Abstract
BackgroundPlasmodium falciparum malaria in India is characterized by high rates of severe disease, with multiple organ dysfunction (MOD)—mainly associated with acute renal failure (ARF)—and increased mortality. The objective of this study is to identify cytokine signatures differentiating severe malaria patients with MOD, cerebral malaria (CM), and cerebral malaria with MOD (CM-MOD) in India. We have previously shown that two cytokines clusters differentiated CM from mild malaria in Maharashtra. Hence, we also aimed to determine if these cytokines could discriminate malaria subphenotypes in Odisha.MethodsP. falciparum malaria patients from the SCB Medical College Cuttack in the Odisha state in India were enrolled along with three sets of controls: healthy individuals, patients with sepsis and encephalitis (n = 222). We determined plasma concentrations of pro- and anti-inflammatory cytokines and chemokines for all individuals using a multiplex assay. We then used an ensemble of statistical analytical methods to ascertain whether particular sets of cytokines/chemokines were predictors of severity or signatures of a disease category.ResultsOf the 26 cytokines/chemokines tested, 19 increased significantly during malaria and clearly distinguished malaria patients from controls, as well as sepsis and encephalitis patients. High amounts of IL-17, IP-10, and IL-10 predicted MOD, decreased IL-17 and MIP-1α segregated CM-MOD from MOD, and increased IL-12p40 differentiated CM from CM-MOD. Most severe malaria patients with ARF exhibited high levels of IL-17.ConclusionWe report distinct differences in cytokine production correlating with malarial disease severity in Odisha and Maharashtra populations in India. We show that CM, CM-MOD and MOD are clearly distinct malaria-associated pathologies. High amounts of IL-17, IP-10, and IL-10 were predictors of MOD; decreased IL-17 and MIP-1α separated CM-MOD from MOD; and increased IL-12p40 differentiated CM from CM-MOD. Data also suggest that the IL-17 pathway may contribute to malaria pathogenesis via different regulatory mechanisms and may represent an interesting target to mitigate the pathological processes in malaria-associated ARF.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0731-6) contains supplementary material, which is available to authorized users.
Highlights
Plasmodium falciparum malaria in India is characterized by high rates of severe disease, with multiple organ dysfunction (MOD)—mainly associated with acute renal failure (ARF)—and increased mortality
In a previous study done in Gondia, an endemic malaria region in the state of Maharashtra in India, we identified two cytokine clusters that could differentiate cerebral malaria (CM) from mild malaria (MM) using a two-way coupled clustering approach [23]
High amounts of IL-17, IP-10, and IL-10 were predictors of MOD; decreased IL-17 and MIP-1α separated cerebral malaria with MOD (CM-MOD) from MOD; and increased IL-12p40 differentiated CM from CM-MOD
Summary
Plasmodium falciparum malaria in India is characterized by high rates of severe disease, with multiple organ dysfunction (MOD)—mainly associated with acute renal failure (ARF)—and increased mortality. Several studies show that severe malaria is associated with increased TNF-α, IFN-γ, and IL-1β but decreased IL-10 and TGF-β [11,12,13,14,15,16,17]. Increase pro-inflammatory cytokines (e.g., IFN-γ and TNF-α) were associated with protection [18, 19]. Despite their complex network with multiple regulatory pathways, their changed expression patterns have potential as disease biomarkers. Several studies in human have identified cytokines profiles able to differentiate malaria clinical subphenotypes [20,21,22]
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