This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Project 3: Role of Herpesvirus Us Glycoproteins in Severe Inflammatory Disease P.I. Project 3: Dr. Patrick M. Smith Abstract, Introduction, Specific Aims, and Progress. Many viruses infect humans, resulting in an almost endless range of outcomes of infection from subclinical disease to death. The delineation of mechanisms by which virus infection of humans results in serious outcomes including pneumonia, hepatitis, and encephalitis, is of particular importance because these clinical presentations are relatively common and are associated with significant morbidity and mortality. Mouse models have been used with success to reproduce many aspects of human disease from, to name only a few, lower respiratory disease by viral pathogens such as respiratory syncytial virus (RSV) and Influenzavirus A, to oncogenic transformation, persistent infection, and the establishment of latent infection by human herpesviruses. Intranasal infection of the mouse with equineherpes virus 1 (EHV-1) results in either a protective immune response within the lungs or a fatal immunopathological response, depending on the expression of only a very few viral gene products. This model allows us to assess how viral-host interactions can shift from protective to fatally immunopathologic as the result of only a very few virally-encoded glycoproteins. EHV-1 strain KyA is attenuated in the mouse (and equine) and causes no clinical signs of disease. In contrast, the RacL11 strain of EHV-1 induces a severe inflammatory infiltration in the lung, such that the majority of infected mice succumb to infection at days 3 to 6 post infection. To identify EHV-1 determinants responsible for these immunopathological responses, we focused on genes that have been deleted in the attenuated KyA strain but expressed in the pathogenic RacL11 strain. Compared to RacL11, KyA genes encoding glycoproteins I (gI) and E (gE) deleted and 1242 base pairs of the EUS4 gene that encodes gp2. By generating recombinant KyA with restored expression of differing combinations of these glycoproteins, we can assess the role that each plays in EHV-1 virulence. We recently published that restoration of the full-length form of gp2 to KyA (KyARgp2F) completely restored respiratory virulence to this otherwise fully attenuated EHV-1 strain indicating that gp2 is the sole determinant in EHV-1 respiratory disease in the mouse model. The restoration of gI and gE to KyA (KgIgE) resulted in neurologic disease and isolation of infectious KgIgE from the brain tissue, indicating that gI and gE allow entry of EHV into the central nervous system and spread to the brain. A complete listing of all recombinant EHV recently generated or in progress is listed below in Table 1. Recent work regarding each of these important EHV-encoded glycoproteins will be described below in context with each Specific Aim of the original proposal.

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Louisiana State University Hsc Shreveport
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Kim, Jung Heon; Collins-McMillen, Donna; Buehler, Jason C et al. (2017) Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34+ Human Progenitor Cells. J Virol 91:
Martinez, Nicholas E; Sato, Fumitaka; Kawai, Eiichiro et al. (2015) Th17-biased ROR?t transgenic mice become susceptible to a viral model for multiple sclerosis. Brain Behav Immun 43:86-97
Kawai, Eiichiro; Sato, Fumitaka; Omura, Seiichi et al. (2015) Organ-specific protective role of NKT cells in virus-induced inflammatory demyelination and myocarditis depends on mouse strain. J Neuroimmunol 278:174-84
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Fernando, Viromi; Omura, Seiichi; Sato, Fumitaka et al. (2014) Regulation of an autoimmune model for multiple sclerosis in Th2-biased GATA3 transgenic mice. Int J Mol Sci 15:1700-18
Martinez, Nicholas E; Karlsson, Fridrik; Sato, Fumitaka et al. (2014) Protective and detrimental roles for regulatory T cells in a viral model for multiple sclerosis. Brain Pathol 24:436-51
Sato, Fumitaka; Omura, Seiichi; Kawai, Eiichiro et al. (2014) Distinct kinetics of viral replication, T cell infiltration, and fibrosis in three phases of myocarditis following Theiler's virus infection. Cell Immunol 292:85-93
DiGiuseppe, Stephen; Bienkowska-Haba, Malgorzata; Hilbig, Lydia et al. (2014) The nuclear retention signal of HPV16 L2 protein is essential for incoming viral genome to transverse the trans-Golgi network. Virology 458-459:93-105
Sato, Fumitaka; Martinez, Nicholas E; Shahid, Maira et al. (2013) Resveratrol exacerbates both autoimmune and viral models of multiple sclerosis. Am J Pathol 183:1390-1396

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