Platelet Factor 4 Mediates Inflammation in Experimental Cerebral Malaria

Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.
Cell host & microbe (Impact Factor: 12.33). 09/2008; 4(2):179-87. DOI: 10.1016/j.chom.2008.07.003
Source: PubMed


Cerebral malaria (CM) is a major complication of Plasmodium falciparum infection in children. The pathogenesis of CM involves vascular inflammation, immune stimulation, and obstruction of cerebral capillaries. Platelets have a prominent role in both immune responses and vascular obstruction. We now demonstrate that the platelet-derived chemokine, platelet factor 4 (PF4)/CXCL4, promotes the development of experimental cerebral malaria (ECM). Plasmodium-infected red blood cells (RBCs) activated platelets independently of vascular effects, resulting in increased plasma PF4. PF4 or chemokine receptor CXCR3 null mice had less severe ECM, including decreased T cell recruitment to the brain, and platelet depletion or aspirin treatment reduced the development of ECM. We conclude that Plasmodium-infected RBCs can directly activate platelets, and platelet-derived PF4 then contributes to immune activation and T cell trafficking as part of the pathogenesis of ECM.

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    • "The zinc finger transcription factor KLF4 interacts with CREB and plays a wide range of roles, including the regulation of cell growth and differentiation [34]. Interestingly, evidence is emerging that KLF4 is involved in the pathophysiology of inflammatory diseases, including parasite infection [35–38]. We speculate that KLF4 plays a role in regulating ghrelin expression in response to helminth infection. "
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    ABSTRACT: Background The ghrelin axis is involved in the regulation of metabolism, energy balance, and the immune, cardiovascular and reproductive systems. The manipulation of this axis has potential for improving economically valuable traits in production animals, and polymorphisms in the ghrelin (GHRL) and ghrelin receptor (GHSR) genes have been associated with growth and carcass traits. Here we investigate the structure and expression of the ghrelin gene (GHRL) in sheep, Ovis aries. Results We identify two ghrelin mRNA isoforms, which we have designated Δex2 preproghrelin and Δex2,3 preproghrelin. Expression of Δex2,3 preproghrelin is likely to be restricted to ruminants, and would encode truncated ghrelin and a novel C-terminal peptide. Both Δex2 preproghrelin and canonical preproghrelin mRNA isoforms were expressed in a range of tissues. Expression of the Δex2,3 preproghrelin isoform, however, was restricted to white blood cells (WBC; where the wild-type preproghrelin isoform is not co-expressed), and gastrointestinal tissues. Expression of Δex2 preproghrelin and Δex2,3 preproghrelin mRNA was elevated in white blood cells in response to parasitic worm (helminth) infection in genetically susceptible sheep, but not in resistant sheep. Conclusions The restricted expression of the novel preproghrelin variants and their distinct WBC expression pattern during parasite infection may indicate a novel link between the ghrelin axis and metabolic and immune function in ruminants.
    BMC Veterinary Research 09/2014; 10:211. DOI:10.1186/s12917-014-0211-x · 1.78 Impact Factor
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    • "). In addition, PF4 has been reported to worsen experimental cerebral pathology in mice, presumably mediated through the chemokine domain (Srivastava et al., 2008). Thus, we reasoned that synthetic small molecules capable of adopting amphipathic secondary structures analogous to a HDP could potentially reproduce the potent, selective antiparasitic activity of PF4 while improving tissue distribution and decreasing complications arising from chemokine signaling. "
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    ABSTRACT: Plasmodium falciparum pathogenesis is affected by various cell types in the blood, including platelets, which can kill intraerythrocytic malaria parasites. Platelets could mediate these antimalarial effects through human defense peptides (HDPs), which exert antimicrobial effects by permeabilizing membranes. Therefore, we screened a panel of HDPs and determined that human platelet factor 4 (hPF4) kills malaria parasites inside erythrocytes by selectively lysing the parasite digestive vacuole (DV). PF4 rapidly accumulates only within infected erythrocytes and is required for parasite killing in infected erythrocyte-platelet cocultures. To exploit this antimalarial mechanism, we tested a library of small, nonpeptidic mimics of HDPs (smHDPs) and identified compounds that kill P. falciparum by rapidly lysing the parasite DV while sparing the erythrocyte plasma membrane. Lead smHDPs also reduced parasitemia in a murine malaria model. Thus, identifying host molecules that control parasite growth can further the development of related molecules with therapeutic potential.
    Cell host & microbe 12/2012; 12(6):815-23. DOI:10.1016/j.chom.2012.10.017 · 12.33 Impact Factor
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    • "Interestingly, some host cells, particularly platelets, can act as effectors of cytokines [reviewed in (Grau & Lou, 1993; Lou et al, 1997) and see Pathogenesis: Consequences to the host of parasite surface proteins – cytoadherence and sequestration]. Furthermore, iRBC can directly activate platelets, independently of vascular effects, at least in the experimental murine model (Srivastava et al, 2008). Beyond this ‘non-coagulation-related’ platelet involvement, triggering of coagulation by iRBC and its role in severe malaria pathogenesis has been reviewed elsewhere – with the suggestion that the interaction between cytoadherence, inflammation and coagulation is needed to explain CM pathogenesis (van der Heyde et al, 2006; Francischetti et al, 2007; Moxon et al, 2009). "
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    ABSTRACT: Residence in the human erythrocyte is essential for the lifecycle of all Plasmodium that infect man. It is also the phase of the life cycle that causes disease. Although the red blood cell (RBC) is a highly specialized cell for its function of carrying oxygen to and carbon dioxide away from tissues, it is devoid of organelles and lacks any cellular machinery to synthesize new protein. Therefore in order to be able to survive and multiply within the RBC membrane the parasite needs to make many modifications to the infected RBC (iRBC). Plasmodium falciparum (P. falciparum) also expresses parasite-derived proteins on the surface of the iRBC that enable the parasite to cytoadhere to endothelial and other intravascular cells. These RBC modifications are at the root of malaria pathogenesis and, in this ancient disease of man, have formed the epicentre of a genetic 'battle' between parasite and host. This review discusses some of the critical modifications of the RBC by the parasite and some of the consequences of these adaptations on disease in the human host, with an emphasis on advances in understanding of the pathogenesis of severe and cerebral malaria (CM) from recent research.
    British Journal of Haematology 05/2011; 154(6). DOI:10.1111/j.1365-2141.2011.08755.x · 4.71 Impact Factor
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