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IMV Executive Assistant

email: virology@umn.edu

tel. (612) 624-1926

fax. (612) 625-1108

 

18-242 Moos Tower
515 Delaware St. SE
Minneapolis, MN 55455

General Questions:

virology@umn.edu

Leslie A. Schiff,
Professor

Microbiology, Medical School

Phone: 612-626-0623

Email: schif002@umn.edu

Education

Ph.D., Tufts University, 1985

Research Interests

Virus-host interactions, viral entry, translational control in virus-infected cells, viral immune avoidance mechanisms

A major research focus in my laboratory is to understand viral and cellular determinants that control reovirus entry into host cells. Current dogma holds that early in infection by mammalian reoviruses, exposure to low pH and protease uncoats virions to intermediate subvirion particles (ISVPs).ISVPs have the capacity to penetrate cell membranes by virtue of exposure of the membranolytic protein mu 1. Joe Golden's research indicates that many cell lines and primary cells are unable to support reovirus replication. Infection with ISVPs results in a productive infection within 90% of the cell lines that are restrictive to viral infection. The fact that ISVPs and not virions can infect these restrictive cells indicates that the block in these cells is at the step of virion to ISVP conversion (uncoating). We are currently examining the nature of the block to uncoating present within these cells to understand the cellular and molecular determinants of virion entry.

We are also studying the spectrum of proteases that participate in reovirus virion entry. In L929 mouse fibroblast cells, cathepsin L, an acid-dependent, lysosomal cysteine protease, is required for virion uncoating. Loss of this protease causes cells to become restrictive to infection by virions but not ISVPs. Some evidence suggests that cells that lack cathepsin L are still able to support virion infection, presumably by using an alternative protease to facilitate uncoating. Ongoing work is aimed at identifying the specific protease(s) that facilitate reovirus entry in these cells.

We are investigating the fundamental question of how viral protein synthesis comes to predominate over cellular translation in virus-infected cells. Because a strain polymorphism in reovirus-induced host translational shutoff mapped to the gene encoding viral protein sigma 3 (a dsRNA-binding protein), it has long been hypothesized that the mechanism of shutoff in reovirus-infected cells required the activity of PKR. PKR is a dsRNA-activated eIF2a kinase. Active (phosphorylated) PKR phosphorylates eIF2alpha, halting translation initiation. It has been proposed that strain differences in sigma 3 expression, localization or activity regulate the activation state of PKR -and thus levels of translation- in infected cells.

Selected Recent Publications

  • Smith, J.S., Schmechel, S.C., Raghavan, A., Abelson, M., Reilly, C., Katze, M.G., Kaufman, R.J., Bohjanen, P.R. and Schiff, L.A. (2006). Reovirus induces and benefits from a cellular integrated stress response. J. Virol. Feb;80(4):2019-2033.
  • Smith JA, Schmechel SC, Williams BR, Silverman RH, Schiff LA (2005). Involvement of the interferon-regulated antiviral proteins PKR and RNase L in reovirus-induced shutoff of cellular translation. J Virol. Feb; 79(4): 2240-50. Abstract
  • Golden, JW., Schiff, LA (2005). Neutrophil elastase, an acid-independent serine protease, facilitates reovirus uncoating and infection in U937 promonocyte cells. Virol J. May 31; 2:48 Abstract
  • Nibert ML, Odegard AL, Agosto MA, Chandran K, Schiff LA (2005). Putative autocleavage of reovirus mu1 protein in concert with outer-capsid disassembly and activation for membrane permeabilization. J Mol Biol. 2005 Jan 21;345(3):461-74. Abstract
  • Golden, J.W., Bahe, J.A., Lucas, W.T., Nibert M.L., and Schiff, L.A. (2004). Cathepsin S. Supports Acid-independent Infection by Some Reoviruses. J Biol Chem. Mar 5;279(10):8547-5). Abstract
  • Golden, J.W., Linke, J., Schmechel, S.C., Thoemke, K. and Schiff, L.A. (2002). Addition of exogenous protease facilitates reovirus infection in many restrictive cells. J. Virol. 76(15):7430-7443. Abstract
  • Jane-Valbuena, J., Breun, L.A., Schiff, L.A., and Nibert, M.L. (2002) Sites and determinants of early cleavages in the proteolytic processing pathway of reovirus surface protein sigma 3. J. Viriol 76(10):5184-5197. Abstract
  • Olland, A.M., Jane-Valbuena, J., Schiff, L.A., Nibert, M.L., and Harrison, S.C. (2001) Structure of the reovirus outer capsid protein sigma 3 at 1.8 angstroms resolution. EMBO J. 20(5):1-11. Abstract
  • Schiff, L.A. and Nibert, M.L. Reoviruses and their replication (2001) In: Virology. D.M. Knipe, R. Lamb, P. Howley eds. Lippincott Williams & Wilkins, Inc.
  • Gillian, A.L., Schmechel, S.C., Livny, J., Schiff, L.A., and Nibert, M.L. (2000) Reovirus nonstructural protein sNS binds in multiple copies to single-strand RNA molecules and exhibits ATP-independent duplex-unwinding activity. J. Virol. 74(13): 5939-5948. Abstract
  • Chandran, K., Walker, S.B., Chen, Y., Contreras, C.M., Schiff, L.A., Baker, T.S., and Nibert, M.L. (1999) Infectious virion-like particles generated by recoating reovirus cores with baculovirus- expressed m1 and s3 proteins. J. Virol. 73(5): 3941-3950. Abstract
  • Jane-Valbuena, J., Nibert, M.L., Walker, S.B., Baker, T.S., Chen, Y., Centonze, V.E. and Schiff, L.A. (1999) Reovirus virion-like particles obtained by recoating ISVPs with baculovirus-expressed s3 protein: an approach for analyzing s3 functions during virus entry. J. Virol. 73(4): 2963-2973. Abstract
  • Schiff, L.A. (1998) Reovirus outer capsid proteins s3 and m1: Interactions that influence viral entry, assembly and translational control. In: Current Topics in Microbiology and Immunology. Vol. 233/ 1 pp. 167-183. K.L Tyler and M.B.A. Oldstone, eds. Springer Verlag.
  • Schmechel, S., Anderson, R., Chute, M., Meurs, E., Skinner, P. and Schiff, L. (1997) Preferential translation of reovirus mRNA by a s3-dependent mechanism. Virology, 232 (1): 62-73. Abstract
  • Nibert, M., Schiff, L.A. and Fields, B.N. Reoviruses and their replication. (1996) In: Virology. B. Fields, D.M. Knipe, R.M. Chanock, M. Hirsch, J.L. Melnick, T. Monath, B. Roizman, eds. Raven Press, Inc.
  • Shepard, D.A., Ehnstrom, J.G., Skinner, P.J. and Schiff, L. (1996) Mutations in the zinc-binding motif of the reovirus capsid protein sigma3 eliminate its ability to associate with capsid protein mu1. J. Virol. 70:2065-2068. Abstract
  • Shepard, D., Ehnstrom, J., and Schiff, L. (1995) Association of reovirus outer capsid proteins sigma3 and mu1 renders sigma3 protease sensitive. J. Virol. 69: 8180-8184. Abstract
  • Kedl, R., Schmechel, S., and Schiff, L. (1995). Comparative sequence analysis of the reovirus S4 gene from 13 serotype 1 and serotype 3 field isolates. J. Virol. 69: 552-559. Abstract

Featured News & Events

'Wisc-e-sota', a Joint UMN-UW Virology Training Grant Symposium was first held on Friday, Sepbember 20th, 2013 at the Uniiversity of Wisconsin-La Crosse, Cartwright Center. This was the inaugural collaborative symposium of the NIH T32-supported virology training programs at the University of Wisconsin-Madison and the University of Minnesota-Twin Cities. Talks and poster sessions were presented by students, postdocs and faculty. The second UMN-UW Virology Training Grant Symposium will be held in the Fall 2014. Details to follow.

The 2014 IMV Symposium will be held on May 12, 2014 and Mark Denison (Vanderbilt) and Bert Semler (UC-Irvine) will be the Keynote Speakers. Click on the link below to register and submit abstracts.

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