TY - JOUR
T1 - The interferon-stimulated gene Ifi27l2a restricts West Nile virus infection and pathogenesis in a cell-typeand region-specific manner
AU - Lucas, Tiffany M.
AU - Richner, Justin M.
AU - Diamond, Michael S.
N1 - Funding Information:
This work was funded by HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) under grants U19 AI083019, U19 AI106772, R01 AI104972, and R01 AI104002. HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) provided funding to Tiffany Lucas and Justin Richner under grant numbers 5T32AI007172-33 and 5F32AG043223-02.
Publisher Copyright:
© 2016, American Society for Microbiology.
PY - 2016
Y1 - 2016
N2 - The mammalian host responds to viral infections by inducing expression of hundreds of interferon-stimulated genes (ISGs). While the functional significance of many ISGs has yet to be determined, their cell type and temporal nature of expression suggest unique activities against specific pathogens. Using a combination of ectopic expression and gene silencing approaches in cell culture, we previously identified Ifi27l2a as a candidate antiviral ISG within neuronal subsets of the central nervous system (CNS) that restricts infection by West Nile virus (WNV), an encephalitic flavivirus of global concern. To investigate the physiological relevance of Ifi27l2a in the context of viral infection, we generated Ifi27l2a-/- mice. Although adult mice lacking Ifi27l2a were more vulnerable to lethal WNV infection, the viral burden was greater only within the CNS, particularly in the brain stem, cerebellum, and spinal cord. Within neurons of the cerebellum and brain stem, in the context of WNV infection, a deficiency of Ifi27l2a was associated with less cell death, which likely contributed to sustained viral replication and higher titers in these regions. Infection studies in a primary cell culture revealed that Ifi27l2a-/- cerebellar granule cell neurons and macrophages but not cerebral cortical neurons, embryonic fibroblasts, or dendritic cells sustained higher levels of WNV infection than wild-type cells and that this difference was greater under conditions of beta interferon (IFN-β) pretreatment. Collectively, these findings suggest that Ifi27l2a has an antiviral phenotype in subsets of cells and that at least some ISGs have specific inhibitory functions in restricted tissues.
AB - The mammalian host responds to viral infections by inducing expression of hundreds of interferon-stimulated genes (ISGs). While the functional significance of many ISGs has yet to be determined, their cell type and temporal nature of expression suggest unique activities against specific pathogens. Using a combination of ectopic expression and gene silencing approaches in cell culture, we previously identified Ifi27l2a as a candidate antiviral ISG within neuronal subsets of the central nervous system (CNS) that restricts infection by West Nile virus (WNV), an encephalitic flavivirus of global concern. To investigate the physiological relevance of Ifi27l2a in the context of viral infection, we generated Ifi27l2a-/- mice. Although adult mice lacking Ifi27l2a were more vulnerable to lethal WNV infection, the viral burden was greater only within the CNS, particularly in the brain stem, cerebellum, and spinal cord. Within neurons of the cerebellum and brain stem, in the context of WNV infection, a deficiency of Ifi27l2a was associated with less cell death, which likely contributed to sustained viral replication and higher titers in these regions. Infection studies in a primary cell culture revealed that Ifi27l2a-/- cerebellar granule cell neurons and macrophages but not cerebral cortical neurons, embryonic fibroblasts, or dendritic cells sustained higher levels of WNV infection than wild-type cells and that this difference was greater under conditions of beta interferon (IFN-β) pretreatment. Collectively, these findings suggest that Ifi27l2a has an antiviral phenotype in subsets of cells and that at least some ISGs have specific inhibitory functions in restricted tissues.
UR - http://www.scopus.com/inward/record.url?scp=84961117135&partnerID=8YFLogxK
U2 - 10.1128/JVI.02463-15
DO - 10.1128/JVI.02463-15
M3 - Article
C2 - 26699642
AN - SCOPUS:84961117135
SN - 0022-538X
VL - 90
SP - 2600
EP - 2615
JO - Journal of Virology
JF - Journal of Virology
IS - 5
ER -