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When the November outbreak of severe acute respiratory syndrome (SARS) hit China and spread throughout south-east Asia, scientists from the world health organization sprung forth to find the agent causing such severe illness. Weeks later, a novel member of the coronavirus family was isolated and thought to be the etiologic agent of SARS, aptly named, SARS coronavirus (SARS-CoV). SARS provided a worldwide scare and caused an epidemic that reminded us of how chillingly quick we can be infected with life-threatening viruses. This virus is interesting because of the method in which it established an epidemic and its effects of society shortly after outbreak.
SARS-CoV has been classified as a Group IV coronavirus in the Baltimore classification system; it has a single-stranded plus-sense RNA genome. SARS-CoV RNA is around 30 Kbp long and contains the genes for replication and structure. The genome is 5'-3' with short untranslated regions at the ends; two open reading frames (ORFs) encode for enzymes needed for replication, Rep, followed by four ORFs for the structural proteins; the gene for hemagglutinin (common to most coronavirus) was not present. The ORFs for viral replicase and associated proteins are transcribed as a large polyprotein which undergoes proteolytic cleavage in 11-13 sites. Like most coronavirus, SARS-CoV has four ORFs that encode for its structural proteins that make up the nucleocapsid and envelope receptors: E, M, N and S. The N protein is the nucleocapsid protein that binds to the genomic RNA and forms a helical nucleocapsid. The N protein is comprised of 422 amino acids with hydrophobic regions at the core of the structure, with a highly conserved motif common to members of coronavirus located at the N-terminus. S proteins are the surface spikes and envelope-integrated glycoprotein receptors of the SARS-CoV responsible for host attachment and entry. However, unlike the S proteins of most coronaviruses, the S polyprotein is not cleaved into S1 and S2 because the cleavage site in the peptide chain was not observed. The M protein (membrane) aids in budding and maturation; it is associated with E (envelope) proteins to aid in budding and is directly involved with the attachment of envelope protein S.
It is thought that SARS arose from a mutation in a nonhuman version of a coronavirus that gained the ability to jump to human hosts because the RNA genome is susceptible to errors in replication; studies of the native fauna of southern China have identified palm civets and raccoon dogs as hosts to a SARS-CoV-like virus which contains a 29-bp sequence exclusive to the animals, but no natural animal reservoir has been found for the human-tropic virus. The viral replication cycle of SARS-CoV starts with attachment and entry. The S protein, more precisely the S1 domain, on the envelope surface of the virus attaches to the metallopeptidase, angiotensin-converting enzyme 2 (ACE2). After attachment, entry is mediated by the S protein which collapses and exposes the membrane fusion peptide to the transmembrane region of S proteins and mediates host cell and viral membrane fusion. Method of uncoating has yet to be articulated. Since the genome is plus-sense RNA, it can be directly transcribed by cellular ribosomes into more template and early mRNA which will encode for rep gene products, such as viral RNA polymerase, helicase and protease. The viral RNA polymerase will create a complementary strand using the genomic RNA as a template; from the newly synthesized complementary strand, subgenomic plus-sense mRNAs can be transcribed to encode for the other proteins. Assembly begins with N proteins that associate with the viral genome to form the nucleocapsid; M, E, and S proteins are inserted into membranes of the endoplasmic reticulum or golgi, and the assembled nucleocapsids will bud from these organelles, forming a virion with an envelope integrated with viral proteins which will be exocytosed.
SARS is usually infecting the lower respiratory tract through inhalation of droplet nuclei originating from infected hosts when they sneeze or cough. It has been shown that it can be contracted through the oral-fecal route as well, demonstrated by the Amoy Gardens scenario. The virus infects epithelium and mucosal layers of the respiratory tract, usually causing a fever greater than 38oC and flu-like symptoms, 10-20% of patients develop diarrhea, and most will develop a life-threatening pneumonia. Lung samples isolated from rhesus macaques with SARS-CoV displayed signs of pneumonia, alveolar damage caused by virus replication and flooding with protienaceous fluid; there were some signs of syncytial cells in the lumen of the bronchioles, although syncytia is not a common occurrence in SARS patients. Viral clearance can be accredited to the adaptive immune response, however, there is evidence that shows that some infections of SARS-CoV can down-regulate the humoral response and cause antibody counts to decrease, leading to increased chances of death. There is also evidence suggesting that SARS can activate a "cytokine storm" which can result in shock and lead to death. Sequelae resulting from SARS include pulmonary fibrosis, osteoporosis, avascular necrosis, and is linked to post-SARS depression and other psychological manifestations. However, the long-term sequelae of SARS are not conclusive, and are not common in literature.
Treatment of SARS includes the use of anti-virals such as ribavirin and neuraminidase-inhibitors, although both treatments are controversial because they are counter-intuitive, ribavarin and neuraminidase-inhibitors have shown little to no efficacy. More common treatment techniques include steroids and assisted breathing devices. Antibiotics are also routinely prescribed to prevent opportunistic and/or nosocomial bacterial infections. In some severe cases, a protease inhibitor usually for HIV treatment was used. There have been vaccines made for SARS that are currently in clinical trials, one of which is a SARS-CoV inactivated by UV radiation and formaldehyde is currently being researched as a first-generation vaccine for SARS. The inactivated vaccine is great for first generation, but once more potent neutralizing epitopes are discovered, research will be driven in that direction. Another, more recent vaccine is using the S proteins as antigenic determinants to up regulate antibody production, however there are safety concerns with using fully expressed S proteins as it did cause liver failure after test animals were inoculated with SARS-CoV. According to Jiang et al., a vaccine for SARS should, "1) elicit highly potent neutralizing antibody responses against a broad spectrum of viral strains; 2) induce protection against infection and transmission; and 3) be safe by not inducing any infection-enhancing antibodies or harmful immune or inflammatory responses." The prognosis of SARS with treatment is at 11% worldwide; there is no data for untreated SARS, but one could assume it is much higher than with treatment. The CDC and WHO have mobilized since the SARS epidemic and set out rules and regulations to ensure safety for the public, this includes prevention techniques. The CDC recommends that during transmission periods in which a person is in a risk area, frequent hand washing with soap and wearing protective masks can prevent disease. Currently, global surveillance and personal vigilance are promoted to prevent another epidemic.
The effect that SARS has had on society and on control of the disease was something very unique during the SARS epidemic of 2003. The demographic of infection is not discriminate in any way, everyone is equally susceptible to SARS-CoV, however not everyone reacts the same way; elderly patients and infants that contract SARS are often at higher risk for death caused by the disease, much like influenza infections. During the initial outbreak, the Chinese government decided to use quarantines to impede the spread of the virus through the respiratory route, which was a radical and controversial decision to make. Businesses faltered during the years after the epidemic due to stigma from the outbreak; tourism to areas where the virus was found also decreased for some time after the outbreak. There were social implications when it was reported that the disease arose from China; Chinese products and culture were scapegoated for the spread of the disease, and fear associated with stigma lead to the marginalization of some expatriate populations - this had a secondary effect on businesses in asian-prominent districts of large cities (Chinatowns). In China, use of surgical masks whenever leaving residence was widely observed, and public transportation and public areas were often deserted; strict measures were taken on air travel to prevent the spread of the disease, although the virus did make its way to the western hemisphere in this manner. Epidemiology reports characterize two specific clusters, known as super-spread events (SSEs), which consist of the SSE which lead to 125 infections in patients at the Prince Wales Hospital in Hong Kong and the Amoy Gardens apartment complex quarantine SSE in which 300-plus people contracted SARS from a fecal-oral route. These reports classify SARS as a moderately transmissible.
The SARS coronavirus is a very interesting virus because it was found to be a novel virus that features some odd mutations that allowed it to jump from the animal host to humans. SARS-CoV genome shares many homologous nucleotide sequences to other respiratory tract infecting coronaviruses, but has evolved to become extremely virulent, even when the hemagglutinin receptor is missing. The ability to induce a cytokine storm and its highly mutable genome makes it increasingly hard to develop successful vaccines. It also caused somewhat of an international scare when it was reported, causing businesses to weaken and very quick global awareness. It produced a response that was very drastic: quarantines; and it reinvented procedures for handling some viral epidemics. Most interestingly, it has disappeared with speed, but the possibility remains that it is currently lying dormant in some unknown reservoir, mutating and waiting to infect us again.