TY - JOUR
T1 - Interferon regulatory factors 3 and 7 have distinct roles in the pathogenesis of alphavirus encephalomyelitis
AU - Schultz, Kimberly L.W.
AU - Troisi, Elizabeth M.
AU - Baxter, Victoria K.
AU - Glowinski, Rebecca
AU - Griffin, Diane E.
N1 - Funding Information:
These studies were supported by research grants R01 NS038932 (D. E. G.), R01 NS087539 (D. E. G.), T32 AI007247 (K. L. W. S.), T32 AI007417 (E. M. T.), T32 OD011089 (V. K. B.) and F31 NS101775 (E. M. T.) from the US National Institutes of Health.
Publisher Copyright:
© 2019 The Authors.
PY - 2019/1
Y1 - 2019/1
N2 - Interferon (IFN) regulatory factors (IRFs) are important determinants of the innate response to infection. We evaluated the role(s) of combined and individual IRF deficiencies in the outcome of infection of C57BL/6 mice with Sindbis virus, an alphavirus that infects neurons and causes encephalomyelitis. The brain and spinal cord levels of Irf7, but not Irf3 mRNAs, were increased after infection. IRF3/5/7−/− and IRF3/7−/− mice died within 3–4 days with uncontrolled virus replication, similar to IFNα receptor-deficient mice, while all wild-type (WT) mice recovered. IRF3−/− and IRF7−/− mice had brain levels of IFNα that were lower, but brain and spinal cord levels of IFNβ and IFN-stimulated gene mRNAs that were similar to or higher than WT mice without detectable serum IFN or increases in Ifna or Ifnb mRNAs in the lymph nodes, indicating that the differences in outcome were not due to deficiencies in the central nervous system (CNS) type I IFN response. IRF3−/− mice developed persistent neurological deficits and had more spinal cord inflammation and higher CNS levels of Il1b and Ifnγ mRNAs than WT mice, but all mice survived. IRF7−/− mice died 5–8 days after infection with rapidly progressive paralysis and differed from both WT and IRF3−/− mice in the induction of higher CNS levels of IFNβ, tumour necrosis factor (TNF) α and Cxcl13 mRNA, delayed virus clearance and more extensive cell death. Therefore, fatal disease in IRF7−/− mice is likely due to immune-mediated neurotoxicity associated with failure to regulate the production of inflammatory cytokines such as TNFα in the CNS.
AB - Interferon (IFN) regulatory factors (IRFs) are important determinants of the innate response to infection. We evaluated the role(s) of combined and individual IRF deficiencies in the outcome of infection of C57BL/6 mice with Sindbis virus, an alphavirus that infects neurons and causes encephalomyelitis. The brain and spinal cord levels of Irf7, but not Irf3 mRNAs, were increased after infection. IRF3/5/7−/− and IRF3/7−/− mice died within 3–4 days with uncontrolled virus replication, similar to IFNα receptor-deficient mice, while all wild-type (WT) mice recovered. IRF3−/− and IRF7−/− mice had brain levels of IFNα that were lower, but brain and spinal cord levels of IFNβ and IFN-stimulated gene mRNAs that were similar to or higher than WT mice without detectable serum IFN or increases in Ifna or Ifnb mRNAs in the lymph nodes, indicating that the differences in outcome were not due to deficiencies in the central nervous system (CNS) type I IFN response. IRF3−/− mice developed persistent neurological deficits and had more spinal cord inflammation and higher CNS levels of Il1b and Ifnγ mRNAs than WT mice, but all mice survived. IRF7−/− mice died 5–8 days after infection with rapidly progressive paralysis and differed from both WT and IRF3−/− mice in the induction of higher CNS levels of IFNβ, tumour necrosis factor (TNF) α and Cxcl13 mRNA, delayed virus clearance and more extensive cell death. Therefore, fatal disease in IRF7−/− mice is likely due to immune-mediated neurotoxicity associated with failure to regulate the production of inflammatory cytokines such as TNFα in the CNS.
KW - CNS inflammation
KW - CXCL13
KW - Cell death
KW - Mice
KW - Sindbis virus
KW - Tumor necrosis factor
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U2 - 10.1099/jgv.0.001174
DO - 10.1099/jgv.0.001174
M3 - Article
C2 - 30451651
AN - SCOPUS:85059397510
SN - 0022-1317
VL - 100
SP - 46
EP - 62
JO - Journal of General Virology
JF - Journal of General Virology
IS - 1
M1 - 001174
ER -