title: Leishmaniavirus-Dependent Metastatic Leishmaniasis Is Prevented by Blocking IL-17A.
abstract: Cutaneous leishmaniasis has various outcomes, ranging from self-healing reddened papules to extensive open ulcerations that metastasise to secondary sites and are often resistant to standard therapies. In the case of L. guyanensis (L.g), about 5-10% of all infections result in metastatic complications. We recently showed that a cytoplasmic virus within L.g parasites (LRV1) is able to act as a potent innate immunogen, worsening disease outcome in a murine model. In this study, we investigated the immunophenotype of human patients infected by L.g and found a significant association between the inflammatory cytokine IL-17A, the presence of LRV1 and disease chronicity. Further, IL-17A was inversely correlated to the protective cytokine IFN-γ. These findings were experimentally corroborated in our murine model, where IL-17A produced in LRV1+ L.g infection contributed to parasite virulence and dissemination in the absence of IFN-γ. Additionally, IL-17A inhibition in mice using digoxin or SR1001, showed therapeutic promise in limiting parasite virulence. Thus, this murine model of LRV1-dependent infectious metastasis validated markers of disease chronicity in humans and elucidated the immunologic mechanism for the dissemination of Leishmania parasites to secondary sites. Moreover, it confirms the prognostic value of LRV1 and IL-17A detection to prevent metastatic leishmaniasis in human patients.
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Mary-Anne
authors.initials: MA
authors.lastname: Hartley
authors.affiliation: Immunologie des Leishmanioses, Institut Pasteur de la Guyane, Cayenne, French Guiana.
authors.forename: Eliane
authors.initials: E
authors.lastname: Bourreau
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Matteo
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Patrik
authors.initials: P
authors.lastname: Castiglioni
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Remzi Onur
authors.initials: RO
authors.lastname: Eren
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Prevel
authors.affiliation: Service de Dermatologie, Centre Hospitalier Andrée Rosemon, Cayenne, French Guiana.
authors.forename: Pierre
authors.initials: P
authors.lastname: Couppié
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Hickerson
authors.affiliation: World Health Organization Immunology Research and Training centre (WHO-IRTC), Epalinges, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Launois
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Beverley
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ronet
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Nicolas
authors.identifier: http://orcid.org/0000-0003-0136-7245
authors.initials: N
authors.lastname: Fasel