Herbert Fabien, Tchitchek Nicolas, Bansal Devendra, Jacques Julien, Pathak Sulabha, Bécavin Christophe, Fesel Constantin, Dalko Esther, Cazenave Pierre-André, Preda Cristian, Ravindran Balachandran, Sharma Shobhona, Das Bidyut, Pied Sylviane
CIIL-Center for Infection and Immunity of Lille, Team 04: Basic and Clinical Immunology of Parasitic Diseases, INSERM U1019, CNRS UMR 8204, Univ Lille Nord de France, Institut Pasteur de Lille, 1, rue du Prof Calmette, 59019, Lille Cedex, France.
CEA, DSV/iMETI, Immunology of Viral Infections and Autoimmune Diseases Research Unit, UMR1184, IDMIT Infrastructure, Fontenay-aux-Roses, France.
J Transl Med. 2015 Nov 24;13:369. doi: 10.1186/s12967-015-0731-6.
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. 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.
P. 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.
Of 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.
We 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.
印度的恶性疟原虫疟疾具有严重疾病发生率高的特点，伴有多器官功能障碍（MOD）——主要与急性肾衰竭（ARF）相关——且死亡率增加。本研究的目的是确定在印度区分患有MOD的重症疟疾患者、脑型疟疾（CM）患者以及伴有MOD的脑型疟疾（CM-MOD）患者的细胞因子特征。我们之前已经表明，在马哈拉施特拉邦，两个细胞因子簇可将CM与轻度疟疾区分开来。因此，我们还旨在确定这些细胞因子是否能够区分奥里萨邦的疟疾亚表型。
招募了来自印度奥里萨邦SCB医学院科塔克分院的恶性疟原虫疟疾患者以及三组对照：健康个体、脓毒症患者和脑炎患者（n = 222）。我们使用多重检测法测定了所有个体的促炎和抗炎细胞因子及趋化因子的血浆浓度。然后，我们使用一系列统计分析方法来确定特定的细胞因子/趋化因子组是否是疾病严重程度的预测指标或某一疾病类别的特征。
在检测的26种细胞因子/趋化因子中，19种在疟疾期间显著增加，并且能明显区分疟疾患者与对照，以及脓毒症和脑炎患者。高水平的白细胞介素-17（IL-17）、干扰素诱导蛋白10（IP-10）和白细胞介素-10（IL-10）可预测MOD，IL-17和巨噬细胞炎性蛋白-1α（MIP-1α）水平降低可将CM-MOD与MOD区分开来，白细胞介素-12p40水平升高可将CM与CM-MOD区分开来。大多数患有ARF的重症疟疾患者表现出高水平的IL-17。
我们报告了印度奥里萨邦和马哈拉施特拉邦人群中与疟疾疾病严重程度相关的细胞因子产生的明显差异。我们表明，CM、CM-MOD和MOD是明显不同的与疟疾相关的病理状态。高水平的IL-17、IP-10和IL-10是MOD的预测指标；IL-17和MIP-1α水平降低可将CM-MOD与MOD区分开来；白细胞介素-12p40水平升高可将CM与CM-MOD区分开来。数据还表明，IL-17途径可能通过不同的调节机制促成疟疾发病机制，并且可能是减轻疟疾相关ARF病理过程的一个有意义的靶点。
