Chitinase 3-like 1 is induced by Plasmodium falciparum malaria and predicts outcome of cerebral malaria and severe malarial anaemia in a case–control study of African children

BACKGROUND: Severe and fatal malaria are associated with dysregulated host inflammatory responses to infection. Chitinase 3-like 1 (CHI3L1) is a secreted glycoprotein implicated in regulating immune responses. Expression and function of CHI3L1 in malaria infection were investigated. METHODS: Plasma levels of CHI3L1 were quantified in a case–control study of Ugandan children presenting with Plasmodium falciparum malaria. CHI3L1 levels were compared in children with uncomplicated malaria (UM; n = 53), severe malarial anaemia (SMA; n = 59) and cerebral malaria (CM; n = 44) using the Kruskall Wallis-test, and evaluated for utility in predicting fatal (n = 23) versus non-fatal (n = 80) outcomes in severe disease using the Mann Whitney U test, receiver operating characteristic curves, and combinatorial analysis. Co-culture of P. falciparum with human peripheral blood mononuclear cells and the Plasmodium berghei ANKA experimental model of cerebral malaria were used to examine the role of CHI3L1 in severe malaria. RESULTS: In children presenting with falciparum malaria, CHI3L1 levels were increased in SMA and CM versus UM (p < 0.001). Among severe malaria cases, CHI3L1 levels at presentation predicted subsequent death (area under receiver operating characteristic curve 0.84 [95% CI 0.76-0.92]) and in combination with other host biomarkers, predicted mortality with high sensitivity (100% [85.7-100]) and specificity (81.3% [71.3-88.3]). Plasmodium falciparum stimulated CHI3L1 production by human peripheral blood mononuclear cells in vitro. CHI3L1 was increased in plasma and brain tissue in experimental cerebral malaria, but targeted Chi3l1 deletion did not alter cytokine production or survival in this model. CONCLUSIONS: These data suggest that plasma CHI3L1 measured at presentation correlates with malaria severity and predicts outcome in paediatric SMA and CM, but do not support a causal role for CHI3L1 in cerebral malaria pathobiology in the model tested.