College of Veterinary Medicine

Veterinary Microbiology and Pathology

Michele Hardy


Michele HardyMichele Hardy
Professor and Chair, Department of Veterinary Microbiology and Pathology
509.335.6030
mhardy@vetmed.wsu.edu

 

Our laboratory studies enteric virus-host cell interactions in the context of the cell intrinsic antiviral defense response, and immune responses that are initiated and regulated at the gut mucosa.

We have a long-standing interest in how viruses have evolved to modulate the interferon (IFN)-mediated antiviral response, and the cellular proteins in key signaling pathways that viruses target for inhibitory activity. Specifically, we have studied the enteric rotavirus, a virus that is ubiquitous and causes life-threatening gastroenteritis in neonatal domestic livestock and in children. While rotavirus replication, gene expression, structure, and antigenic properties have been well studied, the interactions between rotavirus proteins and host cell proteins important in these pathways has only recently received significant research attention. For example, we and others have shown that rotavirus nonstructural protein NSP1 inhibits the activity of several proteins in the IFN induction and signaling pathways, and the repertoire of identified cellular targets is increasing. Our current studies seek to understand the breadth of molecular mechanisms rotaviruses use to modulate the antiviral response to facilitate replication and spread in the gut.

In recent efforts to identify natural compounds that may reduce rotavirus replication in the animal to the extent that either the severity or duration of disease was reduced, we identified a triterpenoid compound 18b-glycyrrhetinic acid (GRA) that shortens the duration of virus shedding in an adult mouse model. We subsequently determined that oral administration of GRA results in recruitment of B cells to isolated lymphoid follicles (ILF) in the gut. ILF are dynamic lymphoid tissues that play a key role in maintaining inflammatory homeostasis by regulating IgA synthesis in response to changes in the composition of intestinal microbiota. Our current studies seek to define mechanisms by which GRA interacts with specific cell populations in the gut to stimulate signaling pathways that result in B cell recruitment and consequent maturation of ILF.

Select publications

Graff, J.W., D.N. Mitzel, C.M. Weisend, M.F. Flenniken and M.E. Hardy. 2002 Interferon regulatory factor 3 is a cellular partner of rotavirus NSP1. J Virol 76: 9545-9550.

Shaneyfelt, M. and M.E. Hardy. 2006. Natural products that reduce rotavirus infectivity identified by a high-throughput screening assay. Virology J 3:68; doi:10.1186/1743-422X-3-68

Graff J.W, J. Ewen, K. Ettayebi, and M.E. Hardy. 2007. The zinc binding domain of rotavirus NSP1 is required for proteasome-dependent degradation of IRF3. J Gen Virol 88:613-20.

Graff, J.W., K. Ettayebi and M.E. Hardy 2009. Rotavirus NSP1 inhibits NFkB activation by inducing proteasome-dependent degradation of b-TrCP: A novel mechanism of IFN antagonism. PLoS Pathogens 5(1): eoi:10.1371/journal.ppat.1000280.

Sen, A., N. Feng, K. Ettayebi, M.E. Hardy, and H.B. Greenberg. 2009. IRF3 inhibition by rotavirus NSP1 is host cell and viral strain independent, but independent of NSP1 proteasomal degradation. J Virol. 83:10322-10335. PMC2753142

Zambrano, J.L., M.S. Shaneyfelt, W Maaty, B. Bothner and M.E. Hardy. 2011. Rotavirus infection activates the UPR but modulates its activity. Virology J 8:859

Hendricks, J.M., C. Riccardi, D.W. Pascual, and M.E. Hardy. 2012. 18b-glycyrrhetinic acids delivered orally induces B cell recruitment to the intestinal mucosa and attenuates rotavirus shedding in a mouse model. PLoS One, 7(11): e49491

Hardy, M.E., JM Hendricks, JM Paulson, and NR Faunce. 2012. 18b-glycyrrhetinic acid reduces rotavirus replication in culture. Virology J. 9:96.

Long, D, J. Mead, J.M. Hendricks, M.E. Hardy, and J. M. Voyich. 2013 18b-glycyrrhetinic acid attenuates MRSA survival and virulence gene expression. Anti Microb Agents and Chemotherapy, 57(1): 241-7

Last Edited: Nov 04, 2013 9:11 AM   

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