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Journal of Virology, September 2009, p. 9329-9338, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00836-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Immune Adaptor Molecule SARM Modulates Tumor Necrosis Factor Alpha Production and Microglia Activation in the Brainstem and Restricts West Nile Virus Pathogenesis{triangledown}

Kristy J. Szretter,1 Melanie A. Samuel,2 Susan Gilfillan,3 Anja Fuchs,1 Marco Colonna,3 and Michael S. Diamond1,2,3*

Departments of Medicine,1 Molecular Microbiology,2 Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 631103

Received 24 April 2009/ Accepted 30 June 2009

Sterile alpha and HEAT/Armadillo motif (SARM) is a highly conserved Toll/interleukin-1 receptor (TIR)-containing adaptor protein that is believed to negatively regulate signaling of the pathogen recognition receptors Toll-like receptor 3 (TLR3) and TLR4. To test its physiological function in the context of a microbial infection, we generated SARM–/– mice and evaluated the impact of this deficiency on the pathogenesis of West Nile virus (WNV), a neurotropic flavivirus that requires TLR signaling to restrict infection. Although SARM was preferentially expressed in cells of the central nervous system (CNS), studies with primary macrophages, neurons, or astrocytes showed no difference in viral growth kinetics. In contrast, viral replication was increased specifically in the brainstem of SARM–/– mice, and this was associated with enhanced mortality after inoculation with a virulent WNV strain. A deficiency of SARM was also linked to reduced levels of tumor necrosis factor alpha (TNF-{alpha}), decreased microglia activation, and increased neuronal death in the brainstem after WNV infection. Thus, SARM appears to be unique among the TIR adaptor molecules, since it functions to restrict viral infection and neuronal injury in a brain region-specific manner, possibly by modulating the activation of resident CNS inflammatory cells.

* Corresponding author. Mailing address: Departments of Medicine, Molecular Microbiology, and Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Ave., Box 8051, St. Louis, MO 63110. Phone: (314) 362-2842. Fax: (314) 362-9230. E-mail: diamond{at}borcim.wustl.edu

{triangledown} Published ahead of print on 8 July 2009.

Journal of Virology, September 2009, p. 9329-9338, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00836-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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