CXCL4 and CXCL10 predict risk of fatal cerebral malaria
Article type: Research Article
Authors: Wilson, Nana O. | Jain, Vidhan | Roberts, Christina E. | Lucchi, Naomi | Joel, Pradeep K. | Singh, Mrigendra P. | Nagpal, Avinash C. | Dash, Aditya P. | Udhayakumar, Venkatachalam | Singh, Neeru; | Stiles, Jonathan K.
Affiliations: Morehouse School of Medicine, Department of Microbiology, Biochemistry and Immunology, Atlanta, Georgia, USA | National Institute of Malaria Research Field Unit (ICMR), Jabalpur, Madhya Pradesh, India | Spelman College, Biology Department, Atlanta, Georgia, USA | Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA | Nethaji Subhash Chandra Bose Medical College Hospital, Jabalpur, Madhya Pradesh, India | National Institute of Malaria Research (ICMR), New Delhi, India | Regional Medical Research Center for Tribals (ICMR), Jabalpur, Madhya Pradesh, India
Note: [] Corresponding author: Jonathan K. Stiles, Morehouse School of Medicine, Department of Microbiology, Biochemistry and Immunology, BMSB Room 349D, 720 Westview Dr. SW, Atlanta, GA 30310, USA. Tel.: +1 404 742 1586; Fax: +1 404 752 1179; E-mail: jstiles@msm.edu
Abstract: Plasmodium falciparum in a subset of patients can lead to a diffuse encephalopathy known as cerebral malaria (CM). Despite treatment, mortality caused by CM can be as high as 30% while 10% of survivors of the disease may experience short- and long-term neurological complications. The pathogenesis of CM involves alterations in cytokine and chemokine expression, local inflammation, vascular injury and repair processes. These diverse factors have limited the rate of discovery of prognostic predictors of fatal CM. Identification of reliable early predictors of CM severity will enable clinicians to adjust this risk with appropriate management of CM. Recent studies revealed that elevated levels of CXCL10 expression in cerebrospinal fluid and peripheral blood plasma independently predicted severe and fatal CM. CXCR3, a promiscuous receptor of CXCL10, plays an important role in pathogenesis of mouse model of CM. In this study the role of corresponding CXCR3 ligands (CXCL11, CXCL10, CXCL9 & CXCL4) in fatal or severe CM was evaluated by comparing their levels in 16 healthy control (HC), 26 mild malaria (MM), 26 cerebral malaria survivors (CMS) and 12 non-survivors (CMNS) using enzyme linked immunosorbent assay (ELISA). Levels of CXCL4 and CXCL10 were significantly elevated in CMNS patients (p < 0.05) when compared with HC, MM and CMS. Elevated plasma levels of CXCL10 and CXCL4 were tightly associated with CM mortality. Receiver Operating Characteristic (ROC) curve analysis revealed that CXCL4 and CXCL10 can discriminate CMNS from MM (p < 0.0001) and CMS (p <0.0001) with an area under the curve (AUC)=1. These results suggest that CXCL4 and CXCL10 play a prominent role in pathogenesis of CM associated death and may be used as functional or surrogate biomarkers for predicting CM severity.
Keywords: CXCL4, CXCL10, PF4, IP-10, malaria, cerebral malaria, Plasmodium falciparum, ROC curve
DOI: 10.3233/DMA-2011-0763
Journal: Disease Markers, vol. 30, no. 1, pp. 39-49, 2011
