title: Plasmodium berghei histamine-releasing factor favours liver-stage development via inhibition of IL-6 production and associates with a severe outcome of disease.
abstract: Plasmodium spp., which causes malaria, produces a histamine-releasing factor (HRF), an orthologue of mammalian HRF. Histamine-releasing factor produced by erythrocytic stages of the parasite is thought to play a role in the pathogenesis of severe malaria. Here, we show in a rodent model that HRF is not important during the erythrocytic but pre-erythrocytic phase of infection, which mainly consists in the transformation in the liver of the mosquito-injected parasite form into the erythrocyte-infecting form. Development of P. berghei ANKA cl15cy1 liver stages lacking HRF is impaired and associated with an early rise in systemic IL-6, a cytokine that strongly suppresses development of Plasmodium liver stages. The defect is rescued by injection of anti-IL-6 antibodies or infection in IL-6-deficient mice and parasite HRF is sufficient to decrease IL-6 synthesis, indicating a direct role of parasite HRF in reducing host IL-6. The target cells modulated by HRF for IL-6 production at early time points during liver infection are neutrophils. Parasite HRF is thus used to down-regulate a cytokine with anti-parasite activity. Our data also highlight the link between a prolonged transition from liver to blood-stage infection and reduced incidence of experimental cerebral malaria.
authors.affiliation: Institut Pasteur, Unité de Biologie des Interactions Hôte Parasites, Paris, F-75015, France; Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, CEDEX 15, Paris, F-75724, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Mathieu
authors.forename: Claudia
authors.initials: C
authors.lastname: Demarta-Gatsi
authors.forename: Adeline
authors.initials: A
authors.lastname: Porcherie
authors.forename: Sara
authors.initials: S
authors.lastname: Brega
authors.forename: Sabine
authors.initials: S
authors.lastname: Thiberge
authors.forename: Karine
authors.initials: K
authors.lastname: Ronce
authors.forename: Leanna
authors.initials: L
authors.lastname: Smith
authors.forename: Roger
authors.initials: R
authors.lastname: Peronet
authors.forename: Rogerio
authors.initials: R
authors.lastname: Amino
authors.forename: Robert
authors.initials: R
authors.lastname: Ménard
authors.forename: Salaheddine
authors.initials: S
authors.lastname: Mécheri
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D008099:Liver / Q000469:parasitology* / Q000473:pathology; D008288:Malaria / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D010962:Plasmodium berghei / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D016896:Treatment Outcome; D000090324:Tumor Protein, Translationally-Controlled 1; D000093242:Interleukin-6 Inhibitors
chemical_list: D014408:Biomarkers, Tumor; D000090324:Tumor Protein, Translationally-Controlled 1; D000093242:Interleukin-6 Inhibitors