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The risk of severe malaria from the zoonotic parasite Plasmodium knowlesi approximates that from P. falciparum. In severe falciparum malaria, neutrophil activation contributes to inflammatory pathogenesis, including acute lung injury. The role of neutrophil activation in the pathogenesis of severe knowlesi malaria has not been examined. We evaluated 213 patients with P. knowlesi mono-infection (138 non-severe, 75 severe) and 49 Plasmodium-negative controls from Malaysia. Markers of neutrophil activation (soluble neutrophil elastase [NE], citrullinated histone [CitH3] and circulating neutrophil extracellular traps [NETs]) were quantified in peripheral blood by microscopy and immunoassays. Findings were correlated with malaria severity, ALI clinical criteria, biomarkers of parasite biomass, haemolysis, and endothelial activation. Neutrophil activation increased with disease severity, with median levels higher in severe than non-severe malaria and controls for NE (380[IQR:210–930]ng/mL, 236[139–448]ng/mL, 218[134–307]ng/mL, respectively) and CitH3 (8.72[IQR:3.0–23.1]ng/mL, 4.29[1.46–9.49]ng/mL, 1.53[0.6–2.59]ng/mL, respectively)[all p<0.01]. NETs were higher in severe malaria compared to controls (126/μL[IQR:49–323] vs 51[20–75]/μL, p<0.001). In non-severe malaria, neutrophil activation fell significantly upon discharge from hospital (p<0.03). In severe disease, NETs, NE, and CitH3 were correlated with parasitaemia, cell-free haemoglobin and angiopoietin-2 (all Pearson's r>0.24, p<0.05). Plasma NE and angiopoietin-2 were higher in knowlesi patients with ALI than those without (p<0.008); neutrophilia was associated with an increased risk of ALI (aOR 3.27, p<0.01). In conclusion, neutrophil activation is increased in ALI and in proportion to disease severity in knowlesi malaria, is associated with endothelial activation, and may contribute to disease pathogenesis. Trials of adjunctive therapies to regulate neutrophil activation are warranted in severe knowlesi malaria. Author summary: The most common malaria in Malaysia is caused by animal-to-human transmission of Plasmodium knowlesi from its natural monkey hosts to humans via mosquito bites. As the human immune system responds to such infection, white blood cells such as neutrophils are recruited, activated and release products with pathogen-killing activity. There is increasing evidence that neutrophil products cause damage to the host and contribute to severe disease. While this has been studied in human-only malaria, the role of neutrophils in zoonotic P. knowlesi malaria is poorly understood. In this study, we examined three markers of neutrophil activation (neutrophil elastase, citrullinated histone H3 and neutrophil extracellular traps) in hospital patients with severe and non-severe knowlesi malaria from Sabah, East Malaysia. Compared to healthy controls, neutrophil activation was increased in patients with knowlesi malaria in proportion to disease severity. The increase in neutrophil activation was also linked to different types of severe malaria manifestations, especially acute lung injury. These findings have implications for development of new strategies to prevent host organ damage for better treatment of severe knowlesi malaria. [ABSTRACT FROM AUTHOR]

Background: Plasmodium knowlesi is a zoonotic parasite that causes malaria in humans. The pathogen has a natural host reservoir in certain macaque species and is transmitted to humans via mosquitoes of the Anopheles Leucosphyrus Group. The risk of human P. knowlesi infection varies across Southeast Asia and is dependent upon environmental factors. Understanding this geographic variation in risk is important both for enabling appropriate diagnosis and treatment of the disease and for improving the planning and evaluation of malaria elimination. However, the data available on P. knowlesi occurrence are biased towards regions with greater surveillance and sampling effort. Predicting the spatial variation in risk of P. knowlesi malaria requires methods that can both incorporate environmental risk factors and account for spatial bias in detection. Methods & results: We extend and apply an environmental niche modelling framework as implemented by a previous mapping study of P. knowlesi transmission risk which included data up to 2015. We reviewed the literature from October 2015 through to March 2020 and identified 264 new records of P. knowlesi, with a total of 524 occurrences included in the current study following consolidation with the 2015 study. The modelling framework used in the 2015 study was extended, with changes including the addition of new covariates to capture the effect of deforestation and urbanisation on P. knowlesi transmission. Discussion: Our map of P. knowlesi relative transmission suitability estimates that the risk posed by the pathogen is highest in Malaysia and Indonesia, with localised areas of high risk also predicted in the Greater Mekong Subregion, The Philippines and Northeast India. These results highlight areas of priority for P. knowlesi surveillance and prospective sampling to address the challenge the disease poses to malaria elimination planning. Author summary: Plasmodium knowlesi is a parasite that can cause malaria when it infects humans. Although most people do not experience severe illness from Plasmodium knowlesi infection, a small number will develop serious or even fatal disease. The parasite is found naturally in some monkeys throughout Southeast Asia, and spreads from these monkeys to humans through mosquitoes. Previous research predicted where the risk of being infected is highest according to what we know about the environment across Southeast Asia, such as if there are forests in an area or if the altitude is high. In this work, we extend this previous research with more up-to-date data on environmental conditions and infections to predict the risk of being infected with Plasmodium knowlesi. We show that the risk Plasmodium knowlesi poses to humans is high across much of Southeast Asia, and that the disease will continue to challenge national goals to eliminate malaria. [ABSTRACT FROM AUTHOR]