Coronaviruses David A. J. Tyrrell Steven H. Myint GENERAL CONCEPTS Clinical Presentation Coronaviruses cause acute, mild upper respiratory infection (common cold). Structure Spherical or pleomorphic enveloped particles containing single-stranded (positivesense) RNA associated with a nucleoprotein within a capsid comprised of matrix protein. The envelope bears club-shaped glycoprotein projections. Classification Coronaviruses (and toroviruses) are classified together on the basis of the crown or halo-like appearance of the envelope glycoproteins, and on characteristic features of chemistry and replication. Most human coronaviruses fall into one of two serotypes: OC43-like and 229E-like. Multiplication The virus enters the host cell, and the uncoated genome is transcribed and translated. The mrnas form a unique "nested set" sharing a common 3' end. New virions form by budding from host cell membranes. Pathogenesis Transmission is usually via airborne droplets to the nasal mucosa. Virus replicates locally in cells of the ciliated epithelium, causing cell damage and inflammation. Host Defenses The appearance of antibody in serum and nasal secretions is followed by resolution of the infection. Immunity wanes within a year or two. Epidemiology
Incidence peaks in the winter, taking the form of local epidemics lasting a few weeks or months. The same serotype may return to an area after several years. Diagnosis Colds caused by coronaviruses cannot be distinguished clinically from other colds in any one individual. Laboratory diagnosis may be made on the basis of antibody titers in paired sera. The virus is difficult to isolate. Nucleic acid hybridization tests (including PCR) are now being introduced. Control Treatment of common colds is symptomatic; no vaccines or specific drugs are available. Hygiene measures reduce the rate of transmission. INTRODUCTION Coronaviruses are found in avian and mammalian species. They resemble each other in morphology and chemical structure: for example, the coronaviruses of humans and cattle are antigenically related. There is no evidence, however, that human coronaviruses can be transmitted by animals. In animals, various coronaviruses invade many different tissues and cause a variety of diseases, but in humans they are only proved to cause mild upper respiratory infections, i.e. common colds. On rare occasions, gastrointestinal coronavirus infection has been associated with outbreaks of diarrhoea in children, but these enteric viruses are not well characterized and are not discussed in this chapter. Clinical Manifestations Coronaviruses invade the respiratory tract via the nose. After an incubation period of about 3 days, they cause the symptoms of a common cold, including nasal obstruction, sneezing, runny nose, and occasionally cough (Figs. 60-1 and 60-2). The disease resolves in a few days, during which virus is shed in nasal secretions. There is some evidence that the respiratory coronaviruses can cause disease of the lower airways but it is unlikely that this is due to direct invasion. Other manifestations of disease such as multiple sclerosis have been attributed to these viruses but the evidence is not clear-cut.
FIGURE 60-1 Clinical manifestations and pathogenesis of coronavirus infections. FIGURE 60-2 Immunopathogenesis of coronavirus infections.
Structure Coronavirus virions are spherical to pleomorphic enveloped particles (Fig. 60-3). The envelope is studded with projecting glycoproteins, and surrounds a core consisting of matrix protein enclosed within which is a single strand of positive-sense RNA (Mr 6 x 106) associated with nucleoprotein. The envelope glycoproteins are responsible for attachment to the host cell and also carry the main antigenic epitopes, particularly the epitopes recognized by neutralizing antibodies. OC43 also possesses a haemagglutin. FIGURE 60-3 Electron micrograph showing human coronavirus 229E. Bar, 100 mn (Courtesy S.Sikotra, Leicester Royal Infirmary, Leicester, England.) Classification and Antigenic Types The coronaviruses were originally grouped into the family Coronaviridae on the basis of the crown or halo-like appearance given by the glycoprotein-studded envelope on electron microscopy. This classification has since been confirmed by unique features of the chemistry and replication of these viruses. Most human coronaviruses fall into one of two groups: 229E-like and OC43-like. These differ in both antigenic determinants and culturing requirements: 229E-like coronaviruses can usually be isolated in human embryonic fibroblast cultures; OC43-like viruses can be isolated, or adapted to growth, in suckling mouse brain. There is little antigenic cross-reaction between these two types. They cause independent epidemics of indistinguishable disease. Multiplication
It is thought that human coronaviruses enter cells, predominantly, by specific receptors. Aminopeptidase-N and a sialic acid-containing receptor have been identified to act in such a role for 229E and OC43 respectively. After the virus enters the host cell and uncoats, the genome is transcribed and then translated. A unique feature of replication is that all the mrnas form a "nested set" with common 3' ends; only the unique portions of the 5' ends are translated. There are 7 mrnas produced. The shortest mrna codes for the nucleoprotein, and the others each direct the synthesis of a further segment of the genome. The proteins are assembled at the cell membrane and genomic RNA is incorporated as the mature particle forms by budding from internal cell membranes. Pathogenesis Studies in both organ cultures and human volunteers show that coronaviruses are extremely fastidious and grow only in differentiated respiratory epithelial cells. Infected cells become vacuolated, show damaged cilia, and may form syncytia. Cell damage triggers the production of inflammatory mediators, which increase nasal secretion and cause local inflammation and swelling. These responses in turn stimulate sneezing, obstruct the airway, and raise the temperature of the mucosa. Host Defenses Although mucociliary activity is designed to clear the airways of particulate material, coronaviruses can successfully infect the superficial cells of the ciliated epithelium. Only about one-third to one-half of infected individuals develop symptoms, however. Interferon can protect against infection, but its importance is not known. Because coronavirus infections are common, many individuals have specific antibodies in their nasal secretions, and these antibodies can protect against infection. Most of these antibodies are directed against the surface projections and neutralize the infectivity of the virus. Cell-mediated immunity and allergy have been little studied, but may play a role. Epidemiology The epidemiology of coronavirus colds has been little studied. Waves of infection pass through communities during the winter months, and often cause small outbreaks in families, schools, etc. (Fig. 60-2). Immunity does not persist, and subjects may be reinfected, sometimes within a year. The pattern thus differs from that of rhinovirus infections, which peak in the fall and spring and generally elicit long-lasting immunity. About one in five colds is due to coronaviruses. The rate of transmission of coronavirus infections has not been studied in detail. The virus is usually transmitted via inhalation of contaminated droplets, but it may also be transmitted by the hands to the mucosa of the nose or eyes. Diagnosis There is no reliable clinical method to distinguish coronavirus colds from colds caused by rhinoviruses or less common agents. For research purposes, virus can be cultured from nasal swabs or washings by inoculating organ cultures of human fetal or nasal tracheal epithelium. The virus in these cultures is detected by electron microscopy or
other methods. The most useful method for laboratory diagnosis is to collect paired sera (from the acute and convalescent phases of the disease) and to test by ELISA for a rise in antibodies against OC43 and 229E. Complement fixation tests are insensitive; other tests are inconvenient and can be used only for one serotype. Direct hybridization and polymerase chain reaction tests for viral nucleic acid have been developed and, particularly with the latter, are the most sensitive assays currently available for detecting virus. Control Although antiviral therapy has been attempted, the treatment of coronavirus colds remains symptomatic. The likelihood of transmission can be reduced by practising hygienic measures. Vaccines are not currently available. FIGURE 60-4 Seasonal incidence of coronavirus infections REFERENCES Gwaltney JM, Jr: Virology and immunology of the common cold. Rhinology, 23:265, 1985. Myint S, Johnstone S, Sanderson G, Simpson H: An evaluation of 'nested' RT-PCR methods for the detection of human coronaviruses 229E and OC43 in clinical specimens. Mol Cell Probes, 8: 357-364, 1994. Sanchez CM, Jimenez G, Laviada MD, et al: Antigenic homology among coronaviruses related to transmissible gastroenteritis virus. Virology, 174:410, 1990. Schmidt OW, Allan ID, Cooney MK, et al: Rises in titers of antibody to human coronaviruses OC43 and 229E in Seattle families during 1975-1979. Am J Epidemiol, 123:862, 1986.
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