Kyeong-Ok Chang DVM, 1989, Seoul National University MS, 1991, Seoul National University PhD, 1999, The Ohio State University Assistant Professor, Veterinary Virology Phone: (785)532-3849 Fax: (785)532-4039 Email: kchang@vet.ksu.edu

Research

Caliciviruses (Family Caliciviridae) are important animal and human pathogens associated with a wide spectrum of diseases. There are four genera established in the family: Norovirus, Sapovirus, Vesivirus, and Lagovirus. Viruses in the genera Norovirus and Sapovirus cause gastroenteritis in humans and animals (including pigs, cattle and minks). Noroviruses are major causes of food and water borne viral gastroenteritis and Category B Bioterrorism Agents/Diseases. However the lack of cell culture and animal models for noroviruses has greatly hindered the researches on theses fastidious viruses. The overall goal of my research is to establish cell culture and animal models for noroviruses using porcine enteric calcivirus (PEC) and murine norovirus (MNV).

The Cowden strain of PEC (a Sapovirus) that causes diarrhea in gnotobiotic pigs was adapted in a continuous cell line (LLC-PK), but viral growth is dependent on the presence of intestinal content fluid filtrate (IC, obtained from uninfected gnotobiotic pigs) or bile acids in the medium. In prior research, I discovered that the IC or bile acid effects on the growth of PEC were associated with the induction of a protein kinase A (PKA) signaling pathway, and the induction of this PKA pathway down-regulated interferon-mediated STAT1 activation, a key element in innate immunity against virus infection. Based on this observation, I proposed a novel mechanism for enteric calicivirus growth dependent on bile acids, ubiquitous molecules present in the intestine at the site of the virus replication that involves the PKA pathway and a down-regulation of innate immunity. My current research goals are to explore the recently developed reverse genetics system of PEC to identify genetic factors for virus adaptation and virulence in gnotobiotic pigs; and to examine the roles of bile acids and innate immunity in the growth of PEC and related fastidious viruses including noroviruses in cell culture.

Murine norovirus-1 (MNV-1) was originally found in a STAT1 deficient mouse colony associated with high mortality. Recently, the MNV-1 was isolated in cultured primary dendritic cells and macrophages, and was inhibited by the interferon-αβ receptor and STAT1, which suggests the importance of innate immunity in enteric calicivirus replication in vivo and in vitro. I am interested in the further analysis of innate immunity on the growth of MNV-1 in vitro, and the establishment of a mouse model of MNV-1 to understand the mechanisms of cell culture adaptation and pathogenesis of noroviruses, respectively.

Selected Publications

Chang, K.O., S.V. Sosnovtsev, G. Belliot, K.Y. Green. 2005. Replication of Norwalk Virus RNAs in Cell Culture and their Clearance by Alpha- Interferon. Submitted .

Chang, K.O., S.V. Sosnovtsev, G. Belliot, Q. Wang, L.J. Saif, K.Y. Green. 2005. A reverse genetics system for porcine enteric calicivirus is dependent on bile acids for recovery of virus in cultured cells. J Virol. 79(3):1409-16.

Sosnovtsev, S.V., G. Belliot, K.O. Chang, O. Onwudiwe, K.Y. Green. 2005. Feline calicivirus VP2 is essential for the production of infectious virions. J Virol. 79(7):4012-24.

Han, M.G., Q. Wang, J.R. Smiley, K.O. Chang, L.J. Saif. 2005. Self-assembly of the recombinant capsid protein of a bovine norovirus (BoNV) into virus-like particles and evaluation of cross-reactivity of BoNV with human noroviruses. J Clin Microbiol. 43(2):778-85

Belliot, G., S.V. Sosnovtsev, K.O. Chang, V. Babu, U. Uche, JJ. Arnold, C.E. Cameron, K.Y. Green. 2005. Norovirus proteinase-polymerase and polymerase are both active forms of RNA-dependent RNA polymerase. J Virol. 79(4):2393-403.

Wobus, C.E., S.M. Karst, A. Krug, K.O. Chang, S.V. Sosnovtsev, G. Belliot, J.M. Mackenzie, K.Y. Green, H.W. Virgin. 2004. Replication of a Norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLoS Biology . 2(12):e432.

Chang, K.O., S.V. Sosnovtsev, G. Belliot, Y. Kim, L.J. Saif, K.Y. Green, 2004. Bile acids are essential for porcine enteric calicivirus replication in association with down-regulation of Stat1. Proc Natl Acad Sci U S A, 101(23):8733-8.

Kuyumcu-Martinez, M., G. Belliot, S.V. Sosnovtsev, K.O. Chang, K.Y. Green, R.E. Lloyd. 2004. The Calicivirus 3CL protease inhibits cellular translation by cleavage of poly(A)-binding protein. J. Virol. 78(15):8172-82.

Gonzalez, A.M., T.V Nguyen, M.S. Azevedo, K. Jeong, F. Agarib, C. Iosef, K.O. Chang, K. Lovgren-Bengtsson, B. Morein, L.J. Saif, 2004. Antibody responses to human rotavirus (HRV) in gnotobiotic pigs following a new prime/boost vaccine strategy using oral attenuated HRV priming and intranasal VP2/6 rotavirus-like particle (VLP) boosting with ISCOM. Clin Exp Immunol. 135(3): 361-72.

Azevedo, M.S., L. Yuan, C. Iosef, K.O. Chang, Y. Kim, T.V. Nguyen, L.J. Saif. 2004. Magnitude of serum and intestinal antibody responses induced by sequential replicating and nonreplicating rotavirus vaccines in gnotobiotic pigs and correlation with protection. Clin. Diagn. Lab. Immunol. 11(1): 12-20.

Nguyen, T.V., C. Iosef, K. Jeong, Y. Kim, K.O. Chang, K. Lovgren-Bengtsson, B. Morein, M.S. Azevedo, P. Lewis, P. Nielsen, L. Yuan, L.J. Saif. 2003. Protection and antibody responses to oral priming by attenuated human rotavirus followed by oral boosting with 2/6-rotavirus-like particles with immunostimulating complexes in gnotobiotic pigs. Vaccine. 21(25-26): 4059-4070.

Hoet, A.E, K.O. Chang, L.J. Saif. 2003. Comparison of ELISA and RT-PCR versus immune electron microscopy for detection of bovine torovirus (Breda virus) in calf fecal specimens. J. Vet. Diagn. Invest. 15(2): 100-6.

Chang, K.O., Y. Kim, K. Green, L.J. Saif. 2002. Cell culture propagation of porcine enteric caliciviruses is dependent on cyclic AMP signaling pathway by intestinal contents. Virology. 304(2): 302-10.

Kim, Y., K.O. Chang, W. Kim, L.J. Saif. 2002. Production of the hybrid triple-layered virus-like-particles (VLPs) of group A and C rotaviruses using a baculovirus express system. Virology. 302(1): 1-8.

Smiley, J.R., K.O. Chang, J. Hayes, J. Vinje, L.J. Saif. 2002. Characterization of an enteropathogenic bovine calicivirus representing a potentially new calicivirus genus. J. Virol. 76(20): 10089-10098.

Iosef, C., K.O. Chang, M. Azevedo, L.J. Saif. 2002. Isotype specific antibody responses to NSP4 of Wa Human rotavirus (HRV) in gnotobiotic pigs inoculated with attenuated or virulent Wa HRV. J. Med. Virol. 68(1): 119-28.

Iosef, C., T.V. Nguyen, K. Jeong, Y. Kim, K.O. Chang, K. Lovgren-Bengssor, B. Morein, M.S.P. Azevedo, L. Yuan, P. Nielsen, P. Lewis, L.J. Saif. 2002. Systemic and intestinal antibody secreting cell responses in gnotobiotic pigs immunized per oral with Wa attenuated human rotavirus (HRV) and Wa 2/6-rotavirus-like-particles associated with immuno-stimulating complexes. Vaccine. 20(13): 1741-1753.

Kim, Y.J., P.R. Nielsen, D. Hodgins, K.O. Chang, L.J. Saif. 2002. Lactogenic antibody responses in cows vaccinated with recombinant bovine rotavirus-like-particles (VLPs) of two serotypes or inactivated bovine rotavirus vaccines. Vaccine. 20 (7-8): 1248-58.

Cho, K.O., M. Hasoksuz, P.R. Nielsen, K.O. Chang, S. Lathrop, L.J. Saif. 2001. Cross-protection studies between respiratory and calf diarrhea and winter dysentery coronavirus strains in calves and RT-PCR and nested PCR for their detection. Arch. Virol. 146: 2401-19.

Yuan, L., A. Geyer, Y. Quan, C. Iosef, M. Azevedo, Y. Kim, K.O. Chang, L.J. Saif. 2001. Protective immunity and antibody-secreting cell responses elicited by combined oral attenuated Wa human rotavirus and intranasal administration of 2/6-VLPs with mutant Escherichia coli heat-labile toxin (LT-R192G) in gnotobiotic pigs. J. Virol. 75(19): 9229-38.

Chang, K.O., O.H. Vandal, L. Luan, D.C. Hodgins, L.J. Saif. 2001. Antibody secreting cell responses to rotavirus proteins in gnotobiotic pigs inoculated with attenuated or virulent Wa human rotavirus. J. Clin. Microbiol. 39(8): 2807-13.

Guo, M., Y. Qian, K.O. Chang, L.J. Saif. 2001. Expression and self-assembly in baculovirus of porcine enteric calicivirus capsids into virus-like particles and their use in an enzyme-linked immunosorbent assay for antibody detection in swine. J. Clin. Microbiol. 39(4): 1487-93.

Yuan, L., A. Geyer, D.C. Hodgins, Z. Fan, Y. Qian, K.O. Chang, S.E. Crawford, V. Parreno, L.A. Ward, M.K. Estes, M.E. Conner, L.J. Saif. 2000. Intranasal administration of 2/6-rotavirus-like particles with mutant Escherichia coli heat-labile toxin (LT-R192G) induces antibody-secreting cell responses but not protective immunity in gnotobiotic pigs. J. Virol. 74(19): 8843-53.

Chang, K.O., A.V. Parwani, L.J. Saif. 2000. Comparative sequence analysis of the VP7 gene of G6, G8 and G10 bovine group A rotavirus and further characterization of G6 subtypes. Arch. Virol. 145:725-737.

Guo, M., K.O. Chang, M.E. Hardy, Q. Zhang, L.J. Saif. 1999. Molecular characterization of a porcine enteric calicivirus genetically related to Sapporo-like human caliciviruses. J. Virol. 73(11): 9625-31.

Chang, K.O., P.R. Nielsen, L.A. Ward, L.J. Saif. 1999. Dual infection of gnotobiotic calves with bovine strains of group A and porcine-like group C rotaviruses influences pathogenesis of the group C rotaviruses. J. Virol. 73(11): 9284-93.

Chang, K.O., Y. Kim, L.J. Saif. 1999. Comparisons of nucleotide and deduced amino acid sequences of NSP4 genes of attenuated and virulent group A and C rotaviruses. Virus Genes. 18(3): 229-33.

Chang, K.O., A.V. Parwani, D. Smith, L.J. Saif. 1997. Detection of group B rotaviruses in fecal samples from diarrheic calves and adult cows and characterization of their VP7 genes. J. Clin. Microbiol. 35(8): 2107-2110.

Chang, K.O., A.V. Parwani, L.J. Saif. 1996. The characterization of VP7 (G type) and VP4 (P type) genes of bovine group A rotaviruses from field samples using RT-PCR and RFLP analysis. Arch. Virol. 141: 1727-1739.

Chang, K.O., A.V. Parwani, L.J. Saif. 1995. Comparative nucleotide and deduced amino acid sequence analysis of VP7 gene of the NCDV Cody(I-801) strain of group A bovine rotavirus. Arch. Virol. 140(7): 1279 - 1284.