Dr. Coombs is not currently accepting new students (September 2020)
The goals of my research program are to better understand virus structure, function, assembly, and pathogenesis.
We have been using mammalian reoviruses (MRV) and avian reoviruses (ARV) as models for understanding how multiple proteins and nucleic acids recognize each other and interact to generate a functionally active macromolecular complex. We have generated and characterized sets of assembly-defective temperature-sensitive (ts) mutants. These mutants, as well as normal wild-type virus, are being examined by biologic, molecular genetic, and mass spectroscopic methods to better understand virus assembly and disassembly. We also are conducting a variety of functional assays of viral RNA-dependent RNA polymerase, an enzyme unique to virtually all RNA viruses but absent from host cells to aid development of therapeutic strategies to combat RNA viruses.
Viruses induce profound changes in cells at both the genomic and protein levels. We are using state-of-the-art Systems Biology approaches, such as quantitative and comparative mass spectrometry, shRNAi, and Activity-Based Protein Profiling to understand the effects induced in the total cellular Proteome (entire protein repertoire, including all modifications) after various cells are infected with either reoviruses or influenza viruses.
There are numerous strategies to combat infections by pathogenic organisms, including vaccination and anti-virals. We are testing the capacities of various anti-viral compounds to attenuate replication of reoviruses and influenza virus. We also are interested in selecting anti-viral-resistant mutants of each virus type to better understand molecular mechanisms of antiviral effects and resistance mechanisms.
Viruses are the primary cause of infectious gastroenteritis and, importantly, many cases are caused by unknown viruses. Thus, we also seek to discover and molecularly characterize novel viral agents. We have discovered two such potentially new viruses that are currently under molecular analyses to allow comparison to other known agents and to establish diagnostic and therapeutic strategies.
Recent work by Dr. Patrick Lee at the University of Calgary has shown that reovirus may have potential as an anti-cancer agent. To be used therapeutically, it will be necessary to grow industrial-sized quantities, and, because of dangers associated with bovine spongiform encephalopathies ("mad cow disease"), preferably in growth media devoid of animal products. In collaboration with Dr. Mike Butler in the Department of Microbiology at our University, we have been experimenting with growing industrial-sized amounts of virus in serum-free media.
There is increased concern about the safety of available drinking water and environmental consequences of contaminated waste water and water runoff. In collaboration with Dr. Jan Oleszkiewicz, of the Department of Engineering, we are using the MRV as a “bio-indicator” to test the efficiency of various treatments during disinfection of water and wastewater.
There also is increased concern about decontaminating medical devices. In collaboration with Dr. Michelle Alfa we are also using MRV “bio-indicators” to test various methods for decontaminating endoscopes and other medical devices.
For a list of Dr. Coombs' publications, please clickhere
Dryden, K.A., Wang, G., Yeager, M., Nibert, M.L., Coombs, K.M., Furlong, D.B., Fields, B.N., and T.S. Baker. (1993). Early steps in reovirus infection are associated with dramatic changes in supramolecular structure and protein conformation: Analysis of virions and subviral particles by cryoelectron microscopy and image reconstruction. J. Cell Biol.122: 1023-1041. [Cover illustration] . PMID: 8394844
Coombs, K.M., Mak, S.-C., and Cox, L. (1994). Studies of the major reovirus core protein σ2: Reversion of the assembly-defective mutant tsC447 is an intragenic process and involves back mutation of Asp-383 to Asn. J. Virol.68: 177-186. PMID: 8254727
Hazelton, P.R., and K.M. Coombs. (1995). The reovirus mutant tsA279 has temperature-sensitive lesions in the M2 and L2 genes: The M2 gene is associated with reduced viral protein production and blockade in transmembrane transport. Virology207: 46-58. PMID: 7871752
Yin, P., Cheang, M, and K.M. Coombs. (1996). The M1 gene is associated with differences in the temperature optimum of the transcriptase activity in reovirus core particles. J. Virol.70: 1223-1227. PMID: 8551584
Shing, M., and K.M. Coombs. (1996). Assembly of the reovirus outer capsid requires µ1/σ3 interactions which are prevented by misfolded σ3 protein in reovirus temperature-sensitive mutant tsG453. Virus Res.46: 19-29. PMID: 9029774
Coombs, K.M.(1998). Stoichiometry of reovirus structural proteins in virus, ISVP, and core particles. Virology243: 218-228. PMID: 9527931
Berry, J.M., Bérnaby,N., Coombs, K.M., and M. Butler. (1999). Production of reovirus type-1 and type-3 from Vero cells grown on solid and macroporous microcarriers. Biotech. Bioeng.62: 12-19. PMID: 10099508
Hazelton, P.R., and K.M. Coombs. (1999). The reovirus mutant tsA279 L2 gene is associated with generation of a spike-less core particle: Implications for capsid assembly. J. Virol.73: 2298-2308. PMID: 9971813
Mendez, I.I., L.L. Hermann, P.R. Hazelton, and K.M. Coombs. (2000). A comparative analysis of Freon substitutes in the purification of reovirus and calicivirus. J. Virol. Meth.90:59-67.PMID: 11011081
Becker, M.M., Goral, M.I., Hazelton, P.R., Baer, G.S., Rodgers, S.E., Brown, E.G.,Coombs, K.M., and T.S. Dermody. (2001). Reovirus σNS protein localizes to viral inclusions and is required for viral assembly. J. Virol.75:1459-1475. [Cover illustration, subsequent month’s cover. PMID: 11152519
Patrick, M., R. Duncan, andK.M. Coombs. (2001). Generation and genetic characterization of avian reovirus temperature-sensitive mutants. Virology 284:113-122. PMID 11352672
Mendez, I., Y.-M. She, W. Ens, and K.M. Coombs. (2003). Digestion pattern of reovirus outer capsid protein sigma3 determined by mass spectrometry. Virology311:289-304. PMID: 12876456
Hermann, L.L. and K.M. Coombs. (2004). Inhibition of reovirus by mycophenolic acid is associated with the M1 genome segment. J. Virol.78:6171-6179. PMID: 15163710
Xu, W., M.K. Patrick, P.R. Hazelton, and K.M. Coombs. (2004). Avian reovirus temperature-sensitive mutant tsA12 has a lesion in the major core protein σA and is defective in assembly. J. Virol.78:11142-11151. PMID: 15452234
Robertson, C.R., L.L. Hermann, and K.M. Coombs. (2004). Mycophenolic acid inhibits replication of avian reovirus. Antiviral Res.64: 55-61. PMID: 15451179
Xu, W., A.T. Tran, M.K. Patrick, and K.M. Coombs. (2005). Assignment of avian reovirus temperature-sensitive mutants in recombination groups B, C, and D to genome segments. Virology338:227-235. [Cover illustration]. PMID: 15955543
Hadžisejdić, I., K. Cheng, J. Wilkins, W. Ens, and K.M. Coombs. (2006). High-resolution mass spectrometric mapping of reovirus digestion. Rapid Comm. Mass Spectrom.20:438-446. PMID: 16395731
Mendez, I.I., S.G. Weiner, Y.-M. She, M. Yeager, and K.M. Coombs. (2008). Conformational changes accompany activation of reovirus RNA dependent RNA transcription. J. Struct. Biol.162:277-289. PMID: 18321727
Tran, A.T., W. Xu, T. Racine, D.A. Silaghi, and K.M. Coombs. (2008). Assignment of avian reovirus temperature-sensitive mutants in recombination groups E, F, and G to genome segments. Virology375:504-513. PMID: 18353422
Douville, R.N., R.-C. Su, K.M. Coombs, F.E.R. Simons, and K.T. Hayglass. (2008). Reovirus serotypes elicit distinctive patterns of recall immunity in humans. J. Virol.82:7515-7523. PMID: 18508904
Coombs, K.M., A. Berard, W. Xu, O. Krokhin, X. Meng, J.P. Cortens, D. Kobasa, J. Wilkins, and E.G. Brown (2010). Quantitative proteomic analyses of influenza virus-infected cultured human lung cells. J. Virol.84:10888-10906. (Spotlight article). PMID: 20702633