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20 July 2022

Kathryn V. Holmes: A Career of Contributions to the Coronavirus Field

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1
Vaccine Development, Bill & Melinda Gates Medical Research Institute, Cambridge, MA 02139, USA
2
Department of Pediatrics-Infectious Diseases, University of Colorado School of Medicine, Aurora, CO 80045, USA
3
Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
4
Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA
Viruses2022, 14(7), 1573;https://doi.org/10.3390/v14071573
This article belongs to the Special Issue Women in Virology
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Abstract

Over the past two years, scientific research has moved at an unprecedented rate in response to the COVID-19 pandemic. The rapid development of effective vaccines and therapeutics would not have been possible without extensive background knowledge on coronaviruses developed over decades by researchers, including Kathryn (Kay) Holmes. Kay’s research team discovered the first coronavirus receptors for mouse hepatitis virus and human coronavirus 229E and contributed a wealth of information on coronaviral spike glycoproteins and receptor interactions that are critical determinants of host and tissue specificity. She collaborated with several research laboratories to contribute knowledge in additional areas, including coronaviral pathogenesis, epidemiology, and evolution. Throughout her career, Kay was an extremely dedicated and thoughtful mentor to numerous graduate students and post-doctoral fellows. This article provides a review of her contributions to the coronavirus field and her exemplary mentoring.

1. Introduction

Over the course of a research career spanning more than five decades, Kathryn (Kay) Holmes has contributed a wealth of critical knowledge to the field of virology. From her Ph.D. work at the Rockefeller University with Purnell Choppin studying cell fusion by simian virus 5, to identifying lymphocytic choriomeningitis virus as a cause of fatal callitrichid hepatitis in primates, to starting a company focused on the development of universal influenza vaccines, Kay has always been fascinated by a diversity of viruses. However, most of her research has focused on coronaviruses. Her interests in coronaviruses have included host and tissue specificity, viral spike/receptor interactions, viral and cell fusion mechanisms, pathogenesis, and epidemiology. Here, we focus on Kay’s contributions to the coronavirus field, which have provided a foundation for current research on and development of vaccines and therapies for pandemic coronaviruses. In addition to her remarkable scientific contributions, one of her most influential activities has been mentoring numerous graduate students and post-doctoral researchers. The authors of this article are a subset of those trainees and are forever grateful for Kay’s enthusiastic support and dedication to launching and supporting our interests in virology and our careers.

2. Characterizing Coronaviral Structural Proteins

In 1977, while at the Uniformed Services University of the Health Sciences, Kay first published work on coronaviruses with Larry Sturman, who had begun to characterize the structural proteins of the murine coronavirus mouse hepatitis virus (MHV-A59) [1]. Initially, they identified and characterized the two membrane-associated envelope proteins of MHV-A59: the spike glycoprotein (S) that makes up the large petal-shaped peplomers on the envelope and the smaller, transmembrane matrix glycoprotein (M) important for virion morphogenesis and assembly [2,3]. They determined that, like many other viral glycoproteins, S was an N-linked glycoprotein. In contrast, they determined that M was an O-linked glycoprotein, potentially making it the first identified viral glycoprotein of this type [4]. Kay also studied the major coronaviral RNA binding protein, nucleocapsid (N), and its role in viral replication [5,6]. Later, Kay and her coauthors defined the role of S in virion attachment and cell-fusing activities [7]. They determined that S was proteolytically cleaved into two different domains, the N-terminal half (90B or S1) and the C-terminal half (90A or S2), during virion maturation or through exogenous protease treatment. They also discovered how the regulation of S cleavage, the location of the cleavage site, the rate of transport of cleaved S to the cell membrane, and the lipid composition of the host cell membrane determined the extent of MHV-A59-induced syncytia formation [7,8,9]. Finally, Kay and her coauthors elucidated how a temperature-dependent, alkaline pH-dependent, irreversible conformational change in S led to the shedding of S1 and viral fusion at the plasma membrane [10,11]. These efforts set the stage for Kay’s later work spanning multiple areas of coronavirus virology, including receptor discovery, further S protein characterization, pathogenesis, and epidemiology (Figure 1).
Figure 1. Contributions to the coronavirus field from Dr. Kay Holmes’ laboratory group. Areas of study are color coded by topics listed on the left for the specified coronaviruses shown in reference to the timeline across the bottom. MHV: mouse hepatitis virus; SARS: severe acute respiratory syndrome coronavirus; Beta-CoVs: betacoronaviruses; 229E: human coronavirus 229E; BCoV: bovine coronavirus; HKU1: human coronavirus HKU1; MERS: Middle East respiratory syndrome coronavirus; CoVs: coronaviruses.

3. Discovering Coronavirus Receptors

3.1. CEACAM1a as a Receptor for MHV

When Kay’s lab identified the MHV-A59 receptor in 1991, only a few viral receptors, including those for HIV, rhinovirus, and poliovirus, had been identified [12,13,14]. As Kay correctly predicted for human and murine coronaviruses, the presence of virus-specific receptors and co-receptors was found to be an important determinant of viral host specificity and cellular tropism within a host [15]. Kay’s interesting observation that the SJL/J mouse strain was resistant to MHV-A59 infection suggested that these mice either lacked the receptor or had a mutated form of it. Confirming this supposition required the development of a creative technique, the virus overlay protein blot assay, which demonstrated MHV-A59 binding to a 110 kDa protein in cell membranes from susceptible, but not resistant, mouse strains [15]. Additional elegant experiments identified the cellular receptor for MHV-A59 as a member of the carcinoembryonic antigen (CEA) glycoprotein family, later known as CEACAM1a [16,17]. Additional strains of MHV, including DVIM that expresses a hemagglutinin esterase protein and JHM, were also shown to require CEACAM1a for infection [18]. Using several techniques, including RT-PCR with degenerate primers based on the N-terminal domain of the putative receptor glycoprotein in susceptible mouse strains and site-directed mutagenesis, Kay and her colleagues showed that MHV-A59 bound to the first Ig-domain of CEACAM1, formerly designated as biliary glycoprotein (BGP1) or MHV receptor (MHVR) [19,20,21,22]. In contrast, MHV-A59 bound with much lower affinity to an allelic variant of CEACAM1 expressed in the resistant SJL/J mouse strain and did not bind to brush border membranes from species other than mouse [23]. These were seminal results in virology that linked receptor binding to host species specificity. CEACAM1a-null mice were resistant to MHV-A59 infection and mice with impaired expression of the four Ig domain isomers of CEACAM1a had reduced susceptibility, further demonstrating the importance of this molecule for viral pathogenesis [24,25]. Interestingly, Kay and collaborators later showed that neurotropic MHV strain JHM could infect and spread in the brain of CEACAM1a-null mice, though less efficiently than in wild-type mice [26]. In total, this body of work represents one of the early molecular approaches to identifying and characterizing a viral receptor and has contributed significantly to our understanding of viral cell entry and pathogenesis.

3.2. APN as a Receptor for HCoV-229E and Other Alphacoronaviruses

Although human coronaviruses were isolated in the 1960s, researchers knew very little about the diversity and function of the human coronavirus S protein or the nature of its receptor even by 1990. The first breakthrough came in 1992 when Kay’s lab identified human aminopeptidase N (hAPN or CD13) as the receptor for human coronavirus 229E (HCoV-229E) [27]. A monoclonal antibody raised against plasma membranes of susceptible cell lines blocked infection by HCoV-229E. In addition, immunoprecipitation assays with this antibody led to identification of hAPN as the potential receptor. Confirmation came from molecular approaches, including the expression of hAPN in a non-permissive mouse cell line, which rendered these cells susceptible to HCoV-229E infection. Further characterization of this protein showed that the hAPN catalytic site was important for receptor activity, but its enzymatic activity was not required for infection. At the same time, porcine (p)APN was determined to be the receptor for the porcine coronavirus TGEV [28], but there was a clear species specificity. HCoV-229E could not use pAPN as its receptor and TGEV could not use hAPN as its receptor [29,30].
Kay’s lab members explored this species specificity further and demonstrated that HCoV-229E bound to membranes of feline, canine, porcine, and human cell lines, and intestinal brush border membranes from these species but only infected human and feline cells [30]. Of note, transfection of the various non-permissive cell lines with genomic RNA of HCoV-229E resulted in virus production. Thus, a step in the viral replication cycle between binding and transcription contributed to species specificity of HCoV-229E. Kay’s group also identified feline (f)APN as the receptor for the two feline coronaviruses FIPV and FeCoV [31]. Interestingly, they determined that fAPN was a universal receptor for the former group 1 coronaviruses, now alphacoronaviruses, including HCoV-229E, TGEV, and the canine coronavirus CCoV. Her lab members further demonstrated that introducing a single glycosylation site in hAPN prevented HCoV-229E infection [32]. However, deletion of the homologous glycosylation site in pAPN did not enable infection by HCoV-229E. These data suggested a role for additional determinants in the species specificity of HCoV-229E. To conduct pathogenesis studies with HCoV-229E in vivo, Kay’s laboratory engineered a transgenic mouse line expressing hAPN, and went on to show that although hAPN was expressed in cells from these transgenic mice and selected cells could be infected in vitro, the mice were resistant to infection in vivo, suggesting that other host factors were required for infection [33]. Additional molecular studies used mutational analysis of APN and the generation of murine/feline chimeras to show that three areas of APN were important for host range, but the determinants were not identical for all alphacoronaviruses [34].
In contrast to the other alphacoronaviruses, HCoV-NL63 was unable to use hAPN or fAPN as a receptor [35]. Surprisingly, Kay’s lab and others subsequently identified angiotensin converting enzyme 2 (ACE2) as an entry receptor for HCoV-NL63 [35,36]. ACE2 has been identified as a receptor for betacoronaviruses SARS-CoV and SARS-CoV-2 [37,38]. Thus, major shifts appear to have occurred in closely related coronaviruses such that they do not necessarily use related receptor proteins, and more distantly related coronaviruses convergently evolved to use the same receptor protein.

3.3. CD209L/L-SIGN as a Receptor for SARS-CoV

When SARS coronavirus (SARS-CoV) emerged in human populations in late 2002, Kay’s laboratory joined efforts by many investigators to characterize the new pandemic virus. Having identified CEACAM1 and APN as receptors for MHV-A59 and multiple alphacoronaviruses, respectively, her lab was uniquely situated to identify a receptor for SARS-CoV. Kay’s group transduced a cell line that was resistant to SARS-CoV infection with a retroviral vector expressing a human lung cDNA library and sorted cells based on SARS-CoV S binding [39]. These cells were used to identify CD209L/L-SIGN as a potential receptor or co-receptor for SARS-CoV entry. Although ACE2 has been shown to be the major receptor for both SARS-CoV and SARS-CoV-2 [37,38,40], other laboratories have reported that CD209L/L-SIGN also may serve as a receptor for SARS-CoV-2 [41].

4. Characterizing Spike: Receptor Interactions and Fusion Activity

In addition to identifying coronavirus receptors and determining their role in viral host range, Kay eagerly explored the molecular interactions between S proteins and their receptors. Starting with MHV-A59 and CEACAM1a, her lab characterized S/receptor interactions using mutational analysis of S and monoclonal antibody binding sites in CEACAM1 [42]. The finding that multiple different CEACAM proteins and isoforms functioned as receptors for MHV-A59 provided insight into receptor determinants of infection [43,44]. After extensive passage of persistently infected murine cells, Kay’s lab discovered a host-range mutant of MHV-A59, MHV/BHK, that was able to infect a wide range of non-murine cell lines [45]. Characterization of this mutant revealed that residue changes within the N-terminal domain of S changed its receptor specificity and viral host range [46,47,48].
Kay collaborated with structural biologists Jia-huai Wang (Harvard Medical School) and Fang Li (University of Minnesota) to solve crystal structures of the murine CEACAM1a protein, the N-terminal domain of MHV-A59 S in complex with CEACAM1a, and the bovine coronavirus S N-terminal domain [49,50,51]. These studies provided structural insight into MHV-A59 S/CEACAM1a and BCoV S/glycan interactions. Kay’s and Fang Li’s groups further solved the crystal structure of the murine CEACAM1b protein, revealing critical insight into the differences in MHV receptor activity of CEACAM1a and CEACAM1b [16,21,52].
Kay’s early work investigated the pH-triggering of MHV-A59 S with and without receptor binding and showed that receptor-independent syncytia formation resulted from a delicate balance between S protein stability and viral fitness [10,11]. Her group subsequently described conformational changes in MHV-A59 S triggered by either receptor binding or pH 8, showing that cleavage between S1 and S2 was not required for conformational changes associated with fusion [53]. Later work from her lab identified a histidine in the 209 position of MHV-A59 S protein as a key pH sensor for this process and showed that a single substitution (G29P) arrested S in a prefusion state, even when bound to its receptor [54,55]. These studies provided vital clues about the molecular mechanisms of S-mediated membrane fusion and viral entry.
After discovering the role of APN proteins as coronaviral receptors, Kay’s lab continued to characterize HCoV-229E S interactions with hAPN. Molecular approaches demonstrated that the S1 region between amino acids 417 and 547 harbored the receptor binding domain of HCoV-229E [56]. However, the initial steps for HCoV-229E entry remained unknown. To investigate this topic, Kay’s lab used drugs to inhibit endosomal acidification and showed that HCoV-229E entered cells via hAPN-dependent endocytosis [57]. Although there was no known cleavage event for the HCoV-229E S glycoprotein, conformational changes that occurred at 37 °C, but not at 4 °C, were observed in vitro using soluble receptor and S protein constructs coupled with neutralization assays [58].
Prior to the identification of a receptor for HCoV-HKU1, Kay’s group generated monoclonal antibodies and recombinant truncated S proteins to map receptor binding function to the C-domain of S1 [59]. This finding contrasted with other betacoronaviruses (MHV, OC43, and BCoV), whose S proteins were shown to bind to receptor proteins or sugars by the N-terminal domain of S1. Alphacoronaviruses, including HCoV-229E, TGEV, and HCoV-NL63, were also found to have receptor binding activity in the C-domain of S1. Thus, Kay and her colleagues provided a new example of the modular nature of CoV S proteins. Binding and entry of two CoVs in the same phylogenetic group could be initiated by different regions of the S glycoprotein.
Following receptor binding by the S1 domain, the C-terminal portion of S, the S2 domain, plays a major role in large conformational changes in S that mediate membrane fusion. In the early days of the SARS-CoV pandemic, Kay partnered with Robert Hodges (University of Colorado Health Sciences Center) to dissect the role S2 played in SARS-CoV infection. Their work resulted in biophysical characterization of the heptad repeats, the juxtamembrane domain, and the fusion peptide of the SARS-CoV S protein [60,61,62]. Locating and targeting the heptad repeats was essential for understanding S2 conformational changes that mediate membrane fusion and designing strategies to interrupt those changes [61,63,64]. In addition to investigating the fusion peptide of SARS-CoV, Kay’s group also identified the fusion peptides in the S glycoproteins of another emergent human CoV, MERS-CoV, and MHV-A59 [62]. Although the amino acid sequences of the fusion peptides of these divergent CoV S proteins were found to be quite different, they had conserved functions and locations within S. These foundational studies have provided critical insight into the ongoing development of therapies and vaccines that may be effective against the currently circulating SARS-CoV-2 virus and future pandemic strains.

5. Understanding Coronaviral Pathogenesis

To better understand disease pathogenesis, Kay applied the cellular and molecular details of CoV biology in murine and primary cell model systems. Much of this work focused on using MHV-A59 as a model for demyelinating disease. In a productive collaboration with Monique Dubois-Dalcq (NIH), Kay and her colleagues characterized cellular and molecular mechanisms of demyelination and remyelination in MHV-A59 infected mice. Their work associated differences in neuropathogenesis among MHV strains with differences in tropism, cytopathic effects, and virion assembly in neuronal versus non-neuronal cell types within cultured cells from murine spinal cords [65]. In multiple mouse strains, they characterized the pathology, kinetics, and location of viral RNAs and antigens and the expression of host genes through the process of MHV-A59-induced demyelination and remyelination [66,67,68,69,70]. In these studies, cell type-specificity was carefully evaluated, and the findings were confirmed using primary cell models [65,71]. This work not only provided critical mechanistic insight into viral demyelination but also into the mechanisms leading to remyelination and recovery from disease.
In addition to dissecting the roles of various cell types in viral demyelinating disease, Kay was also interested in cell-type specificity of CoV infections in the respiratory tract. Using polarized airway epithelial cells and human tracheal explanted tissues, her group showed that HCoV-229E entered and exited polarized airway cells apically [72]. Collaborating with Robert Mason (National Jewish Health), an expert in the isolation and culture of primary, differentiated alveolar epithelial cells, Kay’s group evaluated lung cell-type specificity and immune responses to infection by SARS-CoV, HCoV-229E, and rat coronaviruses [73,74,75,76,77,78]. With Peter Rottier’s group (Utrecht University), Kay and colleagues performed studies to correlate coronavirus entry and exit of polarized cells with infection and spread in the enteric tract. They found that MHV-A59 entered on the apical side but exited the cell from the basolateral side [79]. In contrast, TGEV entered and exited polarized cells from the apical surface [79]. These studies contributed to the knowledge of the cell-type specificity of respiratory CoV infections and established primary cell models to evaluate cell-type contributions to immunity and pathogenesis.

6. Characterizing Coronaviral Epidemiology

Following the SARS epidemic in 2003, renewed interest in human coronaviruses led to the discovery of HCoV-NL63 and HCoV-HKU1 [80,81]. Kay expanded her research into understanding the clinical and molecular epidemiology, pathophysiology, and disease associations of these previously unknown viruses. Her group’s work documented that HCoV-NL63 and HCoV-HKU1 caused significant respiratory disease in children with seasonal and yearly variations [82,83]. These studies also demonstrated that, surprisingly, the N-terminal domain of the HCoV-NL63 S protein was the most variable part of the genome and found evidence of recombination between strains [84]. In contrast, Kay’s group found remarkable sequence conservation in HCoV-HKU1 viruses circulating throughout the world [83].
In addition to this work on “new” human coronaviruses, Kay astutely recognized the role of zoonotic viruses as emerging pathogens. The recognition that SARS-CoV emerged from Asian bats highlighted the importance of bats as reservoir hosts for emerging viruses [85,86,87], and Kay began exploring the extent to which bats could harbor viruses and serve as potential reservoirs for disease outbreaks worldwide. Towards this end, her lab was the first to demonstrate that bats in North America harbored a diverse array of CoVs [88]. Further exploring the ecology of these viruses, her work suggested that the ongoing evolution of CoVs in bats would provide a continued threat of the emergence in new host species [89]. These studies found a high prevalence of alphacoronavirus RNAs in big brown bats in roosts in proximity to human habitations and known to have direct contact with people. These data suggested the significant potential for cross-species transmission of CoVs. Collaborating with others around the world, her lab also found novel CoVs in bats in Latin and South America [90]. Kay’s work in this area expanded knowledge of and the impetus to further study the role of bats in zoonotic viral outbreaks [87], which has been quite relevant to the current COVID-19 pandemic.

7. Mentoring Virologists

In addition to her many meaningful contributions to our understanding of coronaviruses, Kay also served as a dedicated and valued mentor. We recall our experiences not only in the details of virology that we learned, but also in more personal ways. Kay’s holistic approach to mentoring made working with and learning from her unique. We joined Kay’s lab because of her infectious curiosity and enthusiasm. She would read Science magazine while brushing her teeth to keep up on new articles and learn new things. Her joy spread to her mentees and empowered them to be curious about coronaviruses but also other areas of science. Kay’s encouragement led us to put aside fears of not-knowing, introduce ourselves to everyone, and to stay curious. We forged connections leading to collaborations, friendships, and job opportunities.
In Kay’s group, everyone worked on proposals and reviewed data. “Never apologize for your data”, a mantra many of us learned from Kay, was learned alongside thoughtful and elegant experimental design. Kay’s knowledge of techniques, applications of techniques across fields, and fearlessness to try new or out-of-the-box ideas in the lab created a generation of scientists unafraid to step outside the lines. Kay’s reviews of our manuscripts, theses, proposals, and presentations were masterclasses in effectively communicating science. The power of her red pen taught us scientific writing and the importance of constructive criticism. Her extensive edits, suggestions, and red-inked drafts inevitably made the next iteration better and conveyed to us lessons in scientific communication that many of us only appreciated later in our careers.
Kay has always been extremely generous with her time, knowledge, and reagents. One former post-doc remembers that Kay spent entire car trips between Bethesda and the USAMRIID facility, ensuring that he was grounded in virology so that he could make the transition from a cell biologist to a virologist. In many cases, these efforts instilled generosity and curiosity in her students. During the initial SARS-CoV pandemic, her entire group raced to understand this new virus but first worked collaboratively and collectively to generate and share reagents, cell lines, ideas, and data with other researchers with the same goal. Kay’s trainees took concepts, projects, and reagents to their new positions but also brought skills needed for effective collaborations.
Perhaps one measure of Kay’s impact is the diversity of contributions we, her mentees, have made. We are studying infectious diseases, the immune system, and the microbiome. We have written articles, essays, and books. We are researchers and professors involved in policy-making and teaching undergraduates. Many of us are working to understand SARS-CoV-2 as well as develop therapeutics and vaccines to combat this latest coronavirus pandemic. Despite the varied paths we have taken and the different roles we now fill, we all share Kay’s passion for science and her joy in sharing that passion with others.

Author Contributions

Conceptualization, Z.Q. and T.A.M.; writing- original draft preparation, A.B., S.R.D., G.D., S.G., M.H, Z.Q., M.K.S., L.B.T. and T.A.M.; writing- review and editing, M.H., S.J., D.B.T., D.E.W., D.R.W., R.K.W. and T.A.M.; visualization, Z.Q., M.H. and T.A.M. All authors have read and agreed to the published version of the manuscript.

Funding

G.D. was supported by grant R21AI156058 from the National Institutes of Health.

Acknowledgments

We would like to thank all of Kay’s trainees and colleagues that we worked with while training in her lab and we regret any unintentional omissions that are inherent in an article of this scope. We are all extremely grateful for the opportunity to have had Kay as a mentor. Our careers and lives have been shaped by the gifts of her knowledge, enthusiasm, and belief in us as scientists and people.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sturman, L.S. Characterization of a Coronavirus I. Structural Proteins: Effects of Preparative Conditions on the Migration of Protein in Polyacrylamide Gels. Virology 1977, 77, 637–649. [Google Scholar] [CrossRef]
  2. Sturman, L.S.; Holmes, K.V. Characterization of a Coronavirus II. Glycoproteins of the Viral Envelope: Tryptic Peptide Analysis. Virology 1977, 77, 650–660. [Google Scholar] [CrossRef]
  3. Sturman, L.S.; Holmes, K.V.; Behnke, J. Isolation of Coronavirus Envelope Glycoproteins and Interaction with the Viral Nucleocapsid. J. Virol. 1980, 33, 449–462. [Google Scholar] [CrossRef] [PubMed]
  4. Holmes, K.V.; Doller, E.W.; Sturman, L.S. Tunicamycin Resistant Glycosylation of a Coronavirus Glycoprotein: Demonstration of a Novel Type of Viral Glycoprotein. Virology 1981, 115, 334–344. [Google Scholar] [CrossRef]
  5. Robbins, S.G.; Frana, M.F.; Mcgowan, J.J.; Boyle, J.F.; Holmes, K.V. RNA-Binding Proteins of Coronavirus MHV: Detection of Monomeric and Multimeric N Protein with an RNA Overlay-Protein Blot Assay. Virology 1986, 150, 402–410. [Google Scholar] [CrossRef]
  6. Compton, S.R.; Rogers, D.B.; Holmes, K.V.; Fertsch, D.; Remenick, J.; McGowan, J.J. In Vitro Replication of Mouse Hepatitis Virus Strain A59. J. Virol. 1987, 61, 1814–1820. [Google Scholar] [CrossRef] [PubMed]
  7. Sturman, L.S.; Ricard, C.S.; Holmes, K.V. Proteolytic Cleavage of the E2 Glycoprotein of Murine Coronavirus: Activation of Cell-Fusing Activity of Virions by Trypsin and Separation of Two Different 90K Cleavage Fragments. J. Virol. 1985, 56, 904–911. [Google Scholar] [CrossRef]
  8. Frana, M.F.; Behnke, J.N.; Sturman, L.S.; Holmes, K.V. Proteolytic Cleavage of the E2 Glycoprotein of Murine Coronavirus: Host-Dependent Differences in Proteolytic Cleavage and Cell Fusion. J. Virol. 1985, 56, 912–920. [Google Scholar] [CrossRef]
  9. Roos, D.S.; Duchala, C.S.; Stephensen, C.B.; Holmes, K.V.; Purnell, A.; Choppin, W. Control of Virus-Induced Cell Fusion by Host Cell Lipid Composition. Virology 1990, 175, 345–357. [Google Scholar] [CrossRef]
  10. Sturman, L.S.; Ricard, C.S.; Holmes, K.V. Conformational Change of the Coronavirus Peplomer Glycoprotein at pH 8.0 and 37 °C Correlates with Virus Aggregation and Virus-Induced Cell Fusion. J. Virol. 1990, 64, 3042–3050. [Google Scholar] [CrossRef]
  11. Weismiller, D.G.; Sturman, L.S.; Buchmeier, M.J.; Fleming, J.O.; Holmes, K.V. Monoclonal Antibodies to the Peplomer Glycoprotein of Coronavirus Mouse Hepatitis Virus Identify Two Subunits and Detect a Conformational Change in the Subunit Released under Mild Alkaline Conditions. J. Virol. 1990, 64, 3051–3055. [Google Scholar] [CrossRef]
  12. Maddon, P.J.; Dalgleish, A.G.; McDougal, J.S.; Clapham, P.R.; Weiss, R.A.; Axel, R. The T4 Gene Encodes the AIDS Virus Receptor and Is Expressed in the Immune System and the Brain. Cell 1986, 47, 333–348. [Google Scholar] [CrossRef]
  13. Greve, J.M.; Davis, G.; Meyer, A.M.; Forte, C.P.; Yost, S.C.; Marlor, C.W.; Kamarck, M.E.; McClelland, A. The Major Human Rhinovirus Receptor Is ICAM-1. Cell 1989, 56, 839–847. [Google Scholar] [CrossRef]
  14. Mendelsohn, C.L.; Wimmer, E.; Racaniello, V.R. Cellular Receptor for Poliovirus: Molecular Cloning, Nucleotide Sequence, and Expression of a New Member of the Immunoglobulin Superfamily. Cell 1989, 56, 855–865. [Google Scholar] [CrossRef]
  15. Boyle, J.F.; Weismiller, D.G.; Holmes, K.V. Genetic Resistance to Mouse Hepatitis Virus Correlates with Absence of Virus-Binding Activity on Target Tissues. J. Virol. 1987, 61, 185–189. [Google Scholar] [CrossRef]
  16. Williams, R.K.; Jiang, G.-S.; Snyder, S.W.; Frana, M.F.; Holmes, K.V. Purification of the 110-Kilodalton Glycoprotein Receptor for Mouse Hepatitis Virus (MHV)-A59 from Mouse Liver and Identification of a Nonfunctional, Homologous Protein in MHV-Resistant SJL/J Mice. J. Virol. 1990, 64, 3817–3823. [Google Scholar] [CrossRef]
  17. Williams, R.K.; Jiang, G.S.; Holmes, K.V. Receptor for Mouse Hepatitis Virus Is a Member of the Carcinoembryonic Antigen Family of Glycoproteins. Proc. Natl. Acad. Sci. USA 1991, 88, 5533–5536. [Google Scholar] [CrossRef]
  18. Gagneten, S.; Gout, O.; Dubois-Dalcq, M.; Rottier, P.; Rossen, J.; Holmes, K.V. Interaction of Mouse Hepatitis Virus (MHV) Spike Glycoprotein with Receptor Glycoprotein MHVR Is Required for Infection with an MHV Strain That Expresses the Hemagglutinin-Esterase Glycoprotein. J. Virol. 1995, 69, 889–895. [Google Scholar] [CrossRef]
  19. Dveksler, G.S.; Pensiero, M.N.; Cardellichio, C.B.; Williams, R.K.; Jiang, G.S.; Holmes, K.V.; Dieffenbach, C.W. Cloning of the Mouse Hepatitis Virus (MHV) Receptor: Expression in Human and Hamster Cell Lines Confers Susceptibility to MHV. J. Virol. 1991, 65, 6881–6891. [Google Scholar] [CrossRef]
  20. Dveksler, G.S.; Pensiero, M.N.; Dieffenbach, C.W.; Cardellichio, C.B.; Basile, A.A.; Elia, P.E.; Holmes, K.V. Mouse Hepatitis Virus Strain A59 and Blocking Antireceptor Monoclonal Antibody Bind to the N-Terminal Domain of Cellular Receptor. Proc. Natl. Acad. Sci. USA 1993, 90, 1716–1720. [Google Scholar] [CrossRef]
  21. Wessner, D.R.; Shick, P.C.; Lu, J.-H.; Cardellichio, C.B.; Gagneten, S.E.; Beauchemin, N.; Holmes, K.V.; Dveksler, G.S. Mutational Analysis of the Virus and Monoclonal Antibody Binding Sites in MHVR, the Cellular Receptor of the Murine Coronavirus Mouse Hepatitis Virus Strain A59. J. Virol. 1998, 72, 1941–1948. [Google Scholar] [CrossRef] [PubMed]
  22. Dveksler, G.S.; Basile, A.A.; Cardellichio, C.B.; Holmes, K.V. Mouse Hepatitis Virus Receptor Activities of an MHVR/mph Chimera and MHVR Mutants Lacking N-Linked Glycosylation of the N-Terminal Domain. J. Virol. 1995, 69, 543–546. [Google Scholar] [CrossRef] [PubMed]
  23. Compton, S.R.; Stephensen, C.B.; Snyder, S.W.; Weismiller, D.G.; Holmes, K.V. Coronavirus Species Specificity: Murine Coronavirus Binds to a Mouse-Specific Epitope on Its Carcinoembryonic Antigen-Related Receptor Glycoprotein. J. Virol. 1992, 66, 7420–7428. [Google Scholar] [CrossRef] [PubMed]
  24. Hemmila, E.; Turbide, C.; Olson, M.; Jothy, S.; Holmes, K.V.; Beauchemin, N. Ceacam1a −/− Mice Are Completely Resistant to Infection by Murine Coronavirus Mouse Hepatitis Virus A59. J. Virol. 2004, 78, 10156–10165. [Google Scholar] [CrossRef]
  25. Blau, D.M.; Turbide, C.; Tremblay, M.; Olson, M.; Létourneau, S.; Michaliszyn, E.; Jothy, S.; Holmes, K.V.; Beauchemin, N. Targeted Disruption of the Ceacam1 (MHVR) Gene Leads to Reduced Susceptibility of Mice to Mouse Hepatitis Virus Infection. J. Virol. 2001, 75, 8173–8186. [Google Scholar] [CrossRef]
  26. Miura, T.A.; Travanty, E.A.; Oko, L.; Bielefeldt-Ohmann, H.; Weiss, S.R.; Beauchemin, N.; Holmes, K.V. The Spike Glycoprotein of Murine Coronavirus MHV-JHM Mediates Receptor-Independent Infection and Spread in the Central Nervous Systems of Ceacam1a−/− Mice. J. Virol. 2008, 82, 755–763. [Google Scholar] [CrossRef]
  27. Yeager, C.L.; Ashmun, R.A.; Williams, R.K.; Cardellichio, C.B.; Shapiro, L.H.; Look, A.T.; Holmes, K.V. Human Aminopeptidase N Is a Receptor for Human Coronavirus 229E. Nature 1992, 357, 420–422. [Google Scholar] [CrossRef]
  28. Delmas, B.; Gelfi, J.; L’Haridon, R.; Vogel, L.K.; Sjöström, H.; Norén, O.; Laude, H. Aminopeptidase N Is a Major Receptor for the Entero-Pathogenic Coronavirus TGEV. Nature 1992, 357, 417–420. [Google Scholar] [CrossRef]
  29. Delmas, B.; Gelfi, J.; Kut, E.; Sjöström, H.; Noren, O.; Laude, H. Determinants Essential for the Transmissible Gastroenteritis Virus-Receptor Interaction Reside within a Domain of Aminopeptidase-N That Is Distinct from the Enzymatic Site. J. Virol. 1994, 68, 5216–5224. [Google Scholar] [CrossRef]
  30. Levis, R.; Cardellichio, C.B.; Scanga, C.A.; Compton, S.R.; Holmes, K.V. Multiple Receptor-Dependent Steps Determine the Species Specificity of HCV-229E Infection. Adv. Exp. Med. Biol. 1995, 380, 337–343. [Google Scholar] [CrossRef]
  31. Tresnan, D.B.; Levis, R.; Holmes, K.V. Feline Aminopeptidase N Serves as a Receptor for Feline, Canine, Porcine, and Human Coronaviruses in Serogroup I. J. Virol. 1996, 70, 8669–8674. [Google Scholar] [CrossRef]
  32. Wentworth, D.E.; Holmes, K.V. Molecular Determinants of Species Specificity in the Coronavirus Receptor Aminopeptidase N (CD13): Influence of N-Linked Glycosylation. J. Virol. 2001, 75, 9741–9752. [Google Scholar] [CrossRef]
  33. Wentworth, D.E.; Tresnan, D.B.; Turner, B.C.; Lerman, I.R.; Bullis, B.; Hemmila, E.M.; Levis, R.; Shapiro, L.H.; Holmes, K.V. Cells of Human Aminopeptidase N (CD13) Transgenic Mice Are Infected by Human Coronavirus-229E in Vitro, but Not in Vivo. Virology 2005, 335, 185–197. [Google Scholar] [CrossRef]
  34. Tusell, S.M.; Schittone, S.A.; Holmes, K.V. Mutational Analysis of Aminopeptidase N, a Receptor for Several Group 1 Coronaviruses, Identifies Key Determinants of Viral Host Range. J. Virol. 2007, 81, 1261–1273. [Google Scholar] [CrossRef]
  35. Smith, M.K.; Tusell, S.; Travanty, E.A.; Berkhout, B.; van der Hoek, L.; Holmes, K.V. Human Angiotensin-Converting Enzyme 2 (ACE2) Is a Receptor for Human Respiratory Coronavirus NL63. Adv. Exp. Med. Biol. 2006, 581, 285–288. [Google Scholar] [CrossRef]
  36. Hofmann, H.; Pyrc, K.; van der Hoek, L.; Geier, M.; Berkhout, B.; Pöhlmann, S. Human Coronavirus NL63 Employs the Severe Acute Respiratory Syndrome Coronavirus Receptor for Cellular Entry. Proc. Natl. Acad. Sci. USA 2005, 102, 7988–7993. [Google Scholar] [CrossRef]
  37. Li, W.; Moore, M.J.; Vasllieva, N.; Sui, J.; Wong, S.K.; Berne, M.A.; Somasundaran, M.; Sullivan, J.L.; Luzuriaga, K.; Greeneugh, T.C.; et al. Angiotensin-Converting Enzyme 2 Is a Functional Receptor for the SARS Coronavirus. Nature 2003, 426, 450–454. [Google Scholar] [CrossRef]
  38. Zhou, P.; Yang, X.-L.; Wang, X.G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.R.; Zhu, Y.; Li, B.; Huang, C.L.; et al. A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin. Nature 2020, 579, 270–273. [Google Scholar] [CrossRef]
  39. Jeffers, S.A.; Tusell, S.M.; Gillim-Ross, L.; Hemmila, E.M.; Achenbach, J.E.; Babcock, G.J.; Thomas, W.D.; Thackray, L.B.; Young, M.D.; Mason, R.J.; et al. CD209L (L-SIGN) Is a Receptor for Severe Acute Respiratory Syndrome Coronavirus. Proc. Natl. Acad. Sci. USA 2004, 101, 15748–15753. [Google Scholar] [CrossRef]
  40. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.; Nitsche, A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181, 271–280. [Google Scholar] [CrossRef]
  41. Amraei, R.; Yin, W.; Napoleon, M.A.; Suder, E.L.; Berrigan, J.; Zhao, Q.; Olejnik, J.; Chandler, K.B.; Xia, C.; Feldman, J.; et al. CD209L/L-SIGN and CD209/DC-SIGN Act as Receptors for SARS-CoV-2. ACS Cent. Sci. 2021, 7, 1156–1165. [Google Scholar] [CrossRef]
  42. Tsai, J.C.; Zelus, B.D.; Holmes, K.V.; Weiss, S.R. The N-Terminal Domain of the Murine Coronavirus Spike Glycoprotein Determines the CEACAM1 Receptor Specificity of the Virus Strain. J. Virol. 2003, 77, 841–850. [Google Scholar] [CrossRef]
  43. Dveksler, G.S.; Dieffenbach, C.W.; Cardellichio, C.B.; McCuaig, K.; Pensiero, M.N.; Jiang, G.S.; Beauchemin, N.; Holmes, K.V. Several Members of the Mouse Carcinoembryonic Antigen-Related Glycoprotein Family Are Functional Receptors for the Coronavirus Mouse Hepatitis Virus-A59. J. Virol. 1993, 67, 1–8. [Google Scholar] [CrossRef]
  44. Zelus, B.D.; Wessner, D.R.; Williams, R.K.; Pensiero, M.N.; Phibbs, F.T.; de Souza, M.; Dveksler, G.S.; Holmes, K.V. Purified, Soluble Recombinant Mouse Hepatitis Virus Receptor, Bgp1b, and Bgp2 Murine Coronavirus Receptors Differ in Mouse Hepatitis Virus Binding and Neutralizing Activities. J. Virol. 1998, 72, 7237–7244. [Google Scholar] [CrossRef]
  45. Schickli, J.H.; Zelus, B.D.; Wentworth, D.E.; Sawicki, S.G.; Holmes, K.V. The Murine Coronavirus Mouse Hepatitis Virus Strain A59 from Persistently Infected Murine Cells Exhibits an Extended Host Range. J. Virol. 1997, 71, 9499–9507. [Google Scholar] [CrossRef]
  46. Schickli, J.H.; Thackray, L.B.; Sawicki, S.G.; 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, 78, 9073–9083. [Google Scholar] [CrossRef]
  47. Thackray, L.B.; Holmes, K.V. Amino Acid Substitutions and an Insertion in the Spike Glycoprotein Extend the Host Range of the Murine Coronavirus MHV-A59. Virology 2004, 324, 510–524. [Google Scholar] [CrossRef][Green Version]
  48. 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 Murine CEACAM1a by the Murine Coronavirus MHV-A59. Virology 2005, 334, 98–110. [Google Scholar] [CrossRef][Green Version]
  49. Tan, K.; Zelus, B.D.; Meijers, R.; Liu, J.H.; Bergelson, J.M.; Duke, N.; Zhang, R.; Joachimiak, A.; Holmes, K.V.; Wang, J.H. Crystal Structure of Murine sCEACAM1a [1, 4]: A Coronavirus Receptor in the CEA Family. EMBO J. 2002, 21, 2076–2086. [Google Scholar] [CrossRef]
  50. Peng, G.; Xu, L.; Lin, Y.L.; Chen, L.; Pasquarella, J.R.; Holmes, K.V.; Li, F. Crystal Structure of Bovine Coronavirus Spike Protein Lectin Domain. J. Biol. Chem. 2012, 287, 41931–41938. [Google Scholar] [CrossRef]
  51. Peng, G.; Sun, D.; Rajashankar, K.R.; Qian, Z.; Holmes, K.V.; Li, F. Crystal Structure of Mouse Coronavirus Receptor-Binding Domain Complexed with Its Murine Receptor. Proc. Natl. Acad. Sci. USA 2011, 108, 10696–10701. [Google Scholar] [CrossRef] [PubMed]
  52. Peng, G.; Yang, Y.; Pasquarella, J.R.; Xu, L.; Qian, Z.; Holmes, K.V.; Li, F. Structural and Molecular Evidence Suggesting Coronavirus-Driven Evolution of Mouse Receptor. J. Biol. Chem. 2017, 292, 2174–2181. [Google Scholar] [CrossRef] [PubMed]
  53. Zelus, B.D.; Schickli, J.H.; Blau, D.M.; Weiss, S.R.; Holmes, K.V. Conformational Changes in the Spike Glycoprotein of Murine Coronavirus Are Induced at 37 °C Either by Soluble Murine CEACAM1 Receptors or by pH 8. J. Virol. 2003, 77, 830–840. [Google Scholar] [CrossRef] [PubMed]
  54. Li, P.; Shan, Y.; Zheng, W.; Ou, X.; Mi, D.; Mu, Z.; Holmes, K.V.; Qian, Z. Identification of H209 as Essential for pH 8-Triggered Receptor-Independent Syncytium Formation by S Protein of Mouse Hepatitis Virus A59. J. Virol. 2018, 92, e00209-18. [Google Scholar] [CrossRef]
  55. Mi, D.; Ou, X.; Li, P.; Peng, G.; Liu, Y.; Guo, R.; Mu, Z.; Li, F.; Holmes, K.; Qian, Z. Glycine 29 Is Critical for Conformational Changes of the Spike Glycoprotein of Mouse Hepatitis Virus A59 Triggered by Either Receptor Binding or High pH. J. Virol. 2019, 93, e01046-19. [Google Scholar] [CrossRef]
  56. Bonavia, A.; Zelus, B.D.; Wentworth, D.E.; Talbot, P.J.; Holmes, K.V. Identification of a Receptor-Binding Domain of the Spike Glycoprotein of Human Coronavirus HCoV-229E. J. Virol. 2003, 77, 2530–2538. [Google Scholar] [CrossRef]
  57. Blau, D.M.; Holmes, K.V. Human Coronavirus HCoV-229E Enters Susceptible Cells via the Endocytic Pathway. Adv. Exp. Med. Biol. 2001, 494, 193–198. [Google Scholar] [CrossRef]
  58. Breslin, J.J.; Mørk, I.; Smith, M.K.; Vogel, L.K.; Hemmila, E.M.; Bonavia, A.; Talbot, P.J.; Sjöström, H.; Norén, O.; Holmes, K.V. Human Coronavirus 229E: Receptor Binding Domain and Neutralization by Soluble Receptor at 37 °C. J. Virol. 2003, 77, 4435–4438. [Google Scholar] [CrossRef]
  59. Qian, Z.; Ou, X.; Góes, L.G.B.; Osborne, C.; Castano, A.; Holmes, K.V.; Dominguez, S.R. Identification of the Receptor-Binding Domain of the Spike Glycoprotein of Human Betacoronavirus HKU1. J. Virol. 2015, 89, 8816–8827. [Google Scholar] [CrossRef]
  60. Tripet, B.; Howard, M.W.; Jobling, M.; Holmes, R.K.; Holmes, K.V.; Hodges, R.S. Structural Characterization of the SARS-Coronavirus Spike S Fusion Protein Core. J. Biol. Chem. 2004, 279, 20836–20849. [Google Scholar] [CrossRef]
  61. Howard, M.W.; Travanty, E.A.; Jeffers, S.A.; Smith, M.K.; Wennier, S.T.; Thackray, L.B.; Holmes, K.V. Aromatic Amino Acids in the Juxtamembrane Domain of Severe Acute Respiratory Syndrome Coronavirus Spike Glycoprotein Are Important for Receptor-Dependent Virus Entry and Cell-Cell Fusion. J. Virol. 2008, 82, 2883–2894. [Google Scholar] [CrossRef]
  62. Ou, X.; Zheng, W.; Shan, Y.; Mu, Z.; Dominguez, S.R.; Holmes, K.V.; Qian, Z. Identification of the Fusion Peptide-Containing Region in Betacoronavirus Spike Glycoproteins. J. Virol. 2016, 90, 5586–5600. [Google Scholar] [CrossRef]
  63. Tripet, B.; Kao, D.J.; Jeffers, S.A.; Holmes, K.V.; Hodges, R.S. Template-Based Coiled-Coil Antigens Elicit Neutralizing Antibodies to the SARS-Coronavirus. J. Struct. Biol. 2006, 155, 176–194. [Google Scholar] [CrossRef]
  64. Yan, Z.; Hartsock, W.J.; Qian, Z.; Holmes, K.V.; Hodges, R.S. Strategies for Designing Peptide Immunogens to Elicit Alpha-Helical Conformation-Specific Antibodies Reactive with Native Proteins. ACS Symp. Ser. 2012, 1095, 93–136. [Google Scholar] [CrossRef]
  65. Dubois-Dalcq, M.E.; Doller, E.W.; Haspel, M.V.; Holmes, K.V. Cell Tropism and Expression of Mouse Hepatitis Viruses (MHV) in Mouse Spinal Cord Cultures. Virology 1982, 119, 317–331. [Google Scholar] [CrossRef]
  66. Kristensson, K.; Holmes, K.V.; Duchala, C.S.; Zeller, N.K.; Lazzarini, R.A.; Dubois-Dalcq, M. Increased Levels of Myelin Basic Protein Transcripts in Virus-Induced Demyelination. Nature 1986, 322, 544–547. [Google Scholar] [CrossRef]
  67. Jordan, C.A.; Friedrich, V.L., Jr.; Godfraind, C.; Cardellechio, C.B.; Holmes, K.V.; Dubois-Dalcq, M. Expression of Viral and Myelin Gene Transcripts in a Murine CNS Demyelinating Disease Caused by a Coronavirus. Glia 1989, 2, 318–329. [Google Scholar] [CrossRef]
  68. Jordan, C.A.; Friedrich, V.L., Jr.; de Ferra, F.; Weismiller, D.G.; Holmes, K.V.; Dubois-Dalcq, M. Differential Exon Expression in Myelin Basic Protein Transcripts during Central Nervous System (CNS) Remyelination. Cell. Mol. Neurobiol. 1990, 10, 3–18. [Google Scholar] [CrossRef]
  69. Godfraind, C.; Friedrich, V.L.; Holmes, K.V.; Dubois-Dalcq, M. In Vivo Analysis of Glial Cell Phenotypes during a Viral Demyelinating Disease in Mice. J. Cell Biol. 1989, 109, 2405–2416. [Google Scholar] [CrossRef]
  70. Woyciechowska, J.L.; Trapp, B.D.; Patrick, D.H.; Shekarchi, I.C.; Leinikki, P.O.; Sever, J.L.; Holmes, K.V. Acute and Subacute Demyelination Induced by Mouse Hepatitis Virus Strain A59 in C3H Mice. J. Exp. Pathol. 1984, 1, 295–306. [Google Scholar]
  71. Armstrong, R.; Friedrich, V., Jr.; Holmes, K.; Dubois-Dalcq, M. In Vitro Analysis of the Oligodendrocyte Lineage in Mice during Demyelination and Remyelination. J. Cell Biol. 1990, 111, 1183–1195. [Google Scholar] [CrossRef]
  72. Wang, G.; Deering, C.; Macke, M.; Shao, J.; Burns, R.; Blau, D.M.; Holmes, K.V.; Davidson, B.L.; Perlman, S.; McCray, P.B. Human Coronavirus 229E Infects Polarized Airway Epithelia from the Apical Surface. J. Virol. 2000, 74, 9234–9239. [Google Scholar] [CrossRef]
  73. Mossel, E.C.; Wang, J.; Jeffers, S.; Edeen, K.E.; Wang, S.; Cosgrove, G.P.; Funk, C.J.; Manzer, R.; Miura, T.A.; Pearson, L.D.; et al. SARS-CoV Replicates in Primary Human Alveolar Type II Cell Cultures but Not in Type I-like Cells. Virology 2008, 372, 127–135. [Google Scholar] [CrossRef]
  74. Qian, Z.; Travanty, E.A.; Oko, L.; Edeen, K.; Berglund, A.; Wang, J.; Ito, Y.; Holmes, K.V.; Mason, R.J. Innate Immune Response of Human Alveolar Type II Cells Infected with Severe Acute Respiratory Syndrome-Coronavirus. Am. J. Respir. Cell Mol. Biol. 2013, 48, 742–748. [Google Scholar] [CrossRef]
  75. Joel Funk, C.; Wang, J.; Ito, Y.; Travanty, E.A.; Voelker, D.R.; Holmes, K.V.; Mason, R.J. Infection of Human Alveolar Macrophages by Human Coronavirus Strain 229E. J. Gen. Virol. 2012, 93, 494–503. [Google Scholar] [CrossRef]
  76. Funk, C.J.; Manzer, R.; Miura, T.A.; Groshong, S.D.; Ito, Y.; Travanty, E.A.; Leete, J.; Holmes, K.V.; Mason, R.J. Rat Respiratory Coronavirus Infection: Replication in Airway and Alveolar Epithelial Cells and the Innate Immune Response. J. Gen. Virol. 2009, 90, 2956–2964. [Google Scholar] [CrossRef]
  77. Miura, T.A.; Wang, J.; Holmes, K.V.; Mason, R.J. Rat Coronaviruses Infect Rat Alveolar Type I Epithelial Cells and Induce Expression of CXC Chemokines. Virology 2007, 369, 288–298. [Google Scholar] [CrossRef]
  78. Miura, T.A.; Wang, J.; Mason, R.J.; Holmes, K.V. Rat Coronavirus Infection of Primary Rat Alveolar Epithelial Cells. Adv. Exp. Med. Biol. 2006, 581, 351–356. [Google Scholar] [CrossRef]
  79. Rossen, J.W.A.; Bekker, C.P.J.; Strous, G.J.A.M.; Horzinek, M.C.; Dveksler, G.S.; Holmes, K.V.; Rottier, P.J.M. A Murine and a Porcine Coronavirus Are Released from Opposite Surfaces of the Same Epithelial Cells. Virology 1996, 224, 345–351. [Google Scholar] [CrossRef][Green Version]
  80. Van der Hoek, L.; Pyrc, K.; Jebbink, M.F.; Vermeulen-Oost, W.; Berkhout, R.J.; Wolthers, K.C.; Wertheim-van Dillen, P.M.; Kaandorp, J.; Spaargaren, J.; Berkhout, B. Identification of a New Human Coronavirus. Nat. Med. 2004, 10, 368–373. [Google Scholar] [CrossRef]
  81. Woo, P.C.; Lau, S.K.; Chu, C.M.; Chan, K.H.; Tsoi, H.W.; Huang, Y.; Wong, B.H.; Poon, R.W.; Cai, J.J.; Luk, W.K.; et al. Characterization and Complete Genome Sequence of a Novel Coronavirus, Coronavirus HKU1, from Patients with Pneumonia. J. Virol. 2005, 79, 884–895. [Google Scholar] [CrossRef] [PubMed]
  82. Dominguez, S.R.; Robinson, C.C.; Holmes, K.V. Detection of Four Human Coronaviruses in Respiratory Infections in Children: A One-Year Study in Colorado. J. Med. Virol. 2009, 81, 1597–1604. [Google Scholar] [CrossRef] [PubMed]
  83. Dominguez, S.R.; Shrivastava, S.; Berglund, A.; Qian, Z.; Góes, L.G.B.; Halpin, R.A.; Fedorova, N.; Ransier, A.; Weston, P.A.; Durigon, E.L.; et al. Isolation, Propagation, Genome Analysis and Epidemiology of HKU1 Betacoronaviruses. J. Gen. Virol. 2014, 95, 836–848. [Google Scholar] [CrossRef] [PubMed]
  84. Dominguez, S.R.; Sims, G.E.; Wentworth, D.E.; Halpin, R.A.; Robinson, C.C.; Town, C.D.; Holmes, K.V. Genomic Analysis of 16 Colorado Human NL63 Coronaviruses Identifies a New Genotype, High Sequence Diversity in the N-Terminal Domain of the Spike Gene and Evidence of Recombination. J. Gen. Virol. 2012, 93, 2387–2398. [Google Scholar] [CrossRef]
  85. Lau, S.K.; Woo, P.C.; Li, K.S.; Huang, Y.; Tsoi, H.W.; Wong, B.H.; Wong, S.S.; Leung, S.Y.; Chan, K.H.; Yuen, K.Y. Severe Acute Respiratory Syndrome Coronavirus-like Virus in Chinese Horseshoe Bats. Proc. Natl. Acad. Sci. USA 2005, 102, 14040–14045. [Google Scholar] [CrossRef]
  86. Woo, P.C.Y.; Lau, S.K.P.; Li, K.S.M.; Poon, R.W.S.; Wong, B.H.L.; Tsoi, H.; Yip, B.C.K.; Huang, Y.; Chan, K.; Yuen, K. Molecular Diversity of Coronaviruses in Bats. Virology 2006, 351, 180–187. [Google Scholar] [CrossRef]
  87. Calisher, C.H.; Childs, J.E.; Field, H.E.; Holmes, K.V.; Schountz, T. Bats: Important Reservoir Hosts of Emerging Viruses. Clin. Microbiol. Rev. 2006, 19, 531–545. [Google Scholar] [CrossRef]
  88. Dominguez, S.R.; O’Shea, T.J.; Oko, L.M.; Holmes, K.V. Detection of Group 1 Coronaviruses in Bats in North America. Emerg. Infect. Dis. 2007, 13, 1295–1300. [Google Scholar] [CrossRef]
  89. Osborne, C.; Cryan, P.M.; O’Shea, T.J.; Oko, L.M.; Ndaluka, C.; Calisher, C.H.; Berglund, A.D.; Klavetter, M.L.; Bowen, R.A.; Holmes, K.V.; et al. Alphacoronaviruses in New World Bats: Prevalence, Persistence, Phylogeny, and Potential for Interaction with Humans. PLoS ONE 2011, 6, e19156. [Google Scholar] [CrossRef]
  90. Góes, L.G.B.; Ruvalcaba, S.G.; Campos, A.A.; Queiroz, L.H.; de Carvalho, C.; Jerez, J.A.; Durigon, E.L.; Dávalos, L.I.I.; Dominguez, S.R. Novel Bat Coronaviruses, Brazil and Mexico. Emerg. Infect. Dis. 2013, 19, 1711–1713. [Google Scholar] [CrossRef]
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