Enveloped viruses infect cells that express
specific virus receptors by fusion of the viral envelope with host
cell membranes. Membrane fusion is mediated by spike glycoproteins on
the viral envelope. Coronavirus entry is mediated by a single large
spike glycoprotein, S, that undergoes conformational changes when
bound to its specific cellular receptor at 37oC. Our lab
has characterized the spike glycoproteins of murine coronavirus MHV
and human coronavirus HCoV-229E. We have identified receptors for MHV
(murine CEACAM1a), HCoV-229E (human aminopeptidase N), and feline
coronaviruses (feline aminopeptidase N). We are exploring the
structure and functions of the S glycoproteins and their interactions
with their receptors to elucidate the molecular mechanisms of
coronavirus entry.
We are studying animal models that have
genetically manipulated coronavirus receptors to examine the role of
virus receptors in viral pathogenesis.
We are studying
the structure and functions S protein of the SARS-coronavirus (SARS-CoV).
In particular we are interested in identifying the receptor for the
SARS-CoV and identifying conformational changes associated with virus
infection. These studies will reveal new targets for anti-viral drugs
and may show how the SARS-CoV entered the human population from an
animal reservoir.
Selected Publications
Zelus, B.D., Wessner, D.R., Williams, R.K., Pensiero, M. N., Phibbs ,F.T., deSouza,
M., Dveksler, G.S., and Holmes, K.V. Purifed, soluble MHVR, Bgp1b and Bgp2 murine coronavirus receptors
differ in mouse hepatitis virus binding and neutralizing activities. J. Virol. 72:7237-7244 (1998).
Wang, G., Deering, C., Macke, M.,
Shao, J., Burns, R., Blau, D.M., Holmes, K.V., Davidson, B.L.,
Perlman, S., and McCray, P.B., Jr. Human coronavirus 229E infects
polarized airway epithelia from the apical surface. J. Virol.
74:9234-9239 (2000)
Wentworth, D.E. and Holmes, K.V.
Molecular determinants of species specificity in the coronavirus
receptor aminopeptidase N (CD13): Influence of N-linked glycosylation
J Virol.75:9741-52 (2001)
Blau DM, Turbide C, Tremblay M, Olson
M, Letourneau S, Michaliszyn E, Jothy S, Holmes KV, Beauchemin N
Targeted disruption of the Ceacam1 (MHVR) gene leads to reduced
susceptibility of mice to MHV infection. J. Virol.
Sep;75(17):8173-86. (2001)
Nakajima A, Iijima H, Neurath MF,
Nagaishi T, Nieuwenhuis EE, Raychowdhury R, Glickman J, Blau DM,
Russell S, Holmes KV, Blumberg RS. Activation-induced expression of
carcinoembryonic antigen-cell adhesion molecule 1 regulates mouse T
lymphocyte function. J Immunol. Feb 1;168(3):1028-35. (2002)
Tan*, K, Zelus,*
B.D., Meijers*, R., Liu, J.H., Bergelson,
J.M., Duke, N., Zhang,,R., Joachimiak,
A., Holmes, K.V., and Wang,
J.H. Crystal structure of murine
sCEACAM1a[1,4]: A coronavirus receptor in the CEA family EMBO J.
21:2076-2086 (2002)(* indicates co-first authors)
Zelus, B.D., Schickli, J.H., Blau, D.M.,
Weiss, S.R. and Holmes, K.V. Conformational changes in the spike
glycoprotein of murine coronavirus are induced at 37oC
either by soluble murine CEACAM1 receptors or by pH 8. J. Virol.
77:830-840 (2003)
Tsai, J.C., Zelus, B.D., Holmes, K.V.,
and Weiss, S.R. The N-terminal domain of the murine coronavirus spike
glycoprotein determines the CEACAM1 receptor specificity of the virus
strain. J. Virol.77:841-850 (2003)
Bonavia, A, Zelus, B.D., Wentworth,
D.E., Talbot, P.J., and Holmes, K.V. Identification of a receptor
binding domain of the spike glycoprotein of human coronavirus
HCoV-229E. J. Virol. 77:2530-8 (2003)
Breslin, J.J., Mork, I.,
Smith, M.K., Vogel, L.K., Hemmila, E.M., Bonavia, A., Talbot, P.J.,
Sjostrom, H., Noren, O., and Holmes, K.V. Human coronavirus 229E:
Receptor binding domain and neutralization by soluble receptor at 37oC.
J. Virol., 77:4435-4438 (2003)
Holmes, K.V., Editorial perspective: SARS-Associated Coronavirus, N. Eng. J. Med. 348:1948-1951 (2003)
Holmes, K.V., Spotlight
article: SARS Coronavirus: A new challenge for prevention and
therapy, J. Clin. Invest. 111:1605-1609 (2003)
Holmes, K.V. and
Enjuanes, L. Perspective. The SARS Coronavirus: A postgenomic era.
Science 300:1377-1378 (2003).
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