MRCE Project Abstract

2009

Novel Interferon-Dependent Innate Antiviral Mechanisms

Herbert Virgin, MD, PhD

Identification and analysis of IFN-induced antiviral molecules has several benefits: First, the identification of broad-spectrum antivirals and their respective mechanisms; second, the opportunity to seek viral immune evasion mechanisms targeting novel pathways; lastly, we reason that while much is known about the proximal signaling pathways involved in IFN-mediated resistance, less is known about the effector mechanisms responsible for direct control of infection. During the previous funding period we used a discovery process combining microarray analysis of IFN- or virus-induced transcription with screening for anti-viral effects in vivo. We will continue to use this process to identify novel IFN-induced antiviral molecules.

MRCE Publications

Quaranfil, Johnston Atoll and Lake Chad viruses are novel members of the family Orthomyxoviridae. Presti RM, Zhao G, Beatty WL, Mihindukulasuriya KA, Travassos da Rosa AP, Popov VL, Tesh RB, Virgin HW, Wang D. J Virol. 2009 Sep 2.

Autophagy genes in immunity. Virgin HW, Levine B. Nat Immunol: 2009 May;10(5):461-70.

A common role for Atg16L1, Atg5 and Atg7 in small intestinal Paneth cells and Crohn disease. Cadwell K, Patel KK, Komatsu M, Virgin HW 4th, Stappenbeck TS. Autophagy: 2009 Feb;5(2):250-2.

A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK, Kishi C, Kc W, Carrero JA, Hunt S, Stone CD, Brunt EM, Xavier RJ, Sleckman BP, Li E, Mizushima N, Stappenbeck TS, Virgin HW 4th. Nature: 2008 Nov 13;456(7219):259-63.

Early B-cell activation after West Nile virus infection requires alpha/beta interferon but not antigen receptor signaling. Purtha WE, Chachu KA, Virgin HW 4th, Diamond MS. J Virol: 2008 Nov;82(22):10964-74.

MDA-5 recognition of a murine norovirus. McCartney SA, Thackray LB, Gitlin L, Gilfillan S, Virgin Iv HW, Colonna M. PLoS Pathog: 2008 July; 4(7): e1000108.

The autophagy gene ATG5 plays an essential role in B lymphocyte development. Miller BC, Zhao Z, Stephenson LM, Cadwell K, Pua HH, Lee HK, Mizushima NN, Iwasaki A, He YW, Swat W, Virgin HW 4th. Autophagy: 2008 May-Jun;4(3):309-14.

Structure of antibody-neutralized murine norovirus and unexpected. Katpally U, Wobus CE, Dryden K, Virgin HW 4th, Smith TJ. J Virol: 2008 Mar;82(5):2079-88.

Ovarian Tumor Domain-Containing Viral Proteases Evade Ubiquitin- and 1SG15-Dependent Innate Immune Responses. Natalia Frias-Taheli, Nadia V Giannakopoulos, Marjolein Kikkert, Shannon L Taylor, Anne Bridgen, Jason Paragas, Juergen A Richt, Raymond R Rowland, Connie S Schmaljohn, Deborah J Lenschow, Eric J Snijder, Adolfo Garcia-Sastre and Herber Whiting Virgin IV. Cell Host & Microbe: 2007;2:404-416.

Murine noroviruses comprising a single genogroup exhibit biological diversity despite limited sequence divergence. Thackray, LB, Wobus CE, Chachu KA, Liu B, Alegre ER, Henderson KS, Kelley ST, Virgin HW. J Virol: 2007;8(19):10460-10473.

Coronavirus Replication Does Not Require the Autophagy Gene ATG5. Zhao Z, Thackray LB, Miller BC, Lynn TM, Becker MM, Ward E, Mizushima NN, Denison MR, Virgin HW 4th. Autophagy: 2007;3(6):581-585.

IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Lenschow DJ, Lai C, Frias-Staheli N, Giannakopoulos NV, Lutz A, Wolff T, Osiak A, Levine B, Schmidt RE, Garcia-Sastre A, Leib DA, Pekosz A, Knobeloch KP, Horak I, Virgin HW 4th. Proc Natl Acad Sci U S A: 2007;104(4):1371-1376.

Murine norovirus: a model system to study norovirus biology and pathogenesis. Wobus CE, Thackray LB, Virgin HW 4th. J Virol: 2006;80(11):5104-5112.

PKR-dependent autophagic degradation of herpes simplex virus type I. Talloczy Z, Virgin HW 4th, Levine B. Autophagy: 2006;2(1):24-29.

Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. Lenschow DJ, Giannakopoulos NV, Gunn LJ, Johnston C, O'Guin AK, Schmidt RE, Levine B, Virgin HW 4th. J Virol: 2005;79(22):13974-13983.

Proteomic identification of proteins conjugated to ISG15 in mouse and human cells. Giannakopoulos NV, Luo JK, Papov V, Zou W, Lenschow DJ, Jacobs BS, Borden EC, Li J, Virgin HW, Zhang DE. Biochem Biophys Res Commun: 2005;336(2):496-506.

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