Severe acute respiratory syndrome (SARS)
Severe Acute Respiratory Syndrome
The SARS outbreak began with the diagnosis of ‘infectious atypical pneumonia’ (Peng et al. 2003). The index case arose in southern People’s Republic of China, specifically the Guangdong province, in November of 2002 (Oxford et al. 2003, Satija et al. 2007). This disease first left mainland China after a physician who had been treating patients in Guandong traveled to Hong Kong February 21st, 2003, spreading the virus to at least sixteen other guests during the single night he stayed there (Peiris et al. 2004).
From there, SARS made history as the first pandemic transmissible disease of an unknown cause in the 21st century. This disease caused worldwide panic and was contained through stringent quarantine measures (including warnings not to visit countries where SARS was known to be active) (‘Preliminary’ 2003). The pathogenic agent was identified as a novel coronavirus when the SARS CoV was isolated from infected patient’s lungs and sputum, cultivated in a cell line, observed, and inoculated into monkeys who exhibited symptoms similar to those of SARS in humans (Peiris et al. 2003, Ksiazek et al. 2003, Drosten et al. 2003, Fouchier et al. 2003, Chan-Yeung et al. 2003). These tests satisfied Koch’s postulates for the pathogenic agent for SARS. Scientists across the world worked, once the causative agent was identified, to sequence the genome of various strains using random primers and real time PCR along with electron microscopy to investigate and identify the SARS CoV from isolates available (Drosten et al. 2003, Ksiazek et al. 2003, Peiris et al. 2003, Rota et al. 2003, Marra et al. 2003, Qin et al. 2003).
The severe acute respiratory syndrome (SARS) associated coronavirus, more often termed SARS Coronavirus or simply SARS CoV, is a member of the Coronavirus genus. All strains of SARS CoV (including strains Urbani, GD01, and Tor2 – from Vietnam, Guandong, and Toronto respectively) exhibit morphology typical to the coronavirus genus (Satija et al. 2007, Zhao 2007). The SARS coronavirus consists of spherical nucleocapsid about 80 to 120 nm in diameter that is enveloped with visibly individual knobs surrounding, giving the virus an appearance of a halo (or corona) (Satija et al. 2007). Coronaviruses have the largest RNA genomes, coding for a multitude of proteins (Gorbalenya 2006, Fauquet 2005). First discovered in the 1960s, coronaviruses, before the SARS outbreak of 2002 to 2004, were typically associated with being responsible for a fairly large percentage (15 to 30 percent) of colds (Holmes 2001). As colds tend to be self-limiting, very little research if any was conducted before 2003 regarding therapeutic drugs or vaccines to target coronaviruses.
SARS CoV is a positive, single stranded RNA virus with a remarkably large non-segmented genome of almost 30kb (29,740 nucleotides) (Siddell 1995, Marra et al. 2003, Rota et al. 2003, Zeng et al. 2003, Thiel et al. 2003) It has 14 open reading frames and its genome codes for four main structural proteins (S, N, E, and M), 16 nonstructural, and 8 accessory proteins whose functions are not all known (Satija et al. 2007). Coronaviruses can be distinguished genetically and serogically into belonging to one of three groups, and the differences between these groups typically lie in these ‘accessory’ proteins.
The SARS coronavirus genome is set up similarly to other coronaviruses (gene sequence is highly conserved). From this RNA genome, two thirds codes for proteins 1a and 1b (via two open reading frames that are separated by a -1 ribosomal frameshift (Satija et al. 2007). Proteins 1a and 1b are then processed to yield nonstructural proteins which are most likely involved in viral replication.
The S protein (better known as the ‘Spike’ protein) is responsible for SARS CoV knobby protrusions from the envelope. The envelope of the SARS coronavirus is made up of two main proteins, the ~70 amino acid protein ‘E’ which is present in small quantities, and the membrane glycoprotein ‘M’ which is makes up the majority of the envelope. Together, the E and M proteins studded with spike sheath the nucleocapsid (protein ‘N’) which contains the virion (Satija et al. 2007). Since the spike glycoprotein is crucial in mediating viral entry, the sequence and biological conformation of this protein is understandably a major factor in host specificity for the SARS coronavirus. The SARS CoV spike protein has proven capable (along with other coreceptors) of mediating the infection of SARS CoV in humans, masked palm civets, mice, multiple species of bats, and raccoon dogs, indicating a high level of plasticity in this protein (Bolles et al. 2011).
The accessory proteins for SARS CoV are not fully understood, although the cellular localization for some has been determined. Protein 3a for instance, localizes in the golgi bodies and appear to be present in the plasma membrane. This protein may also either especially abundant, especially immunogenic, or be a novel structural protein in SARS coronavirus (Tan et al. 2004, Ito et al. 2005). This is indicated by the fact antibodies specific to 3a appear in a large number of SARS patients, although these antibodies have not yet been demonstrated to inhibit viral infection (Stadler et al. 2005). Protein 3a is also responsible for upregulating the mRNA levels for fibrinogen, (the precursor to fibrin, which is partially responsible for the formation of blood clots) which may be responsible for observed elevated blood coagulation levels (Tan et al. 2005, Zhao 2007).
Another unique feature of the SARS CoV in comparison to other coronaviruses is the expression of the accessory 8a and 8b proteins. Whereas most coronaviruses have a 29 nucleotide deletion separating these two proteins, in SARS coronavirus, this stretch of nucleotides is expressed, fusing the two proteins together into protein 8ab (Guan et al. 2003). Whether this provides any tangible selective benefit or not for the SARS coronavirus is not yet understood, and it may simply be a result of high mutation rates and the fact that the 8a and 8b proteins may not be crucial for viral replication (Stadler et al. 2005).
In the course of the SARS CoV viral life cycle, cell entry is mediated by interaction between the S protein and angiotensin converting enzyme 2 (ACE2) (Li et al. 2003). From here the S protein undergoes a conformational change (possibly in a pH dependent manner) that allows the virus to fuse with the cell membrane and be taken in to the cytoplasm (Yang et al. 2004, Simmons et al. 2004, Ng et al. 2003, Qinfen et al. 2004). From there, SARS CoV replicates in the cytoplasm and will complete its life cycle by exiting the host cell via budding. Since the SARS CoV genome is positive sense, its RNA is already in the correct 5’ to 3’ direction to function as mRNA and begin coding for proteins.
Sera collected from humans before the SARS outbreak was tested and found negative for any antibodies directed against the SARS coronavirus (Peiris et al. 2003, Chan Yeung et al. 2003, Ksiazek et al. 2003). This, along with a similar virus found in palm civets and raccoon dogs with a 99% homology to the SARS coronavirus indicates that SARS CoV most likely had only recently made the jump to humans when the outbreak began in 2002 (Guan et al. 2003, Zhao 2007). Recent data after the emergence event appears to place the SARS coronavirus phylogentically as an adaptation from a SARS like CoV in bats (Lau et al. 2005, Li et al. 2005). This is further supported, in terms of phylogenetics, by data indicating that the coronaviruses in small carnivores such as palm civets are terminal hosts, whereas humans are intermediates (Janies et al. 2008). Regardless of whether SARS CoV arose from a direct human to bat transmission and then passed to palm civets and raccoon dogs, or if a random recombination event from the CoV in palm civets enabled it to more effectively bind to human ACE2 or not, we cannot assume that SARS has gone away forever. Considering the high mutation rates associated with RNA viruses, even with the slightly lowered mutation rate in coronaviruses (probably due to an enzyme with RNA proofreading capabilities), it is likely that SARS or a similar virus could emerge again (Bolles et al. 2011).
The SARS coronavirus is a Group IV virus, of the family Coronaviridae, the genus Coronavirus and the species sars coronavirus. The placement of the SARS coronavirus in terms of coronavirus groups (of which there are three as previously mentioned) was a matter of debate. Currently, the SARS coronavirus is considered to be an offshoot of the group 2 coronaviruses (also sometimes termed betacoronaviruses).
The reason for this is when SARS CoV genome is compared to the genomes of other known coronaviruses, the homologous identity of SARS genes is only 70% maximum, thus leading to debate over whether or not the SARS coronavirus would actually qualify as a member of a new, previously unknown, group of coronaviruses (Drosten et al. 2003, Rota et al. 2003, Marra et al. 2003, Tan et al. 2006).
The exact mechanisms of transmission for the SARS coronavirus have not yet been determined, but SARS appears to be transmitted through close contact with severely ill SARS patients and, more effectively, through the inhalation of viral contaminated respiratory droplets (such as those produced when coughing) (Peiris et al. 2003, Chan Yeung et al. 2003, Ksiazek et al. 2003) Ideal host factors for SARS CoV remain equally unclear, especially since the SARS epidemic was characterized by several key ‘super spreader’ events wherein certain patients appeared to spread the virus far more effectively than usual. These ‘super spreader’ phenomena have yet to be satisfactorily explained (Oxford et al. 2003).
Severe Acute Respiratory Syndrome is a lower respiratory disease is either bi- or triphasic and is characterized by a high fever (38 degrees Celsius, or 100.4 Fahrenheit) in its first stage. Two to four days after the onset of disease, a dry cough usually develops. Then, somewhere between one to two weeks later, the disease may either develop into a moderately severe respiratory disease until recovery or further worsen into what is known as acute respiratory distress syndrome (ARDS) (Peiris et al. 2003c).
The incubation period for this virus ranges from 1 to 14 days, with an observed median incubation period to onset of 4 to 5 as, as reported by WHO (1, SU). High Resolution CT scans are the most effective early diagnosis tool as antibody titers are ineffective as an early diagnosis mechanism (Shaila 2003). It should also be noted that asymptomatic SARS infections were observed, however, individuals that do not present symptoms do not appear to be capable of transmitting the virus (Guan et al. 2003, ‘Preliminary’ 2003).
Symptoms of severe acute respiratory syndrome include, but are not limited to: (Peiris et al. 2003b, Cheng et al. 2004, Li et al 2003a, Ng et al, 2003a)
- Decreased platelet counts
- General malaise
- Prolonged coagulation
- Watery diarrhea
- Shortness of breath
- Evidence of pneumonia
- Acute respiratory distress
- Loss of appetite
- Unproductive cough
SARS is unique among viral diseases in that the viral load present in the upper and lower respiratory tract as well as intestines and feces of hosts does not peak until the tenth day of active, symptomatic infection (Cheng et al. 2004, Drosten et al. 2004, Peiris et al. 2003a). This may explain SARS relatively low infection index of 3 (compared to small pox and influenza that have an infection index of 5 minimum) (Riley et al. 2003, Lipsitch et al. 2003).
In order for a potential case to be considered ‘probable’ or verified as a SARS infection the WHO guidelines of 2004 indicate that at least two different assays (either on different specimens, the same specimen collected at separate points in the illness, or different types of assays must test positive for the result to be considered validated. Serological testing can be used to confirm the presence of anti coronavirus antibodies, however since the viral load takes so long to peak, the concentration of antibodies also take a while to build up, and this test cannot be considered definitive unless it is at least three weeks after the onset of the disease (Shaila 2003).
The SARS epidemic lasted over a hundred days before finally waning. At that time, the number of probable cases recorded by the WHO was slightly over 8000, with slightly less than 800 deaths recorded worldwide (WHO 2003). This would indicate SARS has a fatality rate of approximately 10%, similar to West Nile Virus.
The SARS coronavirus affects individuals differently depending on age. While the mortality rate in the elderly reached approximately 50% during the SARS epidemic, children under twelve years of age had a very good prognosis for recovery (Peiris et al. 2003a, Lee et al. 2006, Tsui et al. 2003, Booth et al. 2003). This may be because pre-existing factors such as heart disease and diabetes type II had a negative impact on recovery in the elderly, but even more minor symptoms typical in adults such as headaches, rigors, and chills were typically milder or absent altogether in young children, who mostly experienced a dry cough and a runny nose (Chiu et al. 2003, Hon et al. 2003).
It is important to note that even at its peak SARS came nowhere near the mortality levels of influenza A or other highly contagious diseases (Schabas 2003). The large portion of cases arose in hospital settings before physicians had acquired knowledge on how to safely treat SARS patients.
While the first SARS cases were treated with broad spectrum antibiotics, the revelation that this disease was caused by a novel coronavirus makes this course helpful only in the possibility of hindering other opportunistic infections from occurring in patients concurrently with severe acute respiratory syndrome (Stadler 2005). To date, no vaccine or antiviral drug has been licensed for use in humans to counteract the SARS coronavirus.
Several drugs were used in an attempt to treat SARS between 2002 and 2004. Among these were systemic steroids, which may have assisted in decreasing viral load. However, these steroids were generally prescribed alongside other treatments and unfortunately no control group with just steroids exists to draw comparisons from and evaluate (Peiris et al. 2003a, Ho et al. 2003, Booth et al. 2003). This makes it impossible to determine the usefulness of systemic steroids as a treatment and equally impossible to evaluate whether or not the potential benefits of this course of treatment outweigh the potential negative consequences in patients. Other drugs that may be helpful against SARS coronavirus include lopinavir/ritonavir which (when used alongside the nucleoside analog ribavirin) appears to potentially decrease the severity of symptoms in severe acute respiratory syndrome (137,138 S). Ribavirin alone (and with steroids) has also been tested, but the data from these studies is currently inconclusive as some reports indicate positive results whereas others actually indicate adverse effects arising from treatment (Booth et al. 2003, Avendano et al. 2003, Knowles et al. 2003, Lee et al. 2003).
The lack of standard therapy does not mean that there is any lack of potential options. Certain therapeutics have shown success in vitro (and one in vivo) against the SARS coronavirus. The most promising are interferons, a type of cytokine, which has been shown to inhibit the replication of the SARS coronavirus. Other therapeutics which have shown promise in in vitro studies include glycyrrhizin (which is only effective against SARS CoV at high concentrations), cinanserin (which inhibits a SARS CoV proteinase), and niclosamide (whose interaction with the SARS coronavirus is poorly understood) (Cinatl et al. 2003, Wu et al. 2004, Chen et al. 2005).
Targets for therapeutic antivirals as well as for vaccines include inhibiting the S protein from binding to ACE2, either by direct interaction with the spike protein, ACE2 itself, or blocking ACE2 allosterically (Li et al. 2005a, Bolles et al. 2011). At the same time, only a few substitutions in the spike receptor binding domain appear to be necessary to allow SARS coronavirus to improve or otherwise alter binding affinity between the virus and host (Rockx et al. 2010). This would imply that any drug targeting the S protein would have to be effective enough that the virus would not simply adapt itself to bind to human ACE2 even more efficiently than its current mechanism. This should not necessarily be impossible, considering a good percentage of antibodies do appear to be directed at the spike protein (Bolles et al. 2011).
In addition to the Spike receptor binding domain as a target, proteinases (such as PL2pro) which are crucial in cleaving the polyproteins synthesized by the SARS CoV genome could be another potential target for inhibition. Another possibility is the simulation of RNA interference via the creation of siRNAs (small 20 or so nucleotide sequences) to induce RNA double strandedness in the SARS CoV genome. This double strandedness could then be recognized by the infected cell’s RNA Induced Silencing Complex (RISC) would then recognize as flagged to destroy. The trick will be in creating stable small RNA chains complementary to intended regions on the SARS coronavirus genome (Shi et al. 2005, Wu et al. 2005, Wang et al. 2004, Elmen et al. 2005).
In terms of passive immunization, monoclonal antibodies have been proven to protect against the SARS coronavirus after administration as little as two days prior before challenging the inoculated organism with SARS CoV (Subbarao et al. 2004,Traggai et al. 2004). Unfortunately, though this form of immunization may be highly beneficial for protection after exposure to the SARS coronavirus, the immune system will not retain any ‘memory’ of its own against SARS via this method. Thusly, it is only effective short term.
Active immunization through the use of vaccinations would be preferable in terms of building memory cells in the immune system to prevent any repeat infections. However, the high recombination rate of coronaviruses makes using a live attenuated virus too risky for use in humans, in case the attenuated SARS coronavirus were to recombine with another virus should someone vaccinated concurrently be infected by another virus, thus activating SARS once again. In order to prevent this, any vaccine for SARS CoV will most likely have to forgo the preferred robustness of the immune response generated from live attenuated vaccines and instead introduce the virus antigens to the immune system in another way (Lai 1992).
This problem could potentially be addressed with a recombinant antigen (also known as a recombinant subunit) vaccine. This type of vaccine would contain epitopes from different ‘S’ proteins as well as other key antigens to produce an effective immune response. An even more promising option would be a recombinant vector vaccine. A recombinant vector vaccine acts as virus like particle, packaged in a ‘vector’ and expressing the full complement of viral proteins while also lacking a viral genome. This produces a robust response as the immune system should ideally treat the vector the same way it would the pathogen the vaccine is immunizing against, and this response carries with it very little risk of causing the actual disease to propagate as one risks with a live attenuated vaccine of a coronavirus (Stadler 2005).
Even the development of a recombinant vector vaccine must be thoroughly tested as adverse effects have been known to occur (for example, exposure to the vaccine leading to an enhancement of viral infection rather than inhibition) both in trials for vaccines against the SARS coronavirus and in the vaccine for a related coronavirus, feline infectious peritonitis virus (Vennema et al. 1990, Traggai et al. 2004).
There are about six known coronaviruses that infect humans. This includes Group 1 coronaviruses HCoV-NH (New Haven Coronavirus), HCOV-229E, HCoV-NL63, and group 2 coronaviruses HCoV-OC43 and HCoV-HKU1 (Holmes 2001, van der Hoek 2004, Gorbalenya et al. 2004, Esper et al. 2005, Woo et al. 2005).
The SARS coronavirus has proven capable of replicating in a variety of hosts, as well as frequently jumping the species barrier between different hosts. As such, it is possible for many unidentified coronaviruses as well as SARS CoV strains to exist in reservoir and alternate hosts.
Diseases with symptoms similar to severe acute respiratory syndrome include influenza, pneumonia, and acute respiratory distress syndrome. SARS can be distinguished from these diseases by the use of HRCT scans as well as culturing through Vero cells, the use of real time PCR, and antibody titers as laid out by the WHO (WHO 2004).
Recently, in September of 2012, a new SARS like coronavirus was identified from a patient in London after a visit to Saudi Arabia in late August (Pebody 2012). This index case presented with a high fever and hypoxia that became progressively severe and required manual respiration. The virus causing this patient’s severe respiratory distress, first believed to be a form of viral pneumonia, was matched to a novel coronavirus identified only a few months before by ProMed and sequenced by the Erasmus Medical Center (‘HPA’). The WHO have been notified, and so far this novel coronavirus does not appear to be spreading to the level of epidemic, although this may be a result of early warning thanks to the WHO’s surveillance (‘Novel’).
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