title: Intracranial Injection of Dengue Virus Induces Interferon Stimulated Genes and CD8+ T Cell Infiltration by Sphingosine Kinase 1 Independent Pathways.
abstract: We have previously reported that the absence of sphingosine kinase 1 (SK1) affects both dengue virus (DENV) infection and innate immune responses in vitro. Here we aimed to define SK1-dependancy of DENV-induced disease and the associated innate responses in vivo. The lack of a reliable mouse model with a fully competent interferon response for DENV infection is a challenge, and here we use an experimental model of DENV infection in the brain of immunocompetent mice. Intracranial injection of DENV-2 into C57BL/6 mice induced body weight loss and neurological symptoms which was associated with a high level of DENV RNA in the brain. Body weight loss and DENV RNA level tended to be greater in SK1-/- compared with wildtype (WT) mice. Brain infection with DENV-2 is associated with the induction of interferon-β (IFN-β) and IFN-stimulated gene (ISG) expression including viperin, Ifi27l2a, IRF7, and CXCL10 without any significant differences between WT and SK1-/- mice. The SK2 and sphingosine-1-phosphate (S1P) levels in the brain were unchanged by DENV infection or the lack of SK1. Histological analysis demonstrated the presence of a cellular infiltrate in DENV-infected brain with a significant increase in mRNA for CD8 but not CD4 suggesting this infiltrate is likely CD8+ but not CD4+ T-lymphocytes. This increase in T-cell infiltration was not affected by the lack of SK1. Overall, DENV-infection in the brain induces IFN and T-cell responses but does not influence the SK/S1P axis. In contrast to our observations in vitro, SK1 has no major influence on these responses following DENV-infection in the mouse brain.
authors.affiliation: Microbiology and Infectious Diseases, School of Medicine, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Wisam H
authors.identifier: http://orcid.org/0000-0002-7423-5692
authors.initials: WH
authors.lastname: Al-Shujairi
authors.affiliation: Microbiology and Infectious Diseases, School of Medicine, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Clarke
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Lorena T
authors.initials: LT
authors.lastname: Davies
authors.affiliation: Vaccine Research Laboratory, Research Centre for Infectious Diseases, and Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alsharifi
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pitson
authors.affiliation: Microbiology and Infectious Diseases, School of Medicine, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Carr
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003715:Dengue / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D003716:Dengue Virus / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007113:Immunity, Innate / Q000276:immunology*; D016899:Interferon-beta / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D014779:Virus Replication; D000099157:Sphingosine Kinase
chemical_list: D000998:Antiviral Agents; D016899:Interferon-beta; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase