CORONAVIRIDAE
History
Coronaviruses were first recognized and grouped together in the 1960s. At this point, coronaviruses were seen in a number of patients displaying common cold like symptoms globally. Human coronaviruses were considered to be only associated with these rather mild symptoms until 2002 when the landscape of coronaviruses and infectious disease surveillance as a whole was dramatically changed with the emergence of severe acute respiratory syndrome (SARS), whose causative agent is a coronavirus commonly referred to as SARS-CoV.
The 2003 SARS epidemic, in which 8,098 people were infected and 774 died, caused the research on, and consequently the knowledge of coronaviruses to increase substantially in the following years. Coronaviruses have maintained their presence in infectious disease news as an outbreak of Middle East respiratory syndrome, whose causative agent is MERS-CoV, occurred in 2012. The striking similarities between SARS-CoV and MERS-CoV caused many to fear the potential for another SARS scale epidemic, but at this point the number of infected individuals has remained relatively low and in a concentrated area.
Molecular Biology
Coronaviruses have the largest genome of any known RNA virus with genome lengths ranging between 26 and 32 kilobases. Coronavirus genomes encode essential RNA virus proteins such as a polymerase and structural proteins to form the capsid of the virus, but also code for numerous smaller accessory genes. Some of these genes modulate the host immune response, but many of their functions remain unknown.
The way in which all of these genes are organized and expressed is rather unique to coronaviruses and is a major factor that went into the classification of this viral family. The gene encoding the coronavirus replicase complex is the only protein encoded by the genomic mRNA and consists of two open reading frames. Because the polymerase is an enzyme and thus is not used up in the chemical reactions involving replication, not as much polymerase is needed as other proteins for continued replication of the virus. As a result, coronaviruses have developed a system in which the translation of the polymerase protein requires a ribosomal frameshift. For this ribosomal frameshift event, a slippery sequence, followed by an RNA pseudoknot is required. Ribosomal frameshifting occurs at a fixed rate when the ribosome bumps into this pseudoknot during translation, backs up one nucleotide on the slippery sequence, and then continues translating in the other open reading frame. Thus this provides a mechanism for generating only enough polymerase necessary to maintain a certain level of replication and infection in the host.
In addition to the genomic mRNA, coronaviruses also contain 8 short subgenomic RNAs located downstream of the replicase gene. These subgenomic RNAs have 5’ and 3’ ends which are identical to that of the full length coronavirus genome, allowing each of these mRNAs to be individually translated. Because the subgenomic RNAs can be individually translated, they can also be differentially expressed to the extent selected by the virus. These subgenomic mRNAs are translated much more often than the polymerase gene because there is no ribosomal frameshift directly necessary for their translation to occur, and they are much shorted in sequence than the polymerase gene.
Clinical Manifestations
Human coronaviruses generally are associated with respiratory infections. This is not only because the virus spread by the respiratory route, but also because the virus spike glycoprotein determines the tropism of the virus and it has an affinity for receptors on cells located in the lungs. Clinically, human coronavirus infections can be differentiated into two distinct categories: mild and severe.
Mild coronavirus infections are relatively common around the world. They result in a common cold-like syndrome which may include signs and symptoms such as: headache, fever, runny nose, sore throat, general discomfort, chills, and cough. These symptoms last about 7 days on average. Human coronaviruses which make up this category are: HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1. Infection with these viruses usually occurs in the upper respiratory tract and is rarely fatal.
Severe coronavirus infections are not as common, but have come in outbreaks. These severe coronavirus infections result in a lethal form of pneumonia known as severe acute respiratory syndrome (SARS), leaving a majority of those infected hospitalized. Associated symptoms include: fever, a nonproductive cough, shortness of breath, and gastrointestinal disease. SARS-CoV and MERS-CoV are the two severe human coronaviruses. Approximately 30% of people infected by these viruses die; many of these deaths are due to a build-up of fluid in the lungs.
Prevention and Treatment
There is no approved vaccine for prevention nor approved drugs for treatment of coronavirus infection. A majority of coronavirus infections are mild, so the only treatments that are utilized, if any, are symptomatic treatments used against the common cold until the infection subsides. SARS-CoV vaccines are currently undergoing development in order to prevent a potential pandemic of the lethal virus.
Things to Know
10 Things to Remember:
1. Largest RNA virus genome
2. A cause of the common cold syndrome
3. SARS and MERS -- Possible pandemic virus
4. Translational frameshifting as method of translating polymerase
5. Subgenomic RNAs on 3’ end that are individually regulated and encode other proteins
6. No vaccine nor antivirals
7. Spike glycoprotein determines tropism
8. Globally distributed
9. Zoonotic disease
10. Easily transmitted via respiratory route
5 New Findings:
1. R for MERS-CoV is between 0.8 and 1.3
2. At least 62% of human cases of MERS-CoV were not detected.
3. Anti-MERS-CoV antibodies have been found in the serum and milk of camels in the Middle East.
4. IFN-β and/or MPA may be beneficial in treating MERS-CoV
5. Bone marrow stromal antigen 2 is a SARS Coronavirus antagonist; yet it is regulated by SARS-CoV ORF7a.
Relevant Links
Stanford Humans and Viruses Information
https://virus.stanford.edu/corona/virushome.html
http://web.stanford.edu/~siegelr/
More Coronavirus Information
http://viralzone.expasy.org/all_by_species/30.html
http://www.cdc.gov/coronavirus/
http://www.nlm.nih.gov/medlineplus/coronavirusinfections.html
http://www.who.int/csr/disease/coronavirus_infections/en/
http://www.webmd.com/lung/coronavirus
Additional References
Vijgen, Leen et al. “Complete Genomic Sequence of Human Coronavirus OC43: Molecular Clock Analysis Suggests a Relatively Recent Zoonotic Coronavirus Transmission Event.” Journal of Virology 79.3 (2005): 1595–1604.
Knipe, David M., and Bernard N. Fields. "Coronaviridae." Fields Virology. Philadelphia: Lippincott Williams & Wilkins, 2007. N. pag.
Kahn, Jeffrey S., and Kenneth Mcintosh. "History and Recent Advances in Coronavirus Discovery." The Pediatric Infectious Disease Journal 24.Supplement (2005): S223-227.
Reusken CB, Farag EA et al. Middle East respiratory syndrome coronavirus (MERS-CoV) RNA and neutralising
antibodies in milk collected according to local customs from dromedary camels, Qatar, April 2014. Euro Surveill. 2014;19(23):pii=20829.
Cauchemez, Simon, Christophe Fraser, Maria D Van Kerkhove, Christl A. Donnelly, Steven Riley, Andrew Rambaut, Vincent Enouf, Sylvie Van Der Werf, and Neil M. Ferguson. "Middle East Respiratory Syndrome Coronavirus: Quantification of the Extent of the Epidemic, Surveillance Biases, and Transmissibility." The Lancet Infectious Diseases 14.1 (2014): 50-56. Web.
Hart, Brit J. et al. "Interferon-β and Mycophenolic Acid Are Potent Inhibitors of Middle East Respiratory Syndrome Coronavirus in Cell-based Assays." Journal of General Virology 95.3 (2014): 571-77.
Taylor, Justin. "BST-2 Restricts SARS Coronavirus and Is Antagonized by SARS-CoV ORF7a." University of Maryland Digital Archive. N.p., n.d.