Abstract
Cerebral malaria continues to be a difficult to treat complication of Plasmodium falciparum infection in children. We have shown that platelets can have major deleterious immune functions in experimental cerebral malaria (ECM). One of the platelet derived mediators we have identified as particularly important is platelet factor 4/CXCL4. Our prior work demonstrated that PF4−/− mice are protected from ECM, have reduced plasma cytokines, and have reduced T-cell trafficking to the brain. We now show that PF4 drives monocyte cytokine production in a Kruppel like factor 4 (KLF4) dependent manner. Monocyte depleted Plasmodium berghei infected mice have improved survival, and KLF4 is greatly increased in control, but not monocyte depleted mice. PF4−/− mice have less cerebral monocyte trafficking and no change in KLF4 expression. These data indicate that PF4 induction of monocyte KLF4 expression may be an important step in the pathogenesis of ECM.
Highlights
Cerebral malaria is a major complication of Plasmodium falciparum infection in children
We have demonstrated using the Plasmodium berghei ANKA mouse model of experimental cerebral malaria (ECM) that platelets are activated by direct CD36 dependent interactions with Plasmodium infected RBC (iRBC) leading to increased circulating levels of platelet factor 4 (PF4/CXCL4) [10]
To demonstrate that PF4 stimulates monocyte TNFa production we isolated primary marrow derived monocytes from mice, incubated these cells with physiologic concentrations of recombinant PF4 for 48 hrs and TNFa production was measured in the supernatant using an ELISA
Summary
Cerebral malaria is a major complication of Plasmodium falciparum infection in children. In 2002 alone there were an estimated 515 million clinical episodes of acute P. falciparum infection worldwide, mainly affecting children less than 5 years of age [1]. Cerebral Malaria (CM) is the result of a combination of vascular and immune system dysfunction. Brain tissue from patients that die of CM reveals multifocal capillary obstruction with parasitized red blood cells (RBC), platelets and leukocytes [2]. Several hypotheses have attempted to explain the noted pathology, but most include cell adhesion to the endothelium or direct infected RBC (iRBC) interactions with platelets as promoting pro-thrombotic immune responses, resulting in further vascular inflammation, immune stimulation and obstruction of cerebral capillaries [2]
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