Article
Loss of IRF9 Prevents Lethal Lymphocytic Choriomeningitis Virus Infection in Mice at the Cost of Viral Persistence and Chronic Inflammation in the CNS
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Authors
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Claudia Köhler
- Philipps University Marburg, Neuropathology, Marburg, Germany
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Magdalena Huber
- Philipps University Marburg, Institute for Medical Microbiology and Hygiene, Marburg, Germany
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Markus Eickmann
- Philipps University Marburg, Institute of Virology, Marburg, Germany
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Wen Li
- The University of Sydney, School of Molecular Bioscience, Sydney, Australia
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Iain L. Campbell
- The University of Sydney, School of Molecular Bioscience, Sydney, Australia
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Markus J. Hofer
- Philipps University Marburg, Neuropathology, Marburg, Germany
| Published: | September 11, 2012 |
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Outline
Text
Functional type I interferon (IFN) signaling is critical for the host response to viruses. Cellular responses to type I IFNs depend largely on STAT1, STAT2 and IRF9. Here we studied the effects of IRF9-deficiency on the host response to a viral infection in the CNS. Wild-type (WT) mice and mice lacking IRF9 (IRF9 KO) were infected intracranially with lymphocytic choriomeningitis (LCM) virus (LCMV). In WT mice, lethal LCM occurred by day 7 with characteristic cerebral seizures and LCMV being largely confined to the CNS. In contrast, LCMV-infection of IRF9 KO mice caused a transient non-fatal clinical disease and virus spread to peripheral organs. Viral RNA levels decreased slowly over time and became undetectable in some peripheral organs such as liver and spleen but remained detectable in the CNS for more than 150 days. In the CNS, sites of viral infection were associated with foci of activated microglia/macrophages and moderate T-cell infiltrates. The persistent infection in the CNS and peripheral organs was paralleled by significantly increased expression of various cytokine mRNAs, including IFN-g and TNF, as well as of the co-inhibitory molecule B7-H1 (PD-L1 or CD274). In conclusion, these findings indicate that the absence of IRF9 prevents lethal LCM but results in persistent infection and chronic inflammation in the CNS. The presence of T-cells and the slow decrease in viral RNA levels in the CNS and peripheral organs argue for a retarded rather than an exhausted or incapacitated anti-viral response.
