Interferon



SARS Coronavirus

SARS virus uses multiple mechanisms to inhibit the host type 1 interferon response with open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins all playing a major role;

From: The Microbiology of Respiratory System Infections, 2016

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Interferon Type I

Vaccine Efficacy

Monospecific Antibody

Infectious Agent

Mutation

Receptor Binding

Coronaviridae

Coronavirinae

Middle East Respiratory Syndrome Coronavirus

Severe Acute Respiratory Syndrome Coronavirus 2

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Respiratory Viruses

H.F. Boncristiani, ... E. Arruda, in Encyclopedia of Microbiology (Third Edition), 2009

Epidemiology

SARS-CoV has a zoonotic origin and horseshoe bats seem to be its natural reservoir. At the beginning of the 2002–03 outbreak, probably animal-to-human interspecies transmission was involved providing the source of an agent that later adapted to efficient human-to-human transmission. Palm civets and perhaps other mammals served as amplification hosts. Interestingly, shortly after a wildlife trade ban was imposed to control the SARS outbreak, there were no further naturally acquired human cases of SARS in Guangdong. SARS-CoV is mainly transmitted among humans by the deposition of infected droplets or aerosols on the respiratory epithelium. In addition, transmission is infrequent during the first 5 days of illness, partly because of the low viral load in respiratory secretions during that phase. Excretion of SARS-CoV in sputa and stools may average 21–27 days after symptom onset, respectively.

Transmission of SARS-CoV among health-care workers and between patients in the hospital setting played a pivotal role in outbreak propagation. Assisting during intubation, suctioning, and manipulating ventilatory apparatuses were high-risk activities. SARS-CoV may persist for up to 2 days on environmental surfaces and 4 days in diarrheal stools.

Approximately, 8500 cases were reported in the outbreak, with fatality rate of at least 10%. At present no circulation of SARS-CoV is registered.

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SARS

Bart L. Haagmans, Albert D.M.E. Osterhaus, in Vaccines for Biodefense and Emerging and Neglected Diseases, 2009

Introduction

Severe acute respiratory syndrome coronavirus (SARS-CoV) first emerged in the human population in November 2002. Phylogenetic analysis of SARS-CoV isolates from animals indicated that this virus most probably originated from bats, was transmitted first to palm civets and subsequently to humans at the wet markets in southern China. Subsequent outbreaks occurred early 2003 in Hong Kong, Hanoi, Toronto, and Singapore, and could be directly traced back to one index patient who acquired the infection in Guangdong and traveled to Hong Kong. A worldwide epidemic was halted through the efforts of the World Health Organization, which responded rapidly to this threat by issuing a global alert, rigorous local containment efforts, warning against unnecessary travel to affected areas, and by creating a network of international experts to combat this virus. In the end only 8096 people became ill, and 774 people died in this first SARS epidemic. Because SARS-CoV could re-emerge and cause another epidemic at any time, development of effective vaccines remains of vital importance.

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Recent Advances in the Discovery of Deubiquitinating Enzyme Inhibitors

Mark Kemp, in Progress in Medicinal Chemistry, 2016

4.1 Viral DUBs

Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are two of the six known human coronaviruses. Both are highly pathogenic with the potential for human to human transmission [54]. Both contain papain-like cysteine proteases termed SARS-CoV PLpro and MERS-CoV PLpro, respectively. In addition to processing viral polyprotein, these proteases function as DUBs (and also as deISGylating enzymes) removing ubiquitin and ISG15 (another ubiquitin-like peptide) from host cell proteins, resulting in antagonism of the host antiviral immune response [55]. Hence, both SARS-CoV PLpro and MERS-CoV PLpro have been proposed as important antiviral targets.

The X-ray structures of both proteases have been solved and found to have most similarity with the USP family of DUBs [25,56–58]. SARS-CoV PLpro has received more attention, with several groups identifying inhibitors. Chou et al. discovered that the immunosuppressive thiopurine drugs 6-mercaptopurine (6MP 4) and 6-thioguanine (6TG 5) (Figure 8) are weak but ligand-efficient inhibitors of SARS-CoV PLpro [59]. The same group has recently found that the compounds have similar potency against MERS-CoV PLpro [60]. In both cases, the group used computational docking studies to predict similar binding modes to a common cavity near the catalytic triad of the two PLpro enzymes.



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Figure 8. Structures of thiopurine inhibitors of SARS-CoV PLpro and MERS-CoV PLpro.

The Mesecar and Ghosh group identified low μM inhibitors of SARS-CoV PLpro by high-throughput screening of approximately 50,000 compounds with RLRGG-AMC (the 'C-terminal 5-mer' of Ub-AMC) as the substrate [56]. Compound optimisation resulted in GRL0617 (6) which has an IC50 of 0.6 μM against SARS-CoV PLpro and has an EC50 of 15 μM in an antiviral cell-based assay (Figure 9). An X-ray structure of 6 in SARS-CoV PLpro showed that it binds within the S4 and S3 subsites of the protease (PDB: 3E9S). These equate to the regions in which the side chains of Lys73-Arg74 of ubiquitin bind. Over 6 years, the same team reported in a series of publications [54,61–63] compounds from related series such as 7 which retain the naphthyl group and bind to the same S4/S3 subsites of SARS-CoV PLpro (PDB: 3MJ5). Their most recent publication shows how a further twofold potency improvement was achieved by changing the benzodioxolane for a 3-fluoro phenyl to give compound 8 (IC50 0.15 μM, antiviral EC50 5.4 μM) [54].



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Figure 9. Structures of SARS-CoV PLpro inhibitors from the Mesecar and Ghosh group.

The X-ray structure of 8 (purple (dark grey in the print version)) in SARS-CoV PLpro (green (grey in the print version)) is shown in Figure 10 with the same viewing orientation as used for Figures 5 and 6 (PDB: 4OW0). Note that the thiol of the active site Cys112 has become oxidised to a sulfonic acid. This structure shows how compound 8 spans the S4 and S3 subsites. Although these sites are appreciably different in USPs [25], consistent with the more than 100-fold selectivity of series representatives over USP2/7/8/20/21 [54], it is notable that the binding site of compound 8 (and also of compounds 6 and 7) is in approximately the same region as the distal binding site of the UCHL1/Ub-VME complex (Figure 6), and also the ligand-binding site described later for USP14.



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Figure 10. X-Ray structure of compound 8 in SARS-CoV PLpro (PDB: 4OW0).

Although progress in SARS-CoV PLpro inhibitor optimisation has been slow, it is nonetheless encouraging to see inhibitors such as 8, relatively potent and devoid of toxicophores [64], binding to a protease that has structural similarities with human DUBs. With high lipophilicity and free benzylic positions, compound 8 is, not surprisingly, unstable in mouse liver microsomes with a T1/2 of 2.8 min. However, more polar analogues do demonstrate that significant stability improvements can be made without sacrificing too much potency for SARS-CoV PLpro [54].

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Human Coronaviruses: General Features

Xin Li, ... Patrick C.Y. Woo, in Reference Module in Biomedical Sciences, 2019

Epidemiology and Clinical Features of Human Coronaviruses

SARS-CoV and MERS-CoV are two highly pathogenic coronaviruses that have claimed thousands of lives globally in the past two decades. However, prior to the SARS-CoV pandemic in 2003, human coronaviruses were only believed to cause symptoms of common cold—mild, self-limiting upper respiratory tract infection. Four human coronaviruses have been identified so far, including two alphacoronaviruses HCoV-229E and HCoV-NL63, and two betacoronaviruses HCoV-OC43 and HCoV-HKU1. HCoV-229E and HCoV-OC43 have been known for more than 50 years, while HCoV-NL63 and HCoV-HKU1 were isolated after the SARS-CoV outbreak. They are characterized by direct human-to-human spread and, in contrary to SARS-CoV and MERS-CoV, are not known to be transmitted from animal reservoir. Nevertheless, significant differences in genetic variability have been observed among the human coronaviruses. HCoV-OC43 isolates from the same location but in different years demonstrated significant sequence variability, while HCoV-229E isolates from around the world displayed minimal genetic divergence. The higher degree of genetic variability likely explains the fact that HCoV-OC43 is able to cross genetic barrier to infect mice neural tissue. These human coronaviruses are globally distributed, although the frequency of isolation of the four viruses varies at different times in different places of the world, typically comprising 10%–40% of respiratory samples testing positive for any respiratory viruses. Human coronaviruses generally demonstrate winter seasonality between the months of December and April, similar to the pattern observed in influenza virus. They are associated with a range of respiratory outcomes, most commonly upper respiratory tract infection of moderate clinical concern, but occasionally also lower respiratory tract involvement including bronchiolitis and pneumonia leading to fatality, especially in neonates, the elderly and individuals with compromised immunity. The mainstay of laboratory diagnosis is via quantitative real-time polymerase chain reaction (qRT-PCR), either in-house developed and validated or commercially available multiplex PCR platforms. The utilization of serologic assays is limited to epidemiologic studies and in cases where the viral RNA is difficult to isolate. There are no directed antiviral agents for human coronaviruses to date, so treatment is largely supportive.

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Emerging Infectious Diseases and the International Traveler

Camilla Rothe, Elaine C. Jong, in The Travel and Tropical Medicine Manual (Fifth Edition), 2017

SARS-CoV

Severe acute respiratory syndrome coronavirus (SARS-CoV), spread by travelers to 30 countries on five continents in 2003, was termed by Heymann et al. (2013) the "first pandemic of the 21st century." The SARS pandemic illustrated the pivotal role of international travelers in the rapid global spread of an air-borne EID and showed the challenges of detecting and detaining infectious individuals. Al-Tawfiq et al. (2014) point out that in addition to significant morbidity and mortality, the SARS pandemic resulted in economic costs of an estimated 100 billion USD.

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Liver Disease Associated With Systemic Viral Infection

Alina M. Allen, Jayant A. Talwalkar, in Zakim and Boyer's Hepatology (Seventh Edition), 2018

Severe Acute Respiratory Syndrome Coronavirus

Severe acute respiratory syndrome (SARS) coronavirus was the etiologic agent of a severe respiratory disease outbreak in the Far East and Canada in 2003. The disease had a case-fatality rate of 9% to 12%. Laboratory abnormalities include elevated lactate dehydrogenase level (70%), lymphopenia (50% to 70%), thrombocytopenia (50%), and hypocalcemia (60%). Mild elevation of serum aminotransferase levels was found in almost 30% of patients on initial presentation and in 76% of patients during the subsequent clinical course and ribavirin treatment.83 Fulminant hepatic failure has not been described. In patients with moderate to marked liver test elevation, liver biopsy findings include marked mitotic activity, moderate lymphocytic infiltrates, and hepatocyte apoptosis.84 SARS coronavirus was detected in the liver tissue by reverse transcription PCR (RT-PCR), but not by electron microscopy; thus it is unclear if direct viral toxicity explains the hepatic abnormalities. No effective therapeutic strategies for SARS have been developed. Antiviral agents such as ribavirin and lopinavir/ritonavir were used because of their broad spectrum of activity against RNA viruses and HIV respectively, but their clinical efficacy has not been proven.

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Severe Acute Respiratory Syndrome (SARS)

J.S.M. Peiris, L.L.M. Poon, in Encyclopedia of Virology (Third Edition), 2008

SARS Virus

SARS coronavirus is a member of the genus Coronavirus within the family Coronaviridae and the order Nidovirales. Coronaviruses are classified on genetic and antigenic characteristics into three groups and SARS CoV is presently regarded as a group 2b coronavirus. It is an enveloped, positive-sense, single-stranded RNA virus with a genome size of approx 29.7 kbp. The virus particle is approximately 100–160 nm in diameter with a distinctive corona of petal-shaped spikes on the surface which is comprised of the spike glycoprotein (S). The S protein is in a trimeric form on the viral surface. It has an N-terminal variable subdomain (S1) which contains the motifs responsible for receptor binding. A more conserved subdomain (S2), which contains heptad repeats and a coiled-coil structure, is important in the membrane fusion process. The S1–S2 subdomains remain in a noncleaved form in the intact SARS CoV virion and cleavage is believed to occur within the endocytic vesicle during the viral entry process. The envelope also contains a transmembrane glycoprotein M and in much smaller amounts, an envelope (E) protein. The M protein is a triple-spanning membrane protein and has a key role in coronavirus assembly. The hemagglutinin-esterase (HE) glycoprotein, found in some group 2 coronaviruses, is absent in SARS CoV. The nucleocapsid protein (N) interacts with the viral genomic RNA to form the viral nucleocapsid. Viral replication complexes are believed to be localized within double-membraned vesicles or autophagosomes.

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Respiratory Viruses

Stuart Weston, Matthew B. Frieman, in Encyclopedia of Microbiology (Fourth Edition), 2019

Highly Pathogenic Coronaviruses—SARS-CoV

Epidemiology

The SARS-CoV outbreak began in the Guangdong province of China in November 2002. However, the outbreak was not fully appreciated until early 2003 when a single infected patient traveled from China to stay at Hotel Metropole in Hong Kong. This patient, staying on the 9th floor, managed to infect over 10 people, who subsequently spread the virus throughout Asia and Canada. One of these patients traveled to Hanoi, Vietnam and was responsible for a hospital-based outbreak of 38 cases. It was from here that the highly contagious nature of this novel pathogen was reported to the WHO by Carlo Urbani, who himself became infected and died from the virus in March 2003. Within weeks of the transmission out of Hong Kong, SARS-CoV had spread to 27 countries and infected thousands of people, with about a third being healthcare workers. The virus responsible for SARS was identified in April 2003. By July 2003, the outbreak was halted through public health measures, although a handful of additional cases were detected in December 2003 to January 2004. In a little over a year, SARS-CoV infected 8098 people and was responsible for 774 deaths, with a predicted economic impact of over 30 billion USD in the Far East alone. No cases of SARS-CoV have been reported since.

SARS-CoV emerged through zoonotic transmission from the natural reservoir host, horseshoe bats. The outbreak was however facilitated by an intermediate, amplification host, of palm civets which were kept in live animal markets in China. These animals appear to be incidental hosts since serological analyses failed to detect antibodies in animals in the wild or in breeding facilities. The virus initially transmitted from animals into the human population and was found to then adapt to facilitate efficient human–human spread. Many surveillance studies have since been performed, and multiple SARS-like viruses have been found in bats, suggesting the potential for re-emergence of a similar pathogen.

Human–human transmission occurs through aerosol droplets or contaminated surfaces and fomites. It has been shown that the virus can persist for up to 2 days on environmental surfaces. Many cases were nosocomial as the majority of virus shedding only occurs after the onset of illness (around 5 days postinfection). Approximately 33%–42% of SARS cases were in healthcare works, while 22%–39% of cases were through transmission between family members. The R0 for the virus is between 2 and 4, but measures to limit spread were highly effective and brought this down to around 0.4 to quell the outbreak.

Pathogenesis and Clinical Features

The incubation period for SARS-CoV infection is typically between 4 and 6 days. Initial presentation is general flu-like symptoms such as fever, myalgia, and lethargy, with respiratory symptoms such as cough and sore throat developing between 2 and 7 days later. The infection then progresses with more severe respiratory symptoms such as shortness of breath, pneumonia and acute respiratory distress syndrome (ARDS). Infection causes diffuse alveolar damage, lung edema, hyaline membrane and syncytium formation. Approximately half of SARS cases resulted in hypoxemia around 9 days after onset of symptoms. Many of these patients required admittance to the ICU and mechanical ventilation. A higher viral load was found to be associated with poorer clinical outcome.

Patients display widespread immune cell infiltration to the lungs. Immunopathology plays a major role in the more severe forms of SARS-CoV infection; indeed, ARDS is heavily associated with upregulation of proinflammatory cytokines and chemokines. The immunopathology of the disease is best evidenced by the fact that the most severe symptoms occur as virus titer begins to decline.

In addition to respiratory disease, SARS-CoV infection was associated with gastrointestinal symptoms such as diarrhea and vomiting. The precise cause for this is unclear and there is no evidence of fecal–oral transmission of the virus. Virus was also detected in the urine of up to 30% of patients.

The median age of SARS patients was under 45, but symptoms were typically more severe in the elderly. The case fatality for SARS-CoV infection was much higher in older patients with 43% of patients over 60 dying from infection, compared to 13% of patients under 60. About 10%–30% of patients had comorbidities associated with infection and the mortality rate in this population was 46%.

Diagnosis

Samples for diagnosis can be recovered from respiratory secretions, feces and urine. There is a higher viral load in the lower respiratory tract, so samples from that area are more reliable, but more invasive and difficult to obtain. RT-PCR, along with serological assays were used to confirm SARS-CoV infection. Virus can be isolated with Vero E6 cells, and indeed this was the approached used to determine that SARS was caused by a novel coronavirus.

Management and Control

The SARS-CoV outbreak was halted by public health intervention, not through any direct acting antiviral or vaccine. Measures such as quarantine in negative pressure rooms, handwashing, disinfection of surfaces, appropriate personal protective equipment and avoidance of contact with bodily fluid all helped to block spread of infection.

Much of the care given to SARS patients was supportive to mitigate issues of hypoxemia and ARDS. In numerous cases ribavirin along with pegylated interferon was used, although this intervention was not thoroughly tested, and retrospective studies have shown that the efficacy is debatable. Corticosteroids and thymosins were also used, but again, no thorough clinical trials were performed, and the role any of these interventions played in disease outcome remains unclear. However, convalescent patient plasma use did seem to be associated with a reduced frequency of poor outcomes when given before day 14 of infection.

To date, there are no approved direct acting antivirals against SARS-CoV. However, many compounds are currently under investigation for treating MERS-CoV infection with many of these being shown to also be effective against SARS-CoV (discussed further in the following section). Protease inhibitors did appear to have some degree of efficacy during the SARS-CoV outbreak. A number of patients received lopinavir, ritonavir or a combination of both. These drugs are licensed for use as HIV-1 protease inhibitors and are part of highly active antiretroviral therapy. Again, the use of these compounds did not undergo rigorous clinical investigation, but when used in combination with ribavirin, with or without corticosteroids, a reduction in viral load was detected and symptoms were found to subside, with disease progression being milder.

Similar to antiviral drug therapy, there is no approved vaccine against SARS-CoV infection. Multiple approaches were undertaken, however, none were successfully trialed in humans. With the emergence of MERS-CoV, there has been a renewed push for countermeasures against HCoV infection with some approaches looking to produce broadly acting vaccines. However, to date these studies are at early stages.

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Coronaviruses

E. Kindler, ... F. Weber, in Advances in Virus Research, 2016

5.1 Inhibition of IFN Induction

Both SARS-CoV and MERS-CoV induce very little—if any—IFN in most cell types (Chan et al., 2013; Cheung et al., 2005; Kindler et al., 2013; Lau et al., 2013; Menachery et al., 2014a; Spiegel et al., 2005; Zhou et al., 2014; Ziegler et al., 2005; Zielecki et al., 2013). In fact, it was recently shown in a mouse model of SARS that the delay in IFN induction is responsible for the activation of proinflammatory monocyte-macrophages and cytokines in the lung, resulting in vascular leakage and impaired adaptive immune responses (Channappanavar et al., 2016). Thus, the high levels of dsRNA that are produced during replication (Weber et al., 2006; Zielecki et al., 2013) do not result in an adequate IFN induction. One of the reasons (besides the active measures described later) is certainly the storage of coronaviral dsRNA inside double-membrane vesicles (Knoops et al., 2008; van Hemert et al., 2008; Versteeg et al., 2007). Moreover, the N protein sequesters IFN-inducing RNA PAMPs (Kopecky-Bromberg et al., 2007; Lu et al., 2011). However, the fact that infection with coronaviruses activates the cytosolic dsRNA-sensing host factors PKR and OAS (Birdwell et al., 2016; Krahling et al., 2009; Zhao et al., 2012), as well as the existence of numerous mechanisms dedicated to suppress dsRNA-dependent IFN induction (see later) strongly suggest that dsRNA stashing alone is not sufficient and that some dsRNA or other PAMPs are exposed to PRRs, thus necessitating the presence of additional, active mechanisms.

While most cell types remain IFN-silent after infection, a notable exception are pDCs, which express high levels of IFN-alpha/beta in response to infection with both SARS-CoV and MERS-CoV (Cervantes-Barragan et al., 2007; Channappanavar et al., 2016; Scheuplein et al., 2015). For the mouse coronavirus MHV-A59 it was shown that IFN induction in pDCs occurs through TLR7 (Cervantes-Barragan et al., 2007), suggesting the same to be true for SARS-CoV and MERS-CoV. Indeed, GU-rich ssRNAs from the SARS-CoV genome were shown to activate an excessive innate immune response via TLR7 (Li et al., 2013). Moreover, the membrane (M) protein and the envelope (E) protein of SARS-CoV are able to activate a TLR-like pathway and NF-kappaB signaling, respectively (DeDiego et al., 2014; Wang and Liu, 2016).

The mouse coronavirus MHV-A59 also naturally induces IFN in brain macrophages/microglia, with MDA5 being the responsible PRR (Birdwell et al., 2016; Roth-Cross et al., 2008). Also in oligodendrocytes IFN induction by MHV occurs through both MDA5 and RIG-I (Li et al., 2010). Interestingly, a general (i.e., not restricted to particular cell types) MDA5-dependent IFN induction can be obtained by ablating the ribose 2′-O-methylation activity of the nsp16. As it was shown for MHV-A59, SARS-CoV, and the mildly human pathogenic coronavirus HCoV-229E, nsp16-mediated 2′-O-methylation of viral mRNA cap structures prevents recognition by MDA5 (Menachery et al., 2014b; Zust et al., 2011).

Besides these "hiding" or "disguising" strategies, active mechanisms targeting specific host factors are in place (Table 1). SARS-CoV was shown to inhibit IRF3 by preventing its hyperphosphorylation, dimerization, and interaction with the cofactor CBP (Spiegel et al., 2005). Curiously, IRF3 initially enters the nucleus of infected cells, but later returns to the cytoplasm. SARS-CoV also inhibits the nuclear import of the related transcription factor IRF7 (Kuri et al., 2009). In this context, the papain-like protease (PLpro) domain of nsp3 (the largest coronaviral protein) of SARS-CoV and the mildly pathogenic HCoV-NL63 both interact with IRF3 and block its activation (Devaraj et al., 2007; Frieman et al., 2009). Moreover, PLpro was shown to drive the deubiquitination (or inhibit ubiquitination) of RIG-I, TBK1, and IRF3 (Clementz et al., 2010; Devaraj et al., 2007; Frieman et al., 2009; Sun et al., 2012). IRF3 activation is also prevented by the M protein of SARS-CoV through inhibiting complex formation between TRAF3 and TBK1 (Siu et al., 2009). Since M was also found to activate a TLR-like signaling pathway (Wang and Liu, 2016), a final picture of M protein function in the context of IFN induction/inhibition remains to be provided. IFN induction is also disturbed by the SARS-CoV nsp1, nsp7, nsp15, ORF3b, ORF6, and ORF9b proteins, respectively (Frieman et al., 2009; Kopecky-Bromberg et al., 2007; Shi et al., 2014; Zust et al., 2007). The anti-IFN function of nsp1 is based on its ability to mediate host mRNA degradation, while sparing viral mRNAs at the same time, and to block host mRNA translation (Huang et al., 2011a; Narayanan et al., 2008; Tanaka et al., 2012). Nsp1 also has a function in evasion from IFN signaling (see later), providing a possible reason why nsp1 mutants are particularly IFN sensitive (Wathelet et al., 2007; Zust et al., 2007). While the mechanisms of other SARS-CoV IFN induction antagonists like nsp7, nsp15, ORF3b, and ORF6 proteins remain to be characterized, for the ORF9b protein it was shown that it drives degradation of MAVS, TRAF3, and TRAF6 by interacting with the host factors PCBP2 and the E3 ubiquitin ligase AIP4 (Shi et al., 2014).

Table 1. Mechanisms and Factors of Human Coronaviruses to Counteract IFN Induction

VirusViral Protein or FunctionMechanismReferencesSARS-CoV (MHV-A59)Storage of dsRNA inside double-membrane vesiclesPrevents exposure of dsRNA to PRRsKnoops et al. (2008), van Hemert et al. (2008), and Versteeg et al. (2007)SARS-CoVNSequesters IFN-inducing RNA PAMPsKopecky-Bromberg et al. (2007) and Lu et al. (2011)SARS-CoV, HCoV-229E (MHV-A59)nsp16Ribose 2′-O-methylation of viral mRNA cap structures prevents recognition by MDA5Menachery et al. (2014b) and Zust et al. (2011)SARS-CoV, NL63PLproInteracts with IRF3, inhibits IRF3 activation, deubiquitinates RIG-I, TBK1, IRF3Clementz et al. (2010), Devaraj et al. (2007), Frieman et al. (2009), and Sun et al. (2012)SARS-CoVMInhibits TRAF3/TBK1 complex formationSiu et al. (2009)SARS-CoVnsp7, nsp15, ORF3b, ORF6Mechanism unclearFrieman et al. (2009) and Kopecky-Bromberg et al. (2007)SARS-CoVnsp1Mediates host mRNA degradationHuang et al. (2011a) and Narayanan et al. (2008)SARS-CoVnsp1Blocks host mRNA translationNarayanan et al. (2008) and Tanaka et al. (2012)SARS-CoVORF9b proteinProteasomal degradation of MAVS, TRAF3, and TRAF6Shi et al. (2014)MERS-CoVORF4a proteinInteracts with dsRNA and the RLR cofactor PACTNiemeyer et al. (2013)MERS-CoVORF4a proteinInteracts with the RLR cofactor PACTSiu et al. (2014)MERS-CoVORF4a, 4b, and ORF5 proteins, MPrevent IRF3 translocationYang et al. (2013)MERS-CoVORF4b proteinBinds TBK1 and IKKepsilonMatthews et al. (2014) and Yang et al. (2015)MERS-CoVPLproDeubiquitinationBailey-Elkin et al. (2014) and Mielech et al. (2014)MERS-CoVnsp1Degrades host mRNAsLokugamage et al. (2015)MERS-CoVUnknownRepressive histone modificationsMenachery et al. (2014a)

Also for MERS-CoV, the reason for the low levels of IFN produced by infected cells (Chan et al., 2013; Kindler et al., 2013; Lau et al., 2013; Menachery et al., 2014a; Zhou et al., 2014; Zielecki et al., 2013) was further investigated. The ORF4a protein inhibits IFN induction by interaction with dsRNA and the RLR cofactor PACT (Niemeyer et al., 2013; Siu et al., 2014). Like the ORF4a, the ORF4b, 5, and M proteins of MERS-CoV were shown to prevent IRF3 translocation (Yang et al., 2013). The ORF4b protein, in particular, inhibits IFN induction by binding to TBK1 and IKKepsilon (Matthews et al., 2014; Yang et al., 2015). In agreement with the data on SARS-CoV, the PLpro of MERS-CoV has deubiquitinating activity and inhibits IFN induction (Bailey-Elkin et al., 2014; Mielech et al., 2014), and the nsp1 mediates host mRNA degradation (Lokugamage et al., 2015). In contrast to SARS-CoV, however, infection with MERS-CoV additionally activates repressive histone modifications that downregulate ISG expression (Menachery et al., 2014a).

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SARS coronavirus infections of the lower respiratory tract and their prevention

N. Petrovsky, in The Microbiology of Respiratory System Infections, 2016

Abstract

The Severe Acute Respiratory Syndrome (SARS) coronavirus was first identified in 2003 when it caused an epidemic of fatal human pneumonia cases that rapidly spread to multiple countries from an epicenter in Hong Kong. The outbreak was eventually controlled by quarantine measures but not before it had caused many fatalities. The original zoonotic source of the SARS virus that caused the outbreak is still unknown but is suspected to be bats. Attempts were made to develop a prophylactic vaccine but the SARS epidemic was over before any vaccines could be tested for human efficacy. As will be discussed in this chapter, coronavirus vaccines present many challenges including low and rapidly waning immunity and the fact that coronavirus vaccines, particularly when formulated with Th2-biased alum adjuvants, can exacerbate coronavirus infection-associated eosinophilic lung immunopathology. Fortunately, this problem can be avoided by formulation of coronavirus vaccines with Th1-type adjuvants that enhance T cell IFN-γ responses, such as, delta inulin or TLR agonists. Hence, appropriate adjuvant selection is vitally important for the development of safe and effective coronavirus vaccines. This chapter will describe the current state of development of SARS vaccines, the issue of coronavirus-associated eosinophilic lung immunopathology and how adjuvants can be used to reduce the risk of this complication.

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