title: Gamma interferon (IFN-γ) receptor restricts systemic dengue virus replication and prevents paralysis in IFN-α/β receptor-deficient mice.
abstract: We previously reported that mice lacking alpha/beta and gamma interferon receptors (IFN-α/βR and -γR) uniformly exhibit paralysis following infection with the dengue virus (DENV) clinical isolate PL046, while only a subset of mice lacking the IFN-γR alone and virtually no mice lacking the IFN-α/βR alone develop paralysis. Here, using a mouse-passaged variant of PL046, strain S221, we show that in the absence of the IFN-α/βR, signaling through the IFN-γR confers approximately 140-fold greater resistance against systemic vascular leakage-associated dengue disease and virtually complete protection from dengue-induced paralysis. Viral replication in the spleen was assessed by immunohistochemistry and flow cytometry, which revealed a reduction in the number of infected cells due to IFN-γR signaling by 2 days after infection, coincident with elevated levels of IFN-γ in the spleen and serum. By 4 days after infection, IFN-γR signaling was found to restrict DENV replication systemically. Clearance of DENV, on the other hand, occurred in the absence of IFN-γR, except in the central nervous system (CNS) (brain and spinal cord), where clearance relied on IFN-γ from CD8(+) T cells. These results demonstrate the roles of IFN-γR signaling in protection from initial systemic and subsequent CNS disease following DENV infection and demonstrate the importance of CD8(+) T cells in preventing DENV-induced CNS disease.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Tyler R
authors.initials: TR
authors.lastname: Prestwood
authors.forename: Malika M
authors.initials: MM
authors.lastname: Morar
authors.forename: Raphaël M
authors.initials: RM
authors.lastname: Zellweger
authors.forename: Robyn
authors.initials: R
authors.lastname: Miller
authors.forename: Monica M
authors.initials: MM
authors.lastname: May
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Yauch
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lada
authors.forename: Sujan
authors.initials: S
authors.lastname: Shresta
mesh_terms: D019264:Adoptive Transfer; D000704:Analysis of Variance; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D002490:Central Nervous System / Q000276:immunology* / Q000821:virology; D003715:Dengue / Q000150:complications / Q000276:immunology* / Q000473:pathology; D003716:Dengue Virus / Q000502:physiology*; D004198:Disease Susceptibility / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010243:Paralysis / Q000209:etiology / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D017471:Receptors, Interferon / Q000378:metabolism*; D012044:Regression Analysis; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000821:virology; D014779:Virus Replication / Q000502:physiology*; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor