title: Rapid Sequestration of Leishmania mexicana by Neutrophils Contributes to the Development of Chronic Lesion.
abstract: The protozoan Leishmania mexicana parasite causes chronic non-healing cutaneous lesions in humans and mice with poor parasite control. The mechanisms preventing the development of a protective immune response against this parasite are unclear. Here we provide data demonstrating that parasite sequestration by neutrophils is responsible for disease progression in mice. Within hours of infection L. mexicana induced the local recruitment of neutrophils, which ingested parasites and formed extracellular traps without markedly impairing parasite survival. We further showed that the L. mexicana-induced recruitment of neutrophils impaired the early recruitment of dendritic cells at the site of infection as observed by intravital 2-photon microscopy and flow cytometry analysis. Indeed, infection of neutropenic Genista mice and of mice depleted of neutrophils at the onset of infection demonstrated a prominent role for neutrophils in this process. Furthermore, an increase in monocyte-derived dendritic cells was also observed in draining lymph nodes of neutropenic mice, correlating with subsequent increased frequency of IFNγ-secreting T helper cells, and better parasite control leading ultimately to complete healing of the lesion. Altogether, these findings show that L. mexicana exploits neutrophils to block the induction of a protective immune response and impairs the control of lesion development. Our data thus demonstrate an unanticipated negative role for these innate immune cells in host defense, suggesting that in certain forms of cutaneous leishmaniasis, regulating neutrophil recruitment could be a strategy to promote lesion healing.
authors.affiliation: Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Epalinges, Switzerland.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Hurrell
authors.affiliation: Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Epalinges, Switzerland.
authors.forename: Steffen
authors.initials: S
authors.lastname: Schuster
authors.affiliation: Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Epalinges, Switzerland.
authors.forename: Eva
authors.initials: E
authors.lastname: Grün
authors.affiliation: Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Epalinges, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Coutaz
authors.affiliation: School of Science and Sport, University of the West of Scotland, Paisley, United Kingdom.
authors.forename: Roderick A
authors.initials: RA
authors.lastname: Williams
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Epalinges, Switzerland.
authors.forename: Werner
authors.initials: W
authors.lastname: Held
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML) Aix Marseille Université, UM2, Marseille, France; INSERM U1104, Marseille, France; CNRS UMR7280, Marseille, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML) Aix Marseille Université, UM2, Marseille, France; INSERM U1104, Marseille, France; CNRS UMR7280, Marseille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Malissen
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: Shida
authors.initials: S
authors.lastname: Yousefi
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: Hans-Uwe
authors.initials: HU
authors.lastname: Simon
authors.affiliation: Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Epalinges, Switzerland; Otto-von-Guericke-University Magdeburg and Helmholtz Centre for Infection Research- Braunschweig, Magdeburg, Germany.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Müller
authors.affiliation: Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Epalinges, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Tacchini-Cottier
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000469:parasitology; D005434:Flow Cytometry; D007894:Leishmania mexicana / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology* / Q000469:parasitology; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000469:parasitology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D012333:RNA, Messenger