The SARS coronavirus

 

The SARS coronavirus, sometimes shortened to SARS-CoV, is the virus that causes severe acute respiratory syndrome (SARS).^[1] In April 16 of 2003, following the outbreak of SARS in Asia and secondary cases elsewhere in the world, the World Health Organization (WHO) issued a press release stating that the coronavirus identified by a number of laboratories was the official cause of SARS. Samples of the virus are being held in laboratories in New York, San Francisco, Manila, Hong Kong, and Toronto.

 

On April 12, 2003, scientists working at the Michael Smith Genome Sciences Centre in Vancouver, British Columbia finished mapping the genetic sequence of a coronavirus believed to be linked to SARS. The team was led by Dr. Marco Marra and worked in collaboration with the British Columbia Centre for Disease Control and the National Microbiology Laboratory in Winnipeg, Manitoba, using samples from infected patients in Toronto. The map, hailed by the WHO as an important step forward in fighting SARS, is shared with scientists worldwide via the GSC website (see below). Dr. Donald Low of Mount Sinai Hospital in Toronto described the discovery as having been made with "unprecedented speed."^[2] The sequence of the SARS coronavirus has since been confirmed by other independent groups.

SARS

Main article: Severe acute respiratory syndrome

SARS, or Severe acute respiratory syndrome, is the disease caused by SARS coronavirus. It causes an often severe illness marked initially by systemic symptoms of muscle pain, headache, and fever, followed in 2–10 days by the onset of respiratory symptoms,^[3] mainly cough, dyspnea, and pneumonia. Another common finding in SARS patients is a decrease in the number of lymphocytes circulating in the blood.^[4]

In the SARS outbreak of 2003, about 9% of patients with confirmed SARS infection died.^[5] The mortality rate was much higher for those over 50 years old, with mortality rates approaching 50% for this subset of patients.^[5]

Biology 

SARS coronavirus is a positive and single stranded RNA virus belonging to a family of enveloped coronaviruses. Its genome is about 29.7kb, which is one of the largest among RNA viruses. The SARS virus has 13 known genes and 14 known proteins. There are 265bp in the 5'UTR and 342bp in the 3'UTR. SARS is similar to other coronaviruses in that its genome expression starts with translation of two large ORFs 1a and 1b, which are two polyproteins.

 

The functions of several of these proteins are known:^[6] ORFs 1a and 1b encode the replicase and there are four major structural proteins: nucleocapsid, spike, membrane and envelope. It also encodes for eight unique proteins, known as the accessory proteins, with no known homologues. The function of these accessory proteins remains unknown.

 

Coronaviruses usually express pp1a (the ORF1a polyprotein) and the PP1ab polyprotein with joins ORF1a and ORF1b. The polyproteins are then processed by enzymes that are encoded by ORF1a. Product proteins from the processing includes various replicative enzymes such as RNA dependent polymerase, RNA helicase, and proteinase. The replication complex in coronavirus is also responsible for the synthesis of various mRNAs downstream of ORF 1b, which are structural and accessory proteins. Two different proteins, 3CLpro and PL2pro, cleave the large polyproteins into 16 smaller subunits.

SARS-Coronavirus follows the replication strategy typical of the Coronavirus genus.

Morphology 

The morphology of the SARS coronavirus is characteristic of the coronavirus family as a whole. These viruses have large pleomorphic spherical particles with bulbous surface projections that form a corona around particles. The envelope of the virus contains lipid and appears to consist of a distinct pair of electron dense shells.

The internal component of the shell is a single-stranded helical ribonucleoprotein. There are also long surface projections that protrude from the lipid envelop. The size of these particles are about 80–90 nm.

Evolution 

SARS is most closely related to group 2 coronaviruses, but it does not segregate into any of the other three groups of coronaviruses. The closest outgroup to the coronaviruses are the toroviruses, with which it has homology in the ORF 1b replicase and the two viron proteins of S and M. SARS was determined to be an early split off from the group 2 coronaviruses based on a set of conserved domains that it shares with group 2.

A main difference between group 2 coronovirus and SARS is the nsp3 replicase subunit encoded by ORF1a. SARS does not have a papain-like proteinase 1.

Symptoms and treatment

Once a person has contracted SARS, the first symptom that they present with is a fever of at least 38°C (100.4°F) or higher. The early symptoms last about 2–7 days and include non-specific flu-like symptoms, including chills/rigor, muscle aches, headaches, diarrhea, sore throat, runny nose, malaise, and myalgia (muscle pain). Next, they develop a dry cough, shortness of breath, and an upper respiratory tract infection.

 

At that time, a chest x-ray is ordered to confirm pneumonia. If the chest appears clear and SARS is still suspected, a HRCT scan will be ordered, because it is visible earlier on this scan. In severe cases, it develops into respiratory failure and acute respiratory distress syndrome (ARDS), and in 70-90% of the cases, they develop lymphopenia (low count of lymphocyte white blood cells).

The incubation period for SARS-CoV is from 2–10 days, sometimes lasting up to 13 days, with a mean of 5 days.^[3] So symptoms usually develop between 2–10 days following infection by the virus. As part of the immune response, IgM antibody to the SARS-CoV is produced. This peaks during the acute or early convalescent phase (week 3) and declines by week 12. IgG antibody is produced later and peaks at week 12.^[7]

Engineering the virus 

Engineering of SARS virus has been done. In a paper published in 2006, a new transcription circuit was engineered to make recombinant SARS viruses. The recombination allowed for efficient expression of viral transcripts and proteins. The engineering of this transcription circuit reduces the RNA recombinant progeny viruses. The TRS (transcription regulatory sequences) circuit regulates efficient expression of SARS-CoV subgenomic mRNAs. The wild type TRS is ACGAAC.

 

A double mutation results in TRS-1 (ACGGAT) and a triple mutation results in TRS-2 (CCGGAT). When the remodeled TRS circuit containing viruses are genetically recombined with wild type TRS circuits, the result is a circuit reduced in production of subgenomic mRNA. The goal of modifying the SARS virus with this approach is to produce chimeric progeny that have reduced viability due to the incompatibility of the WT and engineered TRS circuits.

 

Novel subunit vaccine constructs for an S protein SARS vaccine based on the receptor binding domain (RBD) are being developed by the New York Blood Center. The re-emergence of SARS is possible, and the need remains for commercial vaccine and therapeutic development. However, the cost and length of time for product development, and the uncertain future demand, result in unfavorable economic conditions to accomplish this task. In the development of therapeutics and next-generation vaccines, more work is required to determine the structure/ function relationships of critical enzymes and structural proteins.