however, extrapolation of information to severe knowlesi malaria is not possible until severe knowlesi malaria is properly characterised. There are similarities, patients with severe and fatal knowlesi malaria have hepatorenal dysfunction, acute respiratory distress syndrome and hyperparasitaemia. However, to date, we have not observed severe anaemia or obvious signs of cerebral malaria in severe knowlesi patients. At the parasite level P. knowlesi is phylogenetically distinct from P. falciparum, P. knowlesi does not appear to cytoadhere and, unique to the Plasmodium species of human and non-human primates, has a 24 hour asexual cycle. The aims of the study proposed here are to: properly characterise the severe from of knowlesi malaria to provide a much needed clinical and laboratory case definition for severe knowlesi malaria; measure the pre-treatment cytokine profiles of patients with and without hyperparasitaemia to identify immune markers of severe disease; identify parasite invasion gene polymorphisms associated with hyperparasitaemia in the first instance. In this way we will accumulate information on severe knowlesi malaria with direct application to patient diagnosis, this information is particularly important in the event of a host switch from non-human to human for this potentially virulent parasite. Of equal importance is the application of our findings to the pathophysiology of severe malaria in humans, to compare and contrast with severe falciaprum malaria. The potential of this is far reaching because the relative impact of particular host and parasite markers of severe knowlesi malaria can be tested in representative animal models and used for the rational development of specific tools to prevent and control severe malaria.