title: T cell-dependence of Lassa fever pathogenesis.
abstract: Lassa virus (LASV), the causative agent of Lassa fever (LF), is endemic in West Africa, accounting for substantial morbidity and mortality. In spite of ongoing research efforts, LF pathogenesis and mechanisms of LASV immune control remain poorly understood. While normal laboratory mice are resistant to LASV, we report that mice expressing humanized instead of murine MHC class I (MHC-I) failed to control LASV infection and develop severe LF. Infection of MHC-I knockout mice confirmed a key role for MHC-I-restricted T cell responses in controlling LASV. Intriguingly we found that T cell depletion in LASV-infected HHD mice prevented disease, irrespective of high-level viremia. Widespread activation of monocyte/macrophage lineage cells, manifest through inducible NO synthase expression, and elevated IL-12p40 serum levels indicated a systemic inflammatory condition. The absence of extensive monocyte/macrophage activation in T cell-depleted mice suggested that T cell responses contribute to deleterious innate inflammatory reactions and LF pathogenesis. Our observations in mice indicate a dual role for T cells, not only protecting from LASV, but also enhancing LF pathogenesis. The possibility of T cell-driven enhancement and immunopathogenesis should be given consideration in future LF vaccine development.
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Flatz
authors.forename: Toni
authors.initials: T
authors.lastname: Rieger
authors.forename: Doron
authors.initials: D
authors.lastname: Merkler
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergthaler
authors.forename: Tommy
authors.initials: T
authors.lastname: Regen
authors.forename: Mariann
authors.initials: M
authors.lastname: Schedensack
authors.forename: Lukas
authors.initials: L
authors.lastname: Bestmann
authors.forename: Admar
authors.initials: A
authors.lastname: Verschoor
authors.forename: Mario
authors.initials: M
authors.lastname: Kreutzfeldt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.forename: Uwe-Karsten
authors.initials: UK
authors.lastname: Hanisch
authors.forename: Stephan
authors.initials: S
authors.lastname: Günther
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Pinschewer
mesh_terms: D000818:Animals; D018050:Arenavirus / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000276:immunology / Q000378:metabolism; D007835:Lassa Fever / Q000276:immunology* / Q000517:prevention & control*; D007836:Lassa virus / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D014765:Viral Vaccines / Q000276:immunology; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology
chemical_list: D053762:Interleukin-12 Subunit p40; D014765:Viral Vaccines; D001613:beta 2-Microglobulin