Kathryn V. Holmes

Professor Ph.D., Rockefeller University

Current Research

Major interests: Characterization of coronavirus receptors and analysis of the role of receptor specificity in coronavirus pathogenesis and evolution. We are interested in molecular mechanisms that determine how coronaviruses jump from one host to another to cause emerging diseases of humans and animals.

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 37°C. Our lab has analyzed the spike glycoproteins of murine coronavirus MHV, human coronavirus HCoV-229E and SARS coronavirus SARS-CoV. We have identified receptors for MHV (murine CEACAM1a), HCoV-229E (human and feline aminopeptidase N), and feline coronaviruses (feline aminopeptidase N). We recently discovered that a C-type lectin called L-SIGN or CD209L is an alternative receptor for SARS-CoV and also for HCoV-229E. We are studying receptors for coronaviruses of other species. 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 identifying inhibitors of coronavirus entry for use as candidate anti-viral drugs.

We are studying animal models that have genetically manipulated coronavirus receptors to examine the role of virus receptors in viral pathogenesis. We have shown that knocking out the CEACAM1a gene that encodes the MHV receptor from inbred mice made them resistant to MHV infection and disease. We made transgenic mice that express human APN, the receptor for HCoV-229E, and showed that although cells from these animals are susceptible to infection, the mice are resistant. We are developing small animal models for human diseases.

Recent Publications

Click Here For An Updated List Of Dr. Holmes's Publications

Howard, MV, Travanty, EA, Wennier, ST, Jeffers, SA, Thackray, LB, Holmes, KV., Aromatic amino aids in the juxtamembrane domain of SARS coronavirus spike glycoprotein are important for receptor-dependent virus entry and cell cell fusion (Submitted)

Dominguez,SR, O’Shea,TR, Oko,LM, and Holmes, KV., Detection of Group 1 Coronaviruses in Bats in North America, Emerging Infectious Diseases, Vol. 13 (9):1295; (September, 2007)

Tusell SM, Schittone SA, Holmes KV. Mutational analysis of aminopeptidase N, a receptor for several group 1 coronaviruses, identifies key determinants of viral host range. J Virol. 2007 Feb;81(3):1261-73. Epub 2006 Nov 8.

Dominguez SR, Anderson MS, Glode MP, Robinson CC, Holmes KV. Blinded case-control study of the relationship between human coronavirus NL63 and Kawasaki syndrome. J Infect Dis. 2006 Dec 15;194(12):1697-701.

Tripet B, Kao DJ, Jeffers SA, Holmes KV, Hodges RS. Template-based coiled-coil antigens elicit neutralizing antibodies to the SARS-coronavirus. J Struct Biol. 2006 Aug;155(2):176-94.

Smith MK, Tusell S, Travanty EA, Berkhout B, van der Hoek L, Holmes KV. Human angiotensin-converting enzyme 2 (ACE2) is a receptor for human respiratory coronavirus NL63. Adv Exp Med Biol. 2006;581:285-8. No abstract available.

Wentworth DE, Tresnan DB, Turner BC, Lerman IR, Bullis B, Hemmila EM, Levis R, Shapiro LH, Holmes KV. Cells of human aminopeptidase N (CD13) transgenic mice are infected by human coronavirus-229E in vitro, but not in vivo. Virology. 2005 May 10;335(2):185-97.

Thackray, L.B., Turner, B.C., Holmes, K.V. Substitutions of conserved amino acids in the receptor-binding domain of the spike glycoprotein affect utilization of murin CEACAM1a by the murine coronavirus MHV-A59. Virology, 2005 Mar 30; 334(1):98-110.

Thackray LB, Holmes KV. Amino acid substitutions and an insertion in the spike glycoprotein extend the host range of the murine coronavirus MHV-A59. Virology. 2004 Jul 1;324(2):510-24.

Holmes KV. Structural biology. Adaptation of SARS coronavirus to humans. Science. 2005 Sep 16;309(5742):1822-3. No abstract available.

Wentworth DE, Tresnan DB, Turner BC, Lerman IR, Bullis B, Hemmila EM, Levis R, Shapiro LH, Holmes KV. Cells of human aminopeptidase N (CD13) transgenic mice are infected by human coronavirus-229E in vitro, but not in vivo. Virology. 2005 May 10;335(2):185-97.

Thackray LB, Turner BC, Holmes KV. Substitutions of conserved amino acids in the receptor-binding domain of the spike glycoprotein affect utilization of murine CEACAM1a by the murinecoronavirus MHV-A59. Virology. 2005 Mar 30;334(1):98-110.

Jeffers SA, Tusell SM, Gillim-Ross L, Hemmila EM, Achenbach JE, Babcock GJ, Thomas WD Jr, Thackray LB, Young MD, Mason RJ, Ambrosino DM, Wentworth DE, Demartini JC, Holmes KV. CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus. Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15748-53.

Hemmila E, Turbide C, Olson M, Jothy S, Holmes KV, Beauchemin N. Ceacam1a-/- mice are completely resistant to infection by murine coronaviru mouse hepatitis virus A59. J Virol. 2004 Sep;78(18):10156-65.

Ramakrishna C, Bergmann CC, Holmes KV, Stohlman SA. Expression of the mouse hepatitis virus receptor by central nervous system microglia. J Virol. 2004 Jul:78(14):7828-32.

Schickli, J., Thackray, L.B., Sawicki, S.G., and Holmes, K.V. The N-terminal region of the murine coronavirus spike glycoprotein is associated with the extended host range of viruses from persistently infected murine cells. J. Virol. 2004 Sep; 78(17):9073-83.

Hemmila, E., Turbide, C., Olson, M., Jothy, S., Holmes, K.V., and Beauchemin, N. Ceacam1a -/- Mice Are Completely Resistant to Infection by Murine Coronavirus MHV-A59 J. Virol. 2004 Sep; 78(18):10156-65