Jawetz Chapter 41: Coronaviruses PDF

41 C H A P T E R Coronaviruses...

41 C H A P T E R Coronaviruses Coronaviruses are large, enveloped RNA viruses. The human Classification coronaviruses cause common colds, may cause lower respira- The Coronaviridae is one of two families, along with tory tract infections, and have been implicated in gastroen- Arteriviridae, within the order Nidovirales. Characteristics used teritis in infants. Novel coronaviruses have been identified as to classify Coronaviridae include particle morphology, unique the cause of severe acute respiratory syndrome (SARS) and RNA replication strategy, genome organization, and nucleo- Middle East respiratory syndrome (MERS). Animal corona- tide sequence homology. There are two subfamilies (Corona- viruses cause diseases of economic importance in domestic virinae and Torovirinae) and six genera (Alphacoronavirus, animals. Coronaviruses of lower animals establish persistent Betacoronavirus, Gammacoronavirus, Deltacoronavirus, infections in their natural hosts. The human viruses are dif- Bafinivirus, and Torovirus) in the Coronaviridae family. The ficult to culture and therefore are more poorly characterized. first two and the last genera contain viruses able to infect humans. The toroviruses are widespread in ungulates and PROPERTIES OF CORONAVIRUSES appear to be associated with diarrheal disease. There are six coronaviruses that can infect humans, the Important properties of the coronaviruses are listed in alpha coronaviruses 229E and NL63 and the beta coronavi- Table 41-1. ruses OC43, HKU1, SARS-CoV, and MERS-CoV. There are many coronaviruses that infect animals, with most infecting Structure and Composition one or a few species. Coronaviruses are enveloped, 120- to 160-nm particles that contain an unsegmented genome of single-stranded positive- sense RNA (27–32 kb), the largest genome among RNA Coronavirus Replication viruses. The genomes are polyadenylated at the 3′ end. Iso- Because human coronaviruses do not grow well in cell cul- lated genomic RNA is infectious. The helical nucleocapsid is ture, details of viral replication have come from studies with 9–11 nm in diameter. There are 20-nm-long club- or petal- mouse hepatitis virus, which is closely related to human shaped projections that are widely spaced on the outer sur- strain OC43 (Figure 41-3). The replication cycle takes place face of the envelope, suggestive of a solar corona (Figure 41-1). in the cytoplasm of cells. The viral structural proteins include a 50–60 kDa phosphor- The virus attaches to receptors on target cells by the gly- ylated nucleocapsid (N) protein, a 20–35 kDa membrane (M) coprotein spikes on the viral envelope (either by S or HE). The glycoprotein that serves as a matrix protein embedded in the receptor for human coronavirus 229E is aminopeptidase N, envelope lipid bilayer and interacting with the nucleocapsid, whereas a functional receptor for SARS-CoV is angiotensin- and the spike (S; 180–220 kDa) glycoprotein that makes up converting enzyme 2. The receptor for MERS-CoV is dipep- the petal-shaped peplomers. Some viruses, including human tyl peptidase 4, also known as CD26. Multiple isoforms of coronavirus OC43 (HCoV-OC43), contain a third glycopro- the carcinoembryonic antigen-related glycoprotein family tein (HE; 65 kDa) that causes hemagglutination and has acet- serve as receptors for mouse coronavirus. The particle is then ylesterase activity. internalized, probably by absorptive endocytosis. The S gly- The genome organizations of a representative coronavi- coprotein may cause fusion of the viral envelope with the cell rus is shown in Figure 41-2. The gene order for the proteins membrane. encoded by all coronaviruses is Pol-S-E-M-N-3′. Several open The first event after uncoating is translation of the viral reading frames encoding nonstructural proteins and the HE genomic RNA to produce a virus-specific RNA-dependent protein differ in number and gene order among coronavi- RNA polymerase. The viral polymerase transcribes a full- ruses. The SARS virus contains a comparatively large num- length complementary (minus-strand) RNA that serves ber of interspersed genes for nonstructural proteins at the 3′ as the template for a nested set of five to seven subgenomic end of the genome. mRNAs. Only the 5′ terminal gene sequence of each mRNA 617 Riedel_CH41_p617-p622.indd 617 04/04/19 5:10 PM  618   SECTION IV  Virology TABLE 41-1 Important Properties of Coronaviruses Virions are apparently not formed by budding at the plasma membrane. Large numbers of particles may be seen Virion: Spherical, 120–160 nm in diameter, helical nucleocapsid on the exterior of infected cells and are presumably adsorbed Genome: Single-stranded RNA, linear, nonsegmented, positive- to it after virion release. Certain coronaviruses induce cell sense, 27–32 kb, capped and polyadenylated, infectious fusion; this is mediated by the S glycoprotein and requires pH Proteins: Two glycoproteins and one phosphoprotein. Some viruses 6.5 or higher. Some coronaviruses establish persistent infec- contain a third glycoprotein (hemagglutinin esterase) tions of cells rather than being cytocidal. Envelope: Contains large, widely spaced, club- or petal-shaped Coronaviruses exhibit a high frequency of mutation dur- spikes ing each round of replication, including the generation of a Replication: Cytoplasm; particles mature by budding into high incidence of deletion mutations. Coronaviruses undergo endoplasmic reticulum and Golgi a high frequency of recombination during replication; this is unusual for an RNA virus with a nonsegmented genome and Outstanding characteristics: may contribute to the evolution of new virus strains. Cause colds, SARS, and MERS Display high frequency of recombination CORONAVIRUS INFECTIONS Difficult to grow in cell culture IN HUMANS Pathogenesis is translated. Full-length genomic RNA copies are also tran- scribed off the complementary RNA. Coronaviruses tend to be highly species specific. Most of the Newly synthesized genomic RNA molecules interact in known animal coronaviruses display a tropism for epithe- the cytoplasm with the nucleocapsid protein to form helical lial cells of the respiratory or gastrointestinal tract. Corona- nucleocapsids. There is a preferred binding site for N pro- virus infections in vivo may be disseminated, such as with tein within the leader RNA. The nucleocapsids bud through mouse hepatitis virus, or localized. Coronavirus infections in membranes of the rough endoplasmic reticulum and the humans usually, but not always, remain limited to the upper Golgi apparatus in areas that contain the viral glycoproteins. respiratory tract. Mature virions may then be transported in vesicles to the cell In contrast, the outbreak of SARS-CoV in 2003 was char- periphery for exit or may be released upon cell lysis. acterized by serious respiratory illness, including pneumo- nia and progressive respiratory failure. Virus could also be detected in other organs, including kidney, liver, and small intestine, and in stool. The SARS virus probably originated in a nonhuman host, most likely bats, was amplified in palm civets, and was transmitted to humans in live animal mar- kets. Chinese horseshoe bats are natural reservoirs of SARS- like coronaviruses. In rural regions of southern China, where the outbreak began, people, pigs, and domestic fowl live close together, and there is widespread use of wild species for food and traditional medicine—conditions that promote the emergence of new viral strains. The MERS-CoV outbreak beginning in 2012 was also characterized by pneumonia and respiratory failure, though most patients who died had medical comorbidities. MERS- CoV likely originated in bats and became widespread in cam- els as shown by seropositivity in animals in the region. It is likely that contact with either bats or camels leads to initial human infections, which can then be transmitted from per- son to person. Coronaviruses are suspected of causing some gastroen- teritis in humans. There are several animal models for enteric coronaviruses, including porcine transmissible gastroenteritis virus (TGEV). Disease occurs in young animals and is marked by epithelial cell destruction and loss of absorptive capacity. It is of interest that a novel porcine respiratory coronavirus (PRCV) FIGURE 41-1 Human coronavirus OC43. Note the characteristic appeared in Europe in the 1980s and caused widespread epizo- large, widely spaced spikes that form a “corona” around the virion otics in pigs. Sequence analysis showed that PRCV was derived (297,000×). (Courtesy of FA Murphy and EL Palmer.) from TGEV by a large deletion in the S1 glycoprotein. Riedel_CH41_p617-p622.indd 618 04/04/19 5:10 PM  CHAPTER 41 Coronaviruses    619 SARS-CoV 8a L ORF1a S 3b M 7a N 5′ ORF1b 3a E 6 7b 8b 9b FIGURE 41-2 Genomic organization of coronaviruses. The SARS coronavirus (SARS-CoV) genome is about 29.7 kb. Boxes shaded in yellow represent open reading frames (ORFs) encoding structural proteins; boxes shaded in lavender encode nonstructural proteins. The separate ORFs within each gene are translated from a single mRNA species. S, spike; E, envelope; M, transmembrane; N, nucleocapsid. The ORF1 cleavage products are designated nsp1–16 and include a phosphatase, cysteine proteinases, an RNA-dependent RNA polymerase, a helicase, and an endoribonuclease. (Adapted with permission from Lai MMC, Perlman S, Anderson LJ: Coronaviridae. In Knipe DM, Howley PM [editors- in-chief]. Fields Virology, 5th ed. Lippincott Williams and Wilkins, 2007.) Endocytosis Fusion Exocytosis 5′ 3′ Genomic RNA ORF 1 (+) 3′ 5′ (–) Smooth-walled vesicles Transcription replication (+) Pol HE S Golgi E mRNAs M N ns ERGIC nucleus ER Nucleocapsid FIGURE 41-3 Coronavirus replication cycle. Virions bind to specific receptor glycoproteins or glycans via the spike protein. Penetration and uncoating occur by S protein-mediated fusion of the viral envelope with the plasma membrane or endosomal membranes. Gene 1 of viral genomic RNA is translated into a polyprotein, which is processed to yield the transcriptase–replicase complex. Genomic RNA is used as a template to synthesize negative-stranded RNAs, which are used to synthesize full-length genomic RNA and subgenomic mRNAs. Each mRNA is translated to yield only the protein encoded by the 5′ end of the mRNA, including nonstructural proteins. The N protein and newly synthesized genomic RNA assemble to form helical nucleocapsids. Membrane glycoprotein M is inserted in the endoplasmic reticulum (ER) and anchored in the Golgi apparatus. Nucleocapsid (N plus genomic RNA) binds to M protein at the budding compartment (ERGIC). E and M proteins interact to trigger the budding of virions, enclosing the nucleocapsid. S and HE glycoproteins are glycosylated and trimerized, associate with M protein, and are incorporated into the maturing virus particles. Virions are released by exocytosis-like fusion of vesicles with the plasma membrane. Virions may remain adsorbed to the plasma membranes of infected cells. The entire cycle of coronavirus replication occurs in the cytoplasm. (Reproduced with permission from Lai MMC, Perlman S, Anderson LJ: Coronaviridae. In Knipe DM, Howley PM [editors-in-chief]. Fields Virology, 5th ed. Lippincott Williams and Wilkins, 2007.) Riedel_CH41_p617-p622.indd 619 04/04/19 5:10 PM  620   SECTION IV  Virology Clinical Findings in stool samples. Viremia with SARS and MERS coronavi- ruses is detectable in the plasma by PCR. The human coronaviruses produce “common colds,” usu- ally afebrile, in adults. The symptoms are similar to those B. Isolation and Identification of Virus produced by rhinoviruses, typified by nasal discharge and malaise. The incubation period is from 2 to 5 days, and Isolation of human coronaviruses in cell culture has been symptoms usually last about 1 week. The lower respiratory difficult. However, the SARS and MERS viruses have been tract is seldom involved, although pneumonia may occur. recovered from oropharyngeal specimens using Vero mon- Asthmatic children may suffer wheezing attacks, and respi- key kidney cells. ratory symptoms may be exacerbated in adults with chronic pulmonary disease. SARS-CoV causes severe respiratory C. Serology disease. The incubation period averages about 6 days. Com- Because of the difficulty of virus isolation, serodiagnosis mon early symptoms include fever, malaise, chills, head- using acute and convalescent sera is one means of confirming ache, dizziness, cough, and sore throat, followed a few days coronavirus infections for epidemiologic purposes. ELISA, later by shortness of breath. Many patients have abnormal indirect immunofluorescent antibody assays, and hemagglu- chest radiographs. Some cases progress rapidly to acute tination tests may be used. Serologic diagnosis of infections respiratory distress, requiring ventilatory support. Death with strain 229E is possible using a passive hemagglutination from progressive respiratory failure occurs in almost 10% of test in which red cells coated with coronavirus antigen are cases, with the death rate highest among the elderly. SARS agglutinated by antibody-containing sera. involves a cytokine storm, with elevated levels of multiple chemokines and cytokines in the peripheral circulation for about 2 weeks. Epidemiology MERS-CoV causes mild to severe respiratory illness in Coronaviruses are distributed worldwide. They are a major children and adults. Patients with comorbidities are more cause of respiratory illness in adults during some winter severely affected, as are the elderly. The incubation period months when the incidence of colds is high, but the isolation is 2–13 days, with extended illness in some cases leading to of rhinoviruses or other respiratory viruses is low. They tend pneumonia and death. Laboratory findings include leukope- to be associated with well-defined outbreaks. nia, lymphopenia, thrombocytopenia, and elevated lactate It is estimated that coronaviruses cause 15–30% of all dehydrogenase levels. The mortality rate is stated as up to colds. The incidence of coronavirus infections varies markedly 30%, but this is likely to be an overestimate as mild cases are from year to year, ranging in one 3-year study from 1% to 35%. not typically reported. Antibodies to respiratory coronaviruses appear in Clinical features of coronavirus-associated enteritis have childhood, increase in prevalence with age, and are found not been clearly described. They appear to be similar to those in more than 90% of adults. It appears that reinfection with of rotavirus infections. symptoms can occur after a period of 1 year. However, anti- bodies to SARS and MERS coronaviruses are uncommon, showing that they have not circulated widely in humans. Immunity Coronaviruses are commonly associated with acute As with other respiratory viruses, immunity develops but is respiratory disease in the elderly, along with rhinoviruses, not absolute. Immunity against the surface projection anti- influenza virus, and respiratory syncytial virus. The fre- gen is probably most important for protection. Resistance to quency of coronavirus infection is estimated to be about half reinfection may last several years, but reinfections with simi- that of rhinoviruses and equivalent to those of the latter two lar strains are common. viruses. Most patients (>95%) with SARS or MERS developed Coronaviruses are transmitted by contact with respira- an antibody response to viral antigens detectable by a tory droplets, contaminated surfaces, and fomites (contami- fluorescent antibody test or enzyme-linked immunoassay nated inanimate objects). There is a risk of transmission in (ELISA). the health care setting, with documented hospital outbreaks. The outbreak of SARS erupted in southern China in late 2002 and, by the time it waned in mid-2003, had resulted in Laboratory Diagnosis over 8000 cases in 29 countries, with over 800 deaths (case A. Antigen and Nucleic Acid Detection fatality rate of 9.6%). In almost all cases, there was a history of Coronavirus antigens in cells in respiratory secretions may close contact with a SARS patient or of recent travel to an area be detected using the ELISA test if a high-quality antiserum where SARS was reported. International air travel allowed is available. Enteric coronaviruses can be detected by exami- SARS to spread around the world with unprecedented speed. nation of stool samples by electron microscopy. Polymerase The experience with SARS illustrated that in a globalized chain reaction (PCR) assays are the preferred methods to world, an infectious disease outbreak anywhere places every detect coronavirus nucleic acid in respiratory secretions and country at risk. Riedel_CH41_p617-p622.indd 620 04/04/19 5:10 PM  CHAPTER 41 Coronaviruses    621 Interestingly, a few persons with SARS were identified as (A) Influenza virus “super spreaders”; each appeared to have infected more than (B) Adenovirus 10 contacts. Super spreaders have been described for other (C) Respiratory syncytial virus diseases such as rubella, Ebola, and tuberculosis and presum- (D) Coronavirus (E) Rotavirus ably reflect a certain constellation of host, viral, and environ- mental factors. 2. Based on sequence analysis and serologic assays, the most likely origin of the SARS coronavirus is which of the following? The MERS coronavirus was identified in 2012 as the cause of a patient who died of respiratory failure in Saudi Arabia. (A) Recombination between a human and an animal coronavi- rus that created a new virus Subsequently, it was determined to be the cause of multiple (B) Jump of an animal coronavirus into humans outbreaks of respiratory disease from several countries in the (C) Mutation of a human coronavirus that resulted in increased Arabian Peninsula. The virus appears to be endemic in bats virulence and camels in the region. Infected travelers have spread the (D) Acquisition of human cellular genes by a human coronavi- virus in other countries, and it remains a risk for transmis- rus via recombination that allowed viral evasion of the host sion from pilgrims returning from the annual Hajj in Mecca. immune response Very little is known about the epidemiology of enteric 3. The coronavirus SARS epidemic of 2002–2003 resulted in many coronavirus infections. cases and deaths. What is the primary route of transmission of human coronaviruses? (A) Fecal–oral Treatment, Prevention, and Control (B) Respiratory There is no proven treatment for coronavirus infections (C) Blood and no vaccine. Protease inhibitors used in the treatment of (D) Perinatal mother-to-infant human immunodeficiency virus infections (eg, lopinavir) (E) Sexual activity have in vitro activity against SARS coronavirus. SARS and 4. Coronavirus infections in humans usually cause a common MERS vaccines are under development. cold syndrome. However, a recent outbreak of SARS was char- Control measures that were effective in stopping the acterized by pneumonia and progressive respiratory failure. spread of SARS included isolation of patients, quarantine of The prevention or treatment of these diseases can be accom- those who had been exposed, and travel restrictions, as well plished by as the use of gloves, gowns, goggles, and respirators by health (A) A subunit vaccine care workers. There remains a high suspicion for MERS-CoV (B) A cold-adapted live-attenuated vaccine (C) The antiviral drug amantadine in patients returning from the Arabian Peninsula, which (D) Infection control measures, including isolation and wearing requires appropriate testing and infection control precau- of protective gear tions to prevent further spread. (E) The antiviral drug acyclovir 5. An epidemic of acute respiratory virus infections occurred among the elderly residents of a nursing home. Influenza viruses CHAPTER SUMMARY and coronaviruses, which can cause serious respiratory disease Coronaviruses are enveloped and contain a genome in the elderly, are suspected. Which of the following characteris- tics is shared by these viruses? of single-stranded positive-sense RNA that is the largest genome among RNA viruses. (A) Segmented genome (B) Infectious RNA genome Human coronaviruses typically cause common colds. (C) High frequency of recombination during replication A novel coronavirus that originated in a nonhuman host (D) Single serotype infects humans caused a worldwide outbreak of SARS in 2003. (E) Negative-sense genome MERS-CoV was first detected in 2012, and can cause severe 6. The following are common characteristics of coronaviruses, respiratory disease in some patients. except for one. Which is not correct? Human coronaviruses are distributed worldwide, with the (A) Possess cross-reactive antigens with influenza viruses exception of SARS and MERS viruses. (B) Contain the largest genomes among RNA viruses There is no proven treatment and no vaccine for (C) Can cause gastroenteritis coronaviruses. (D) Are distributed worldwide 7. SARS coronavirus shares some characteristics, but not all, with human coronavirus HCoV-OC43. Which of the following state- REVIEW QUESTIONS ments is true for SARS coronavirus? 1. A 63-year-old woman develops fever, headache, malaise, myal- (A) Causes annual outbreaks during the winter gia, and cough. It is early in the winter respiratory virus season, (B) Is distributed worldwide and the patient’s physician does not know what viruses are pres- (C) Populations at high risk of disease included health care ent in the community. Which of the following viruses is not a workers cause of acute respiratory disease? (D) Natural hosts are palm civets Riedel_CH41_p617-p622.indd 621 04/04/19 5:10 PM  622   SECTION IV  Virology 8. A traveler returning from Mecca presents with pneumonia, Baric RS, Hu Z (editors): SARS-CoV pathogenesis and replication. fever, and cough. What is the best test to diagnose MERS Virus Res 2008;133(Issue 1). [Entire issue.] coronavirus? Booth TF, Kournikakis B, Bastien N, et al: Detection of airborne (A) Coronavirus antigen assay severe acute respiratory syndrome (SARS) coronavirus and (B) Human coronavirus PCR environmental contamination in SARS outbreak units. J Infect (C) MERS-CoV PCR Dis 2005;191:1472. (D) Respiratory viral culture Cheng VCC, Lau SK, Woo PC, Yuen KY: Severe acute respiratory 9. Risk factors for severe MERS coronavirus infection include syndrome coronavirus as an agent of emerging and reemerging which of the following? infection. Clin Microbiol Rev 2007;20:660. Hui DSC, Chan PKS: Severe acute respiratory syndrome and coro- (A) Recent camel exposure navirus. Infect Dis Clin North Am 2010;24:619. (B) Prior coronavirus infection Lee N, Hui D, Wu A, et al: A major outbreak of severe acute respi- (C) Seasonal allergies ratory syndrome in Hong Kong. N Engl J Med 2003;348:1986. (D) Chronic obstructive pulmonary disease Mahony JB: Detection of respiratory viruses by molecular meth- ods. Clin Microbiol Rev 2008;21:716. Answers Perlman S, Dandekar AA: Immunopathogenesis of coronavirus 1. E 4. D 7. C infections: Implications for SARS. Nat Rev Immunol 2005; 2. B 5. C 8. C 5:917. 3. B 6. A 9. D Rota PA, Oberste MS, Monroe SS, et al: Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 2003;300:1394. van Boheemen S, de Graaf M, Lauber C, et al: Genomic char- REFERENCES acterization of a newly discovered coronavirus associated Al-Tawfiq JA, Hinedi K, Ghandour J, et al: Middle East respiratory with acute respiratory distress syndrome in humans. mBio syndrome coronavirus: A case-control study of hospitalized 2012;3:e00473. patients. Clin Infect Dis 2014;59:160. Wong SSY, Yuen KY: The management of coronavirus infections Anderson LJ, Tong S: Update on SARS research and other possibly with particular reference to SARS. J Antimicrob Chemother zoonotic coronaviruses. Int J Antimicrob Agents 2010;36S:S21. 2008;62:437. 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