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.

Laura K Erdman,Wayne Conrad Liles,Kevin C Kain,Carlene Petes,Ziyue Lu,Charles Musoke,Aggrey Dhabangi,Christine M Cserti-Gazdewich,Chun Geun Lee,Jack A Elias

doi:10.1186/1475-2875-13-279

Abstract

BackgroundSevere 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.MethodsPlasma 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.ResultsIn 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.ConclusionsThese 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.

Highlights

Severe and fatal malaria are associated with dysregulated host inflammatory responses to infection
Plasma Chitinase 3-like 1 (CHI3L1) is elevated in children with severe versus uncomplicated malaria To determine whether CHI3L1 correlates with disease severity in human malaria, plasma levels of CHI3L1 were compared among groups of Ugandan children presenting to hospital with P. falciparum infection: uncomplicated malaria (UM; n = 53), cerebral malaria (CM) (n = 44), and severe malarial anaemia (SMA) (n = 59) [29]
At time of presentation to hospital, plasma CHI3L1 was significantly higher in children with CM and SMA compared to uncomplicated malaria (p < 0.001; Figure 1A), indicating that CHI3L1 levels reflect disease severity in malaria infection

Summary

Introduction

Severe and fatal malaria are associated with dysregulated host inflammatory responses to infection. While the sequestration of parasitized erythrocytes is central to severe malaria pathogenesis, disease progression is influenced by host responses to infection, including inflammation. Children with CM have elevated serum/plasma TH1 cytokines compared to uncomplicated cases [4,5], and increased immune cell accumulation and cytokine transcription in the brain [6,7]. These local and systemic responses are thought to contribute to CM by activating brain endothelium, leading to upregulated cell adhesion molecules, parasite sequestration, and microvascular obstruction [8]. Pattern recognition receptors (e.g., Toll-like receptors (TLRs) [16]) and cytokines (e.g., IFN-γ [17]) have been implicated in these inflammatory responses, but the pathways remain ill-defined

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