title: Plasmodium falciparum histones induce endothelial proinflammatory response and barrier dysfunction.
abstract: Plasmodium falciparum is a protozoan parasite of human erythrocytes that causes the most severe form of malaria. Severe P. falciparum infection is associated with endothelial activation and permeability, which are important determinants of the outcome of the infection. How endothelial cells become activated is not fully understood, particularly with regard to the effects of parasite subcomponents. We demonstrated that P. falciparum histones extracted from merozoites (HeH) directly stimulated the production of IL-8 and other inflammatory mediators by primary human dermal microvascular endothelial cells through a signaling pathway that involves Src family kinases and p38 MAPK. The stimulatory effect of HeH and recombinant P. falciparum H3 (PfH3) was abrogated by histone-specific antibodies. The release of nuclear contents on rupture of infected erythrocytes was captured by live cell imaging and confirmed by detecting nucleosomes in the supernatants of parasite cultures. HeH and recombinant parasite histones also induced endothelial permeability through a charge-dependent mechanism that resulted in disruption of junctional protein expression and cell death. Recombinant human activated protein C cleaved HeH and PfH3 and abrogated their proinflammatory effects. Circulating nucleosomes of both human and parasite origin were detected in the plasma of patients with falciparum malaria and correlated positively with disease severity. These results support a pathogenic role for both host- and pathogen-derived histones in P. falciparum-caused malaria.
authors.affiliation: Department of Microbiology Immunology & Infectious Diseases, University of Calgary, Alberta, Canada.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gillrie
authors.affiliation: Department of Microbiology Immunology & Infectious Diseases, University of Calgary, Alberta, Canada.
authors.forename: Kristine
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania.
authors.forename: D Channe
authors.initials: DC
authors.lastname: Gowda
authors.affiliation: Department of Microbiology Immunology & Infectious Diseases, University of Calgary, Alberta, Canada.
authors.forename: Shevaun P
authors.initials: SP
authors.lastname: Davis
authors.affiliation: Temple Autoimmunity Center, Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Marc
authors.initials: M
authors.lastname: Monestier
authors.affiliation: Department of Entomology, Pennsylvania State University, University Park, Pennsylvania.
authors.forename: Liwang
authors.initials: L
authors.lastname: Cui
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Nicholas P J
authors.initials: NPJ
authors.lastname: Day
authors.affiliation: Department of Microbiology Immunology & Infectious Diseases, University of Calgary, Alberta, Canada. Electronic address: mho@ucalgary.ca.
authors.forename: May
authors.initials: M
authors.lastname: Ho
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000469:parasitology; D006657:Histones / Q000494:pharmacology*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D008018:Life Cycle Stages; D008168:Lung / Q000098:blood supply / Q000469:parasitology; D020935:MAP Kinase Signaling System / Q000502:physiology; D016778:Malaria, Falciparum / Q000469:parasitology; D052940:Merozoites; D055806:Microvessels; D010963:Plasmodium falciparum; D011486:Protein C / Q000494:pharmacology; D011994:Recombinant Proteins; D012867:Skin / Q000098:blood supply / Q000469:parasitology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D006657:Histones; D016209:Interleukin-8; D011486:Protein C; D011994:Recombinant Proteins; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases