Published online January 28, 2008
doi:10.1084/jem.20071548
The Journal of Experimental Medicine, Vol. 205, No. 2, 395-408
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Beghdadi et al.
Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease
Walid Beghdadi1,
Adeline Porcherie1,
Bradley S. Schneider1,
David Dubayle3,
Roger Peronet1,
Michel Huerre2,
Takeshi Watanabe4,
Hiroshi Ohtsu5,
Jacques Louis1, and
Salaheddine Mécheri1
1 Unité des Réponses Précoces aux Parasites et Immunopathologie and 2 Unité de Recherche et d'Expertise Histotechnologie et Pathologie, Institut Pasteur, Paris 75015, France
3 Centre National de la Recherche Scientifique, UMR 8119, Université Paris Descartes, 75270 Paris, Cedex 06, France
4 Research Center for Allergy and Immunology, RIKEN, Yokohama 230-0045, Japan
5 Tohoku University School of Engineering, Sendai 980-8579, Japan
CORRESPONDENCE Salaheddine Mécheri: smecheri{at}pasteur.fr
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.
Abbreviations used: APC, allophycocyanin; BBB. blood–brain barrier; CM, cerebral malaria; HDC, histidine decarboxylase; ICAM-1, intercellular adhesion molecule 1; MC, mast cell; MFI, mean fluorescence intensity; MGG, May-Grünwald Giemsa; mRNA, messenger RNA; Pb, Plasmodium berghei; TCTP, translationally controlled tumor protein; VCAM-1, vascular cell adhesion molecule 1.
A. Porcherie and B.S. Schneider contributed equally to this work.
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