Professor and Chair, Department of Veterinary Microbiology and
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.
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:
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
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):
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