In one of these studies the human case had direct contact with an infected camel and the virus isolated from this patient was identical to the virus isolated from the camel [ 99 ]. At the present time it remains to be determined how many MERS-CoV cases can be attributed to an intermediate host as opposed to human-to-human transmission.
It has also been postulated that human-to-camel spread contributed to the outbreak. The virus is only able to use the receptor from certain species such as bats, humans, camels, rabbits, and horses to establish infection. Unfortunately for researchers, the virus is unable to infect mouse cells due to differences in the structure of DPP4, making it difficult to evaluate potential vaccines or antivirals. This unique system makes it possible to test therapeutic interventions and novel vaccines for MERS-CoV in any animal sensitive to adenoviral transductions.
In most cases of self-limited infection, diagnosis of coronaviruses is unnecessary, as the disease will naturally run its course. However, it may be important in certain clinical and veterinary settings or in epidemiological studies to identify an etiological agent. The identification of cases will guide the development of public health measures to control outbreaks. Serologic assays are important in cases where RNA is difficult to isolate or is no longer present, and for epidemiological studies.
To date, there are no antiviral therapeutics that specifically target human coronaviruses, so treatments are only supportive. In vitro, interferons IFNs are only partially effective against coronaviruses [ ]. IFNs in combination with ribavirin may have increased activity in vitro when compared to IFNs alone against some coronaviruses; however, the effectiveness of this combination in vivo requires further evaluation [ ]. The SARS and MERS outbreaks have stimulated research on these viruses and this research has identified a large number of suitable antiviral targets, such as viral proteases, polymerases, and entry proteins.
Significant work remains, however, to develop drugs that target these processes and are able to inhibit viral replication. Only limited options are available to prevent coronavirus infections. Vaccines have only been approved for IBV, TGEV, and Canine CoV, but these vaccines are not always used because they are either not very effective, or in some cases have been reported to be involved in the selection of novel pathogenic CoVs via recombination of circulating strains.
Vaccines for veterinary pathogens, such as PEDV, may be useful in such cases where spread of the virus to a new location could lead to severe losses of veterinary animals. These vaccines include recombinant attenuated viruses, live virus vectors, or individual viral proteins expressed from DNA plasmids. Such antibodies would be most useful for protecting healthcare workers. In general, it is thought that live attenuated vaccines would be the most efficacious in targeting coronaviruses.
This variant only caused mild disease and completely protected swine from TGEV. Despite this success, vaccine development for coronaviruses faces many challenges [ ]. First, for mucosal infections, natural infection does not prevent subsequent infection, and so vaccines must either induce better immunity than the original virus or must at least lessen the disease incurred during a secondary infection.
Second, the propensity of the viruses to recombine may pose a problem by rendering the vaccine useless and potentially increasing the evolution and diversity of the virus in the wild [ ].
Finally, it has been shown in FIPV that vaccination with S protein leads to enhanced disease [ ]. Owing to the lack of effective therapeutics or vaccines, the best measures to control human coronaviruses remain a strong public health surveillance system coupled with rapid diagnostic testing and quarantine when necessary.
For international outbreaks, cooperation of governmental entities, public health authorities, and health care providers is critical.
During veterinary outbreaks that are readily transmitted, such as PEDV, more drastic measures such as destruction of entire herds of pigs may be necessary to prevent transmission of these deadly viruses.
Over the past 50 years the emergence of many different coronaviruses that cause a wide variety of human and veterinary diseases has occurred.
It is likely that these viruses will continue to emerge and to evolve and cause both human and veterinary outbreaks owing to their ability to recombine, mutate, and infect multiple species and cell types. Future research on coronaviruses will continue to investigate many aspects of viral replication and pathogenesis.
First, understanding the propensity of these viruses to jump between species, to establish infection in a new host, and to identify significant reservoirs of coronaviruses will dramatically aid in our ability to predict when and where potential epidemics may occur. As bats seem to be a significant reservoir for these viruses, it will be interesting to determine how they seem to avoid clinically evident disease and become persistently infected.
Second, many of the non-structural and accessory proteins encoded by these viruses remain uncharacterized with no known function, and it will be important to identify mechanisms of action for these proteins as well as defining their role in viral replication and pathogenesis.
These studies should lead to a large increase in the number of suitable therapeutic targets to combat infections. Third, gaining a complete picture of the intricacies of the RTC will provide a framework for understanding the unique RNA replication process used by these viruses. Finally, defining the mechanism of how coronaviruses cause disease and understanding the host immunopathological response will significantly improve our ability to design vaccines and reduce disease burden.
Helena Jane Maier, Email: ku. Erica Bickerton, Email: ku. Paul Britton, Email: ku. National Center for Biotechnology Information , U. Published online Feb Anthony R. Fehr and Stanley Perlman , M. Author information Copyright and License information Disclaimer. Stanley Perlman, Email: ude. Corresponding author. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source.
This article has been cited by other articles in PMC. Abstract Coronaviruses CoVs , enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, an unusually large RNA genome, and a unique replication strategy. Classification Coronaviruses CoVs are the largest group of viruses belonging to the Nidovirales order, which includes Coronaviridae , Arteriviridae , Mesoniviridae , and Roniviridae families.
Open in a separate window. Virion Structure Coronavirus virions are spherical with diameters of approximately nm as depicted in recent studies by cryo-electron tomography and cryo-electron microscopy [ 2 , 3 ]. Coronavirus Life Cycle Attachment and Entry The initial attachment of the virion to the host cell is initiated by interactions between the S protein and its receptor. Table 1 Coronavirus receptors. Replicase Protein Expression The next step in the coronavirus lifecycle is the translation of the replicase gene from the virion genomic RNA.
Table 2 Functions of coronavirus non-structural proteins nsps. Replication and Transcription Viral RNA synthesis follows the translation and assembly of the viral replicase complexes. Pathogenesis Animal Coronaviruses Coronaviruses cause a large variety of diseases in animals, and their ability to cause severe disease in livestock and companion animals such as pigs, cows, chickens, dogs, and cats led to significant research on these viruses in the last half of the twentieth century.
Diagnosis, Treatment, and Prevention In most cases of self-limited infection, diagnosis of coronaviruses is unnecessary, as the disease will naturally run its course. Conclusion Over the past 50 years the emergence of many different coronaviruses that cause a wide variety of human and veterinary diseases has occurred. References 1. Antagonism of the interferon-induced OAS-RNase L pathway by murine coronavirus ns2 protein is required for virus replication and liver pathology.
Cell Host Microbe. Cryo-electron tomography of mouse hepatitis virus: insights into the structure of the coronavirion. Supramolecular architecture of severe acute respiratory syndrome coronavirus revealed by electron cryomicroscopy.
J Virol. Architecture of the SARS coronavirus prefusion spike. Nat Struct Mol Biol. Delmas B, Laude H. Assembly of coronavirus spike protein into trimers and its role in epitope expression.
The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. Monoclonal antibodies to murine hepatitis virus-4 strain JHM define the viral glycoprotein responsible for attachment and cell—cell fusion. Deduced sequence of the bovine coronavirus spike protein and identification of the internal proteolytic cleavage site.
Primary structure of the glycoprotein E2 of coronavirus MHV-A59 and identification of the trypsin cleavage site. Evidence for a coiled-coil structure in the spike proteins of coronaviruses. J Mol Biol. Sequence and topology of a model intracellular membrane protein, E1 glycoprotein, from a coronavirus. Differential maturation and subcellular localization of severe acute respiratory syndrome coronavirus surface proteins S, M and E.
J Gen Virol. A structural analysis of M protein in coronavirus assembly and morphology. J Struct Biol. A severe acute respiratory syndrome coronavirus that lacks the E gene is attenuated in vitro and in vivo.
Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis. PLoS Pathog. Modular organization of SARS coronavirus nucleocapsid protein. J Biomed Sci. Identification of in vivo-interacting domains of the murine coronavirus nucleocapsid protein. Phosphoproteins of murine hepatitis viruses. Specific interaction between coronavirus leader RNA and nucleocapsid protein.
Molenkamp R, Spaan WJ. Identification of a specific interaction between the coronavirus mouse hepatitis virus A59 nucleocapsid protein and packaging signal. Kuo L, Masters PS. Functional analysis of the murine coronavirus genomic RNA packaging signal. Characterization of a critical interaction between the coronavirus nucleocapsid protein and nonstructural protein 3 of the viral replicase-transcriptase complex. Isolation of coronavirus envelope glycoproteins and interaction with the viral nucleocapsid.
Identification of a coronavirus hemagglutinin-esterase with a substrate specificity different from those of influenza C virus and bovine coronavirus. Hemagglutinin-esterase, a novel structural protein of torovirus. Expression of hemagglutinin esterase protein from recombinant mouse hepatitis virus enhances neurovirulence. Luxury at a cost? Recombinant mouse hepatitis viruses expressing the accessory hemagglutinin esterase protein display reduced fitness in vitro.
Localization of neutralizing epitopes and the receptor-binding site within the amino-terminal amino acids of the murine coronavirus spike protein. Viral shedding patterns of coronavirus in patients with probable severe acute respiratory syndrome. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Characterization of an efficient coronavirus ribosomal frameshifting signal: requirement for an RNA pseudoknot.
Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK implications for transplantation.
J Exp Med. Virus-encoded proteinases and proteolytic processing in the Nidovirales. Nidovirus papain-like proteases: multifunctional enzymes with protease, deubiquitinating and deISGylating activities. Virus Res. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage.
Minus-strand copies of replicating coronavirus mRNAs contain antileaders. An RNA stem-loop within the bovine coronavirus nsp1 coding region is a cis-acting element in defective interfering RNA replication.
Mouse hepatitis virus stem-loop 2 adopts a uYNMG U a-like tetraloop structure that is highly functionally tolerant of base substitutions. Hsue B, Masters PS. A contemporary view of coronavirus transcription.
Identification of a noncanonically transcribed subgenomic mRNA of infectious bronchitis virus and other gammacoronaviruses. RNA recombination of coronavirus. Adv Exp Med Biol. Recombination between nonsegmented RNA genomes of murine coronaviruses. Characterization of the budding compartment of mouse hepatitis virus: evidence that transport from the RER to the Golgi complex requires only one vesicular transport step.
J Cell Biol. Replication of coronavirus MHV-A59 in sac-cells: determination of the first site of budding of progeny virions. Eur J Cell Biol. Molecular interactions in the assembly of coronaviruses. Adv Virus Res. The production of recombinant infectious DI-particles of a murine coronavirus in the absence of helper virus. The M, E, and N structural proteins of the severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking, and release of virus-like particles.
Characterization of the coronavirus mouse hepatitis virus strain A59 small membrane protein E. Corse E, Machamer CE. It is a read through product of the coat gene.
It is required for the maturation of the phage i. It resembles to that bacterial beta sub unit, with template site and an active site. But it requires few more proteins from the host cell for its activity. It gets associated with ribosomal S1 subunits It is a maturation protein. A2 functions in host cell recognition. A2 inhibits peptidoglycan formation similar to penicillin.
The replicase has four subunits, one coded by the qb RNA. The 5' end is capped. Encodes 3 Allelovirus or 4 proteins Levivirus. Encodes 4 proteins. From 62 — ntd, A2, maturation protein 75 aa long. From — ntd , coat protein aa long. From — ntd , A1 attachment protein aa long. From — ntd , Replicase protein. From to , from to are noncoding spacers. The replicating enzyme is a complex made up of two virally coded b protein and few host proteins. Beta protein. Viral coded, has enzyme properties.
Alpha subunit. The contribute to the dimer interface. The elongation factors and the protein are encoded by the host. The B-subunits interact via a symmetric network of salt bridges Gytz et al. This dimer is also stabilized by. Tyrosine forms hydrophobic interactions and a hydrogen bond with glutamic acid , while arginine residues of the Beta subunit form a salt bridge with EF-Tu glutamine residues. This results in increased hydrophobic interactions of the neighboring EF-Tu Phe with a hydrophobic cluster of six phenylalanine and one leucine side chains from the fingers domain.
Brown, S. Assembly of Hybrid Bacteriophage Q? Virus-like Particles. Biochemistry, 48 47 , Grumet, R. Pathogen-derived resistance to viral infection using a negative regulatory molecule. Virology, 2 , Gytz, H. Nucleic acids research, 43 22 , Kidmose, Rune T. PNAS, 24 , Payne, S.
Singleton, R. Methods and protocols, 1 2 , Tomita, K. Structures and Functions of Q? Replicase: Translation Factors beyond Protein Synthesis. International Journal Of Molecular Sciences, 15 9 , Back to Top.
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