title: Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease.
abstract: From the inoculation of Plasmodium sporozoites via Anopheles mosquito bites to the development of blood-stage parasites, a hallmark of the host response is an inflammatory reaction characterized by elevated histamine levels in the serum and tissues. Given the proinflammatory and immunosuppressive activities associated with histamine, we postulated that this vasoactive amine participates in malaria pathogenesis. Combined genetic and pharmacologic approaches demonstrated that histamine binding to H1R and H2R but not H3R and H4R increases the susceptibility of mice to infection with Plasmodium. To further understand the role of histamine in malaria pathogenesis, we used histidine decarboxylase-deficient (HDC(-/-)) mice, which are free of histamine. HDC(-/-) mice were highly resistant to severe malaria whether infected by mosquito bites or via injection of infected erythrocytes. HDC(-/-) mice displayed resistance to two lethal strains: Plasmodium berghei (Pb) ANKA, which triggers cerebral malaria (CM), and Pb NK65, which causes death without neurological symptoms. The resistance of HDC(-/-) mice to CM was associated with preserved blood-brain barrier integrity, the absence of infected erythrocyte aggregation in the brain vessels, and a lack of sequestration of CD4 and CD8 T cells. We demonstrate that histamine-mediated signaling contributes to malaria pathogenesis. Understanding the basis for these biological effects of histamine during infection may lead to novel therapeutic strategies to alleviate the severity of malaria.
authors.affiliation: Unité des Réponses Précoces aux Parasites et Immunopathologie, Institut Pasteur, Paris 75015, France.
authors.forename: Walid
authors.initials: W
authors.lastname: Beghdadi
authors.forename: Adeline
authors.initials: A
authors.lastname: Porcherie
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Schneider
authors.forename: David
authors.initials: D
authors.lastname: Dubayle
authors.forename: Roger
authors.initials: R
authors.lastname: Peronet
authors.forename: Michel
authors.initials: M
authors.lastname: Huerre
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohtsu
authors.forename: Jacques
authors.initials: J
authors.lastname: Louis
authors.forename: Salaheddine
authors.initials: S
authors.lastname: Mécheri
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000276:immunology; D005260:Female; D006632:Histamine / Q000097:blood / Q000276:immunology*; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D016779:Malaria, Cerebral / Q000097:blood / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010962:Plasmodium berghei / Q000472:pathogenicity*; D012333:RNA, Messenger / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D011968:Receptors, Histamine / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D006634:Histamine H1 Antagonists; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D011968:Receptors, Histamine; D006632:Histamine; D006640:Histidine Decarboxylase