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Severe acute respiratory syndrome (SARS) which is caused by SARS coronavirus(SARS-CoV) occurred originally from south of China at the end of 2002. Within six month period almost 8000 people were affected and 800 of them died from this disease (1). This highly contagious virus is a great threaten for public. Even it was controlled; its reoccurrence may cause worse effects. Therefore well understanding of its outbreak and treatments are in great needed. This article primarily summarizes recent studies on this virus including viral structure, life cycle, outbreak, pathogenesis, treatment and prevention.
Structure and classification
SARS Coronavirus (SARS-CoV) which is known as the largest positive-sense-single-strand RNA virus so far, which may represent the first member of a new group of coronaviruses according to recent research (3). Its genome is about 30 kb and enveloped as well as capsulated helically. Genomic RNA contains fourteen open reading frames (ORFs). The two large 5'-terminal ORFs, 1a and 1b, are conserved among all corona viruses (2). They could encode polyproteins pp1a and pp1ab which are cleaved by 3CLpro to form viral complex for viral replication and translation (2). Because of this important role in control of coronavirus replication and polyprotein process, 3CLpro is called main protease as well (3). The rest ORFs encode the four major structural proteins: the spike(S), envelope(E), membrane(M) glycoproteins, and nucleocapsid(N) protein (2,3).
Coronavirus Spike (S) protein serves as a ligand for host cell receptors to trigger viral envelope fusion to cellular membrane (3). Its outer subunit (S1) and a transmembrane subunit (S2) are involved in membrane fusion. S1 contributes to binding of receptor, while function element of S2 functions during defusion (1, 2, 3).
The nucleocapsid (N) protein of SARS-CoV takes part in virion assembly. It functions to associate with viral genomic RNA in ribonucleoprotein (RNP) formation (2). It also regulates transforming growth factor-Î² signal pathway in infected cells (1).
Virus envelope consists of envelop (E) protein mainly. Accordingly, structures of E proteins are conservative within different coronavirus groups. As an integral membrane protein, it founds in assembly and budding of SARS-CoV (2, 3).
M protein can be found in virion envelope, it is involved in virion assembly as well. Particularly it determines selection of both genome and S protein during assembly (1). After virus enters cell, M protein targets and attaches to the assembly machine of Golgi complex (2).
Recognition of angiotensin-converting enzyme 2 (ACE2) on host cell by S protein is a beginning signal of the SARS-CoV infection (3). The mechanism of this recognition is efficient binding between ACE2 and S1 domain of S protein (3).
After recognition, coronavirus virion fusion with the host cell membrane could be directly on cell surface or internalized into the endosome (3). There are variable among different species, for SARS-CoV it involves in endosomal pathway. Binding of ACE2 triggers conformation changes of the transmembrane S protein with the help of fusion peptide and HRs (3). Thus, the HRs binds to both fusion peptide and the transmembrane domain to facilitate contact and fusion (3).
The following step is release of SARS-CoV RNA into the cytoplasm. The mechanism of this step has not been certainly understood.
Cap-dependent translation utilizes host cell machinery immediately to express first ORF1a/b which produces RNA-dependent RNA-polymerase. This protein is for replication of genomic RNA and a nested set of subgenomic mRNAs (sg mRNA) (2). They are generated in double membrane vesicles (DMVs) which might originated from ER (1).
Genomic RNA which is bound to N protein is then incorporated into virions located between the endoplasmic reticulum (ER) and the Golgi apparatus (2).
Virus is released from the host cell via exocytosis or apoptosis (1).
Since ACE2 as SARS-CoV receptor on host cells is present in pneumocytes, enterocytes and renal tubular cells. The specific location could explain tissue tropism of SARS-CoV in epithelia of respiratory and gastrointestinal system (4). However, at later phase of infection SARS-CoV also exists in liver, sweat glands, pituitary, pancreas and so on (4). This suggests that SARS is a systemic disease.
Patients infected by SARS-CoV normally occur flu-like symptoms, which include fever, cough, chill and so forth (5). Typical severe symptoms of infection are associated with the lower respiratory tract. About two thirds of the patients immediately present breathe problems and continual fever, while the remaining patients develop such symptoms a week later (4, 5).
The major transmission routes of SARS-CoV could airborne, humanâ€™s droplet. SARS-CoV affects host cells on two ways: cytocide including cellular lysis or apoptosis and immune mediation (3, 5). Results of cell culture support that SARS-CoV lead to disruption of Golgi complexes function and thus syncytia formation in lung tissue (5).
The distinguishing sign of the lungs infected by SARS-CoV is Diffuse Alveolar Damage (DAD) (4). During the beginning week, following symptoms is displayed in infected lungs which include acute edema, alveoli collapse, damage of epithelial cells and fibrous tissue formation in alveoli (4, 5). Some patients present fibrous structure of DAD in second week (4). Additionally, studies of histological staining indicate that infection induces macrophages migration to infected tissue through cellular infiltration (4).
In most patients, it is reported that mucosal lymphoid tissue are typically and completely depleted in the infected appendix, pharynx, and small intestines (3).
No pathological change is observed through microscopic assays (4).
Long term consequence
Generally long term consequence of SARS-Cov infection is unkown so far. In some follow up studies, it is shown that some of the patients are abnormal functionally or psychologically after they recovered from SARS. They usually suffer from psychological trauma as well (5).
Clearance of virus
It has been reported that innate immunity plays key role in virus clearance. Natural killer (NK) cells suppress SARS-CoV replication by killing infected cell, which might be direct via perforin or indirect via IFN-Î³ (3).
The specific defense for viral infection adaptive immunity offers is based on cytotoxic T lymphocyte (CTL) (3). SARS-CoV S protein contains T cell epitopes (HLA-A2) which trigger T cell activation. Memory T cell which could respond to N protein exists for two years even without exposure of antigen (3). There are antibodies involved in humoral immune response against SARS-CoV infection. IgG is the first antibody that is detected in serum (7). Two weeks after onset of SARS other antibodies are also detectable.
Initiation of the innate and/or adaptive immune response results in the secretion of chemokines and other cytokines which are inducer for inflammatory response. They could attract neutrophils and macrophages toward the sites of infection. In human body, they are by bronchial epithelium and AT2 cells to fight against SARS-CoV infection (3).
Antibiotics is used at the beginning of infection due to its nonspecific effects and lack of rapid SARS-CoV diagnosis agents. However, as infection develops there are two major types of treatments including antiviral agents and anti-inflammatory agents (8).
Antiviral agents such as ribavirin, interferons,and lopinavir/ritonavir are used clinically for the treatment, particularly ribavirin (7, 8). However, side effect associated with high-dose ribavirin such as severe hemolysis limits its usage.
As an anti-inflammatory drug corticosteroids have been widely used for SARS therapy (7). Adverse outcomes caused by corticosteroids include immunosuppression and necrosis. It was even reported that high dose corticosteroids resulted in fungal infections in many patients in Hong Kong (7). Patients in Taiwan were treated by another anti-inflammatory agent intravenous immunoglobulin (IVIG). In the rest of China, IVIG from SARS patientsâ€™ serum is available for therapy (7).
To date, vaccine for SARS-CoV is still developing. Based on the principles, potential vaccines are as followed: polyclonal antibodies, inactivated SARS-Co V, recombinant viruses and virus-like particles (7, 8).
Generally, SARS case fatality is about ten percent. It is believed that age is the most critical factor for fatality (6). Compared to seniors over 65 years old whose fatality exceeds fifty percent, children under 12 years old have much better prognosis (4, 6). After treatments, the function of the lungs is recovered to normal in most patients, although about some patients suffer from variable respiratory impairment.
Based on the fact that SARS-CoV transmits via infected droplets, break transmission chain of SARS by separating infected patients from healthy people is an effective way to control its spread (3, 7). Besides quarantine, it is necessary to trace contact history of patients. Personal protections include hand washing and face masks. Actually, all of those activities contribute to the control of SARS outbreak in China 2003.
It is widely accepted that advanced age is primary risk factor of SARS-CoV infection. Compared to young children, adult is more susceptible to SARS-CoV infection. Particularly, adults who are greater than 65 have high risk to be infected (5). For children who are younger than 12 years experience milder symptoms, which might due to their developing immune system.
The first cases of a severe atypical pneumonia appeared in the Guangdong Province of southern China in November 2002. A doctor who was infected lived in a hotel transmitted virus to people in the same floor, thus virus was spread globally by travel from Hong Kong (1, 3). Main countries affected include Canada, Mainland China, Singapore and Vietnam. Quarantine procedures resulted in a good prevention. By early April 2003, epidemic was under control in Hong Kong. In the following month, most infected countries prevent broader outbreak. By June 2003, WHO removed most of the countries from infection outbreak list.
As a severe infected disease, SARS did affect economy and society badly. During the outbreak 2003, people lose their trust to others and they tried not to contact with anyone including normal social activities. Personally, I wore face mask every day if in public area. Honestly, everyone was afraid of infected or even quarantined. Tourism income for the country decreased a lot. Therefore, most of economic and social activities were impact by SARS in China.
As a member of coronavirus family, SARS-CoV has its specific characteristics which results in much severe infection. The structural protein particular S protein on viral surface associates with many function of SARS-CoV, it also could be used to develop vaccine. As a RNA virus, SARS-CoV has typical replication strategy of this type. However, cell tropism it has is due to Limited location of ACE2 receptor which restricts respiratory tissue as its favorable cells. Therefore, visible changes of lungs tissue and severe symptom of lower respiratory tract infection enlighten its pathogen mechanism, which could be used to help diagnosis. When it comes to treatments, Vaccine for SARS is challenging and thus in process of developing. Current antiviral and anti-inflammatory agents somehow are effective to reduce fatalities. Face such easy-spreading virus; control of transmission seems to be wiser. Once the transmission chain is broken, adverse effects on social and economic activities will be restricted to minimize lost.