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287 Current Topics in Microbiology and Immunology Editors R.W. Compans, Atlanta/Georgia M.D. Cooper, Birmingham/Alabama
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Host Factors in Coronavirus Replication Adriaan H. de Wilde, Eric J. Snijder, Marjolein Kikkert and Martijn J. van Hemer
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〔ウイルス 第５ ４巻 第１号，pp．９ ７―１ ０ ５，２ ０ ０ ４〕 トピックス SARS―CoV に関する最新の研究と今後の展望 水 谷 国立感染症研究所 哲 也 ウイルス一部 ２ ０ ０ ３―２ ０ ０ ４年の冬に猛威をふ
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Coronaviruses: Propagation, Quantification, Storage, and Construction of Recombinant Mouse Hepatitis Virus UNIT 15E.1
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The Biology and Pathogenesis of Coronaviruses H. WEGE*,
ST. SIDDELL*, AND
1 Introduction.................. 2 Biology................... 2.1 Members of the Coronavirus Group and Their Relationships 2.1.1 Antigenic Relationships. . . . . 2.1.2 Nucleic Acid Homologies . . . . 2.2 Host Range and Organ Tropism. . 3 Coronaviruses and Disease Spectrum 3.1 Murine Coronaviruses 3.1.1 Murine Hepatitis Virus 184.108.40.206 Hepatitis. . . . . 220.127.116.11 Encephalomyelitis. . 18.104.22.168 Enteritis . . . . . 3.2 Human Coronaviruses 3.3 Avian Coronaviruses. . . 3.3.1 Infectious Bronchitis Virus. 3.3.2 Turkey Coronavirus . . . 3.4 Feline Coronaviruses . . . . . 3.4.1 Feline Infectious Peritonitis Virus 3.5 Other Coronaviruses. . . . . 3.5.1 Bovine Coronavirus . . . . . 3.5.2 Canine Coronavirus . . . . . 3.5.3 Hemagglutinating Encephalomyelitis Virus 3.5.4 Transmissible Gastroenteritis Virus. . . 3.5.5 Rat Coronavirus . . . . . . . . . 4 Pathogenetic' Aspects. . . . . . . . . . . . . 4.1 The Role of Resistance in the Development of Disease . 4.1.1 Acute Infections . . . . . 22.214.171.124 Murine Hepatitis Virus Type 2 . . . . . 126.96.36.199 Murine Hepatitis Virus Type 3 . . . . . . . . 188.8.131.52 Murine Hepatitis Virus JHM . . . . . . . . . 4.1.2 Chronic Infections . . . . . . . . . . . . 4.2 Pathogenicity Associated with Viral Gene Sequences . 5 Conclusions . References. . .
165 166 166 166 168 168 171 171 171 171 173 174 175 176 176 177 178 178 179 179 180 181 181 182 183 183 183 183 184 185 186 187 188 189
1 Introduction The coronaviruses were frrst recognized and morphologically defmed as a group by Tyrrell and co-workers (1968, 1975, 1978). Biochemical studies have recently provided
* Institute ofVrrology and Immunobiology, Versbacher StraBe 7, 0-8700 Wuerzburg, Federal Republic of Germany
M. Cooper et al. (eds.), Current Topics in Microbiology and Immunology © Springer-Verlag Berlin Heidelberg 1982
166 H. Wege et al.
additional information which allows better characterization of these agents. Presently, coronaviruses are defmed as being particles which are pleomorphic to rounded with a diameter of 60-220 nm, surrounded by a fringe or layer oftypical club-shaped spikes. The virion is composed ofabout four to six proteins and possesses a lipid bilayer. The genome consists of a single-stranded polyadenylated RNA which is infectious and of positive polarity. During maturation these viruses are released by internal budding into vesicles derived from the endoplasmatic reticulum. These viruses are widespread in nature and are associated with a great variety of diseases with an acute, subacute, or subclinical disease process. Several reviews have been published describing aspects of the physicochemical and biological properties and the clinical significance of coronaviruses (Mdntosh 1974; Kapikian 1975; Pensaert and Callebaut 1978, Robb and Bond 1979). During the past years new data on the biology of these viruses and on the pathogenesis of diseases, in particular murine-induced coronavirus diseases, have also become available. These recentfmdings are the basis for this review.
2 Biology 2.1 Members of the Coronavirus Group and Their Relationships Table 1lists the coronaviruses described to date, their natural hosts, and the predominant disease type as caused by these viruses. 2.1.1 Antigenic Relationships Our knowledge of the antigenic relationships between the different coronaviruses is
incomplete. The relationships shown in Table 2 are based on results obtained by enzyme-linked immunoassay (Macnaughton 1981; Kraaijeveld et a1. 1980a, b), immunofluorescent and immunoelectron microscopic studies (Pedersen et al. 1978, Pensaert et al. 1981), other serological methods (Reynolds et a1.1980; Gema etal.1981), and the data summarized by Robb and Bond (1979). As shown, the avian and the nonavian coronaviruses each appear to fall into two distinct and unrelated groups. In the case of infectious bronchitis virus (lBV) at least eight different serotypes are at present known (Hopkins 1974) and these again fall into two groups by cluster analyses based on neutralization assays (Darbyshire et al. 1979). Also, comparison of the protein patterns of mv isolates suggested that two groups exist which differ in the electrophoretic migration of the virion glycoproteins (Nagy and Lomniczi 1979; Collins and Alexander 1980). The location of antigenic sites on coronavirion structural proteins has been investigated. Coronaviruses basically contain three major antigens, as has been shown by immunodiffusion experiments (Hajer and Storz 1978; Yaseen and Johnson-Lussenburg 1981) and by the analysis of monospecific antisera prepared against purified coronavirus structural proteins (Schmidt and Kenny 1981). In human, porcine, and murine systems the antigenic sites responsible for the induction ofneutralizing antibodies are associated with the surface glycoproteins (peplomers). Immunological studies with subcomponents prepared from purified virions ofTGEV (Garwes et al. 1978), HCV 229E and MIN-3 (Macnaughton et al. 1981; Hasony and Macnaughton 1981), and HCV-OC43 and 229E (Schmidt
Pig Pig Rat Rat Turkey
TGEV HEV RCV SDAV TCV(TBDCV, TCEV,CET)
Porcine transmissible gastroenteritis virus Porcine hemagglutinating encephalomyelitis virus (vomiting and wasting disease virus) Parker's rat coronavirus c Rat sialodacryoadenitisvirusc Thrkey coronavirus (turkey bluecomb disease coronavirus, turkey coronaviral enteritis virus, coronavirus enteritis of turkeys)
Runde tick coronavirus e
No data on disease in natural host
Hirai et al. 1979 Pensaert and Debouck 1978 Horvath and Mocsari 1981 Traavik et al. 1977
Bass and Sharpee 1975 Caul et al. 1975 Burks et al. 1980
Parker et al. 1970 Jonas et al. 1969 Adams and Hofstad 1971
Doyle and Hutchings 1946 Roe and Alexander 1958
1Y"e/l and Bynoe 1965 Cheever et al. 1949
Binn et al. 1975 Holzworth 1963
&halkand Hawn 1931 Mebus et al. 1973a
In brackets, synonyms used in literature, b Abbreviations used in literature, C Both viruses might be serotypes of the rat coronaviruses, d Probably serotype(s) of human (respiratory) coronaviruses, e Probably a bunyavirus
Parrot coronavirus Porcine CV-777 and other isolates
Foal enteritis coronavirus Human enteric coronavirus d Isolates SD and SK
Diarrhea Diarrhea Demyelinating encephalomyelitis in mice Diarrhea Diarrhea
Human coronavirus Murine hepatitis virus
Horse Man Mouse, man
FECV HECV SD,SK
Diarrhea Peritonitis, granulomatous inflammations in multiple organs Common cold Encephalomyelitis, hepatitis, diarrhea Diarrhea Vomiting and wasting, encephalomyelitis Pneumonitis, rhinitis Adenitis Enteritis
Questionable or unclassified members
Respiratory disease Diarrhea
mV(AffiV) BCV(NCDCV, EBC,BEC)
Avian infectious bronchitis virus Bovine coronavirus (neonatal calf diarrhea coronavirus, enteropathogenic bovine coronavirus, bovine enteric coronavirus) Canine coronavirus Feline infectious peritonitis virus
Predominant clinical disease
Table 1. Coronaviruses - designations, natural host and predominant clinical disease
168 H. Wege et al. Table 2. Antigenic cross-reactions between coronaviruses
Mammalian Group 1
HCV-229 E and other isolates TGEV one serotype CCV one serotype illV one serotype
HCV-OC43 and other isolates MHV many serotypes, also related to RCV andSDAV BCV one serotype HEV one serotype
mv at least 8 serotyes
TCV one serotype No cross-reactions with other strains
No cross-reactions with other strains
Unclassified isolates: Several isolates ofHCV (and HECV), porcine coronavirus CV-777 and others, FECV, RTV
and Kenny 1981) support this conclusion. A similar conclusion was reached by immunoelectron microscopy of bovine coronaviruses (StolZ and Rott 1981). The surface glycoproteins are also involved in complement fIxation and hemagglutinin inhibition. 2.1.2 Nucleic Acid Homologies Some preliminary data on the nucleic acid sequence homology between a few coronaviruses is available. Hybridization with MHV-specific cDNA, representative ofthe entire genome, shows that a close relationship exists between the murine strains MHV-A59, MHV-3 and JHM. Using the same probe no homology between the murine viruses and the human coronavirus 229E could be detected (Weiss and Leibowitz 1981). Using the technique ofT} oligonucleotide fingerprinting Lai and Stahlman (1981a), Weiss and Leibowitz (1981), and Wege et al. (1981a) have shown variation in the genome RNA of murine hepatitis viruses of different neurovirulence (Sect 4.2). This variation seems to be independent of the serological relationships of these strains. In the avian coronavirus group such an analysis also revealed considerable variation within serotypes (Clewley et al.1981). Studies such as these might be useful in characterizing the origin, evolution and spread of both new isolates and live vaccine strains.
2.2 Host Range and Organ Tropism Most coronaviruses cause clinical diseases only in the species from which they were isolated and replicate predominantly in cell lines derived from that host However, transmission to other species can be achieved either experimentally or for some virus strains by a natural route of infection (Table 3). The natural infection of dogs by the porcine strain transmissible gastroenteritis virus (TGEV) and a single case of diarrhea transmitted from cattle to man may indicate a possibly wider host range for enteric infections. The experimental intracerebral inoculation of several coronaviruses into suckling rats, mice,
Cat and other feline species
Only one accidental case report;
Monkeys Rats Hamsters
and Beaudette MHV-JHM
Intracerebral Intracerebral Intracerebral
Intracerebral Intracerebral Intracerebral and intranasal Intranasal Intracerebral
Intracerebral Oral (natural infection) Intracerebral Intracerebral and intracutaneous Oral
Asymptomatic infection Hydrocephalus and encephalitis Clinically inapparent hepatitis, encephalitis Encephalitis
Encephalomyelitis Encephalomyelitis Encephalomyelitis
Woods et al. 1981
Inapparent intestinal infection Inapparent CNS infectio?, inapparent intestinal infection Encephalitis
McIntosh et al. 1969 Estola 1967 Kersting and Pette 1956 Cheever et al. 1949 Cheever et al. 1949 Bailey et al. 1949 Taguchi et al. 1979a Hirano et al. 1980 Takahashi et al. 1980 Wege et al. 1981a (Wege et al. unpublished) Jonas et al. 1969 Bhatt et al. 1972 Haelterman 1962 Reynolds and Garwes 1979
Osterhaus et al. 1978a, b. Woods et al. 1981
Kaye et al. 1975a Akashi et al. 1981
Kaye et al. 1977 StolZ and Rott 1981
McIntosh et al. 1967 McIntosh et al. 1969 Larson et al. 1979
Inapparent intestinal infection Encephalitis Diarrhea
Effect on experirnental host
Other strains not transmissible to mice (Dea et al. 1980a)
Dogs, foxes, cats
Adult rats Suckling rats Suckling mice
Suckling rats Suckling rats
Newborn mice, rats, and hamsters, piglets
BCV Nebraska BCV Kakegawa
HEV-67N BCVLY-138 Suckling mice b Suckling mice, rats, and hamsters Piglets
Suckling mice Mana
Suckling mice, suckling hamsters Dogs
Route of inoculation
Table 3. Host range of coronaviruses
n 0 .... 0
+ +* ++ ++*
++ + ++* +* +
TGEVand HEV others
Symbols: ++ main target for infection; + organs less frequently involved; * involvement in persistenUchronic disease
Target organs Central nervous system Blood vessels Ependym Gonad Intestine Kidney Liver Lymphoid organs Pancreas Parotid gland Peritoneum Respiratory tract
Table 4. Target organs involved in coronavirus infections
The Biology and Pathogenesis of Coronaviruses 171
or hamsters often induces an infection (Table 3). The brain ofsuckling mice is highly susceptible for viruses of avian, human, and mammaljan origin. However, infection under these experimental conditions is not representative for the clinical disease in the natural host A survey of the organs involved in coronavirus infections is summarized in Table 4. Some coronaviruses reveal relatively restricted organ tropism leading to diseases of the respiratory system (HCV, mY, RCV) and gastrointestinal tract only (BCV, CCV, TGEV, TCV). In other coronavirus infections, for example with feline and murine coronaviruses, several organs are involved. The murine coronaviruses represent a group containing many strains with different organ tropism. In addition, feline, murine, and avian coronavirus strains have a strong tendency to establish persistent and chronic diseases.
3 Coronaviroses and Disease Spectrum 3.1 Murine Coronaviruses 3.1.1 Murine Hepatitis Virus
The frrstmurine coronavirus described was MHV-JHM, which was isolated from a spontaneously paralyzed mouse (Cheever et al. 1949). Subsequently, other strains were isolated from different disease conditions and different organs of mice (Table 5). Murine coronavirus infections are often subclinical or inapparent, but clinical disease can be activated by coinfection with leukemia viruses or protozoal agents. These viruses can be transmitted by feces or urine to susceptible strains (Table 5). Vertical transmissio~ by intrauterine infection can also occur with MHV-JHM (Katami et al. 1978) and the respiratory route is important in natural transmission (Carthew and Sparrow 1981; Taguchi et al. 1979c). The prevalent diseases resulting from MHV infection are hepatitis, encephalomyelitis, and enteritis. A strict classification, of all MHVs into hepatotropic, neurotropic, and enterotropic strains is not possible, however, since under certain conditions several organs are affected (Table 4) and the type of disease varies to a great extent with the age and genetic background of the host (Sect 4.1). The role of murine coronaviruses as pathogens of the respiratory tract must also be taken into consideration (Carthew and Sparrow 1981). Variants which differ in organ tropism are easily selected in tissue culture or by animal passages. 184.108.40.206 Hepatitis
Several murine coronavirus strains replicate predominantly in liver tissue and induce an acute fatal-hepatitis by destruction of parenchymal and Kupffer cells (Table 5; Piazza 1969; Hirano et al. 1981a). The highly virulent strains MHV-2, MHV-3, and MHV-A 59 cause hepatitis in adult mice. MHV-1 andMHV-S are less virulent butlead eventually to a similar disease. MHV-8 is enteropathogenic for young mice whereas most of the other strains (Table 5) cause hepatitis only in newborn mice. MHV-N is virulent only for mice which have been immunosuppressed by cortisone treatment Viruses isolated from nude mice (MHV-NuU, NuA and Nu66) cause chronic hepatitis in athymic mice (Sect 4.1.2). However, tissue-culture-adapted MHV-Nu66 and NuA are also hepatotropic for normal mice, indicating an increase in virulence.
Hirano et aI. 1975 Sebesteny and Hill 1974 Tamura et aI. 1976 Ward et aI. 1977 Hirano et aI. 1979 Sabesin et aI. 1972
Cheever et aI. 1949 Broderson et aI. 1976 Krajt1962 Sato et aI. 1976 Ishida et aI. 1978
Burks et aI. 1980
Burks et aI. 1980
MHV-NuU, NuA, Nu66, and other isolates
MHV-JHM MHV-S/CDC b LIVIM MHV-DVlM MHV-D Unclassified isolates Isolate SD
Demyelinating encephalomyelitis in mice
Encephalomyeltits, hepatitis Enteritis Enteritis Enteritis Enteritis, hepatitis
Hepatitis in mice treated with cortisone Hepatitis
Hepatitis Hepatitis, ascites Hepatitis,encephalitis
probably the same strain
a The strains H747, EHF 210 and EHF 120 mentioned in earlier reports (McIntosh 1974) have not been described further; b MHV-S/CDC and LIVIM are
Balb/c mice inoculated with human brain (multiple sclerosis) 2-6 months before isolation Subcultures of 17 CI-1 cells originally inoculated with human brain (multiple sclerosis)
Feces of healthy carrier mice Latent infection of cultured mouse liver cells (NCTC 1469) Spontaneous paralyses of Swiss mice Fatal diarrhea in ICR mice Fatal diarrhea Diarrhea of infant mice Fatal diarrhea in suckling mice
Rowe et aI. 1963
Nelson 1952 Dick et aI. 1956 Manaker et aI. 1961
MHV-2(PRI) MHV-3 MHV-A59
Spontaneous hepatic disease (albino mouse, Parkes strain) Associated with mouse leukemia (Princeton strain) Inoculation of human serum into Swiss mice Inoculation of organ suspensions from mice with Moloney leukemia into Balb/c Acute diarrhea of newborn CD-1 mice housed with other strains Wasting syndrome in nude mice
Gledhill and Andrewes 1951
Conditions of isolation
Straina Predominant effect on host
Table 5. Origin and characteristics of murine coronavirus strains
The Biology and Pathogenesis of Coronaviruses 173
220.127.116.11 Encephalomyelitis Mureine coronaviruses can cause encephalitis is suckling and adult mice (Table 5;
Hirano et al. 1981a). The strain MHV-JHM is especially neurotropic (Cheever et al. 1949; Bailey et al. 1949), causing acute and chronic demyelinating diseases. By the natural intranasal route of infection the virus invades the central nervous system via the olfactory nerve (Goto et al. 1977, 1979), initially replicating in the nasal mucosa and spreading within 6 days to the spinal cord. The outcome of experimental intracerebral infection is similar and necrotic lesions are localized in the hippocampus, olfactory lobes, and periependymal tissues. Demyelination is prevalently confmed to the brain stem and spinal cord. In mice which do not develop an acute disease involvement of grey matter is minimal and viral antigen is detectable in white matter up to 28 days post infection (Pj.) (Weiner 1973). Electron microscopic studies demonstrated that oligodendrocytes are the main target cells for JHM virus (Lampert 1973; Powe1l1975), but especially in young mice virus can also be detected in neurons and ependymal and endothelial cells, indicating the pantropic nature of this infection (Fleury et al. 1980). Infectious virus can be isolated from animals with acute encephalomyelitis at any time during the disease process. Mice which do not show clinical signs within the ftrst weeks pj. or which recover from disease can develop a chronic infection of the central nervous system. Herndon etal. (1975, 1977) observed small foci of active demyelination in Balb/c mice surviving JHM infection for 16 months. Their studies on remyelination in these mice indicated that some of the oligodendroglia cells active in remyelination might be newly generated cells. No information is available about the presence ofviral antigens in the central nervous system or the isolation of infectious virus from these animals. In recent experiments Stohlman and Weiner(1981) induced a chronic infection by intracerebral inoculation of JHM virus into 3-month-old C57 BLl6 mice. No clinical diseases were observed, but during the frrst 12 days pj. infectious virus was recoverable from liver, brain, and spinal cord. Three months pj. small foci of viral antigen were detectable in 70010 of the animals and by elec-. tron microscopy demyelinated lesions were found. At this point immunosuppression did not lead to clinical disease and no infectious virus could be activated or isolated. These results are in contrast to earlier studies by Weiner (1973) who showed that immunosuppression shortly after infaction modilled a nonfatal infection to an acute encephalomyelitis. This indicates, that the virus-host interactions differ signiftcantly between the acute disease and the chronic infection Experiments using cloned JHM virus and temperature-sensitive (TS) mutants of this strain were reported by Haspel et al. (1978). This collection of genetically stable mutants was tested forneurovirulence in Balb/c mice infected at an age of4 weeks. Whereas wildtype virus was lethal for most animals within 6 days, many TS mutants were found to be less neurovirulent Fatal diseases were caused only after the inoculation of about 10 000 times higher doses of infectious virus than was needed for the wild-type virus. Some of the mutants induced demyelination in the spinal cord of survivors, and only very few animals died of an acute encephalomyelitis. Further studies revealed that the wild-type virus replicates in both neuronal cells and oligodendrocytes, whereas a TS mutant selectively replicates in oligodendrocytes of the spinal cord (Knobler et al. 1981a, b). This selective tropism of mutants within the central nervous system is probably an important parameter for the ability to induce demyelination without resulting in fatal encephalomyelitis. Similar observations of different neurovirulence between wild-type
174 H. Wege et al.
and mutant viruses, obtained by mutagens or isolated from persistent infections, have been reported by Robb et al. (1979) and Hirano et al. (1981b). Cheever et al. (1949) described a delayed course of encephalomyelitis with marked demyelination in rats after inoculation of wild-type JHM virus. These original observations have been recently enlarged upon (Nagashima et al. 1978a, b; 1979). The infection of outbred rats (strain Thomae/Chbb) with uncloned JHM virus results in acute or subacute to chronic demyelinating encephalomyelitis which is dependent on the age of the animals, the time of infection, and the virus preparation used. In suckling rats an acute panencephalitis characterized by necrotic lesions in all parts of the central nervous system is found. In weanling rats (age 3-4 weeks), however, a subacute demyelinating encephalomyelitis can occur after an incubation time of several weeks. Demyelinating plaques are sharply demarcated and distributed in the white matter of the central nervous system. A similar disease picture is also found in other rat strains (Sorensen et al. 1980). Preliminary results indicate that the susceptibility of inbred rat strains is dependent on genetic traits (Sorensen et al. 1981). Kinetic studies during the development of subacute demyelinating encephalomyelitis in weanling rats infected with JHM virus suggest a biphasic course of the disease (Wege et al. 1981b). Within 2 weeks p.i. most of the rats develop a clinically silent acute encephalomyelitis in parallel to the replication of the virus in the central nervous system. After this period virus cannot be recovered from these animals, but histologically marked demyelinating lesions are found prior to the development of a subacute encephalomyelitis. By the time a clinically recognizable disease appears JHM virus is again isolatable. Occasionally remissions after acute disease are observed (Sorensen et al. 1980), and surviving rats sometimes develop a late demyelinating encephalomyelitis after an incubation time of up to 8 months (Nagashima et al. 1979). Brain sections of these animals reveal viral antigen and with conventional techniques virus can be isolated. These observations indicate a persistent infection of the brain tissue which is reponsible for a chronic disease process. Whereas wild-type JHM virus varies in its ability to induce subacute and late diseases in weanling rats, TS mutants cause high rates of subacute to chronic diseases. Moreover, suckling rats from immunized mothers can also develop chronic demyelinating diseases if inoculated with TS mutants (Wege et al. 1981b). These observations suggest that the development of acute or subacute to chronic demyelinating disease is dependent on the virulence of the virus and host factors such as age, immune status, and genetic background.
18.104.22.168 Enteritis Several enteropathogenic strains of murine coronaviruses have been isolated during the last few years (Table 5). The fIrst agent of this type was investigated by Kraft (1962) and termed lethal intestinal virus for infant mice (LIVIM). This agent is probably identical with an enterotropic variant of MHV-S described by Rowe et al. (1963) which was later designated MHV-S/CDC by Broderson et al. (1976). These viruses cause an acute intestinal disease with a high mortality rate during the fIrst 3 weeks of life. Intestinal contents from moribund mice contain typical coronavirus particles and the virus spreads by contact infection via the nasal or oral route in newborn mice. Diseased animals are dehy-
The BiolQgy and Pathogenesis of Coronaviruses 175
drated by severe diarrhea. Multinucleated giant cells are found especially in the villi of the small intestines (Biggers et al. 1964). By electron microscopy large numbers of coronavirus particles are detectable in intestinal epithelial cells and in macrophages of the lamina propria of the lower intestines (Hierholzeret al. 1979). The mothers ofaffected litters are clinically healthy but necrotic foci are found in the liver. Orally infected adult animals do not develop dermed clinical signs and shed virus for about 15 days. Intranasal infection by cell-adapted virus leads to a mild diarrhea without mortality. These mice show no evidence of liver or brain disease. Litters from immune mothers are protected against both natural and experimental infection. Strain MIN-S/CDC is serologically related to other MIN prototype strains, especially to MIN-S, and to the human strain OC43 (Hierholzeret al. 1979). Endemics ofLMM disease were reported by Carthew (1977) and a similar virus-designated MIN D-was isolated during a natural outbreak of diarrhea (Ishida et al. 1978; Ishida and FUjiwara 1979). MIN-D tends to produce a more systemic infection with the involvement of liver, brain, lung, and lymphoid organs. Another isolate, MIN-DVIM, causes diarrhea in infant mice and is remarkable for its ability to agglutinate red blood cells from rats and mice (Sato et al. 1976; Sugiyama and Amano 1980).
3.2 Human Coronaviruses Human coronaviruses are often responsible for common colds and are associated with lower respiratory tract diseases and probably enteric diseases. Essentially two groups of isolates can be distinguished. One group grows in tissue cultures of human origin and is related to the prototype strain 229E; the other group can only be maintained in organ cultures, for example strain OC43. The antigenic relationships are summarized in Table 2. These viruses are distributed worldwide and antibodies are present with high prevalence (Monto 1974; Kaye et al. 1975; Gerna et al. 1978). The antibody response to 229E and OC43 appears to have a cycle of several years, with peaks against each strain every 2-3 years. About 15% of common colds are attributed to coronaviruses (Mdntosh et al. 1970; Larson et al. 1980). In children pneumonia and other respiratory distress can be caused by coronaviruses (Mdntosh et al. 1973, 1974). Results of a seroepidemiological survey (Riski and Hovi 1980) indicate a possible association of coronaviruses with more severe diseases such as pneumonia, pleurodynia, myocarditis, and meningitis. An agent termed Tettnang virus has been isolated by inoculation of cerebrospinal fluid from patients with various neuropathies and fever into suckling mice (Malkova et al. 1980). This virus and similar isolates probably respresent MIN strains which naturally infect these mice (Bardos et al. 1980). The development of the common cold was studied in human volunteers inoculated with HCV (Bradbume et al.1967; Beare and Reed 1976, Mdntosh etal. 1978). Virus inoculated by nasal drops causes predominantly coryza, but in contrast to rhinoviruses no cough or mucopurulent nasal discharge occurs. Virus shedding decreases sharply within 3-4 days pj. No evidence for involvement of the lower respiratory tract or intestinal organs was found under experimental conditions. The cilial epithelium is selectively infected and shedding ofantigen-containing cells coincide withe coryza. Rechallenge of volunteers with homologous and heterologous virus 8-12 months pj. revealed that no crossprotection occurs against the heterologous strain but immunity against homologous virus exists (Larson et al. 1980).
176 H. Wege et at.
The systemic immune response against purified HCV 229E and subcomponents have been quantitated by an enzyme-linked immunoassay (Kraaijeveld et al.1980b; Macnaughton et al. 1981) and the results indicate that most of the antibodies produced during infection react with the peplomer protein of the virus. Only small amounts of antibodies recognize the matrix and nucleocapsid protein. No data on the role oflocal immunity in protection against respiratory disease are available. In addition to respiratory diseases some human coronaviruses may be associated with enteric infections (Caul et al.1975; Caul and Clarke 1975; Moore et al. 1977; Caul and Egglestone 1977; Schnagl et al. 1978; Moscovici et al.1980). However, no information exists on the characterization of these agents and their serological relationships to other human coronaviruses (reviewed by Macnaughton and Davies 1981). Coronaviruses have also been associated with an endemic nephropathy (Apostolov et al. 1975), but there are no studies revealing an etiological link between nephropathy and coronaviruses. Two coronavirus strains were recently isolated from mice or mouse tissue culture cells during attempts to isolate viruses from patients with multiple sclerosis (Burks et al. 1980). The frrstisolate, designated SD virus, was isolated after intracerebral inoculation of human brain material into weanling Balb/c mice. Within 2-6 months p.i., mice developed neurological signs and died. From these animals a coronavirus was isolated which replicated in the 17 Cl-l mouse cell line. The second isolate, designated SK virus, was obtained after 12 subcultures of 17 Cl-l cells which had been incubated with brain material from a second patient These isolates are antigenically related to both murine and human coronaviruses and reveal related structural polypeptides as shown by immunoprecipitation (Gerdes et al. 1981a, b). At the present time it cannot be decided whether these isolates have been derived from human or mouse tissue, since it is known that murine coronaviruses establish latency in mouse colonies as well as in mouse tissue cultures (Sabesin 1972). Additionally, serological studies by Leinikki et al. (1981) could not demonstrate any correlation between coronavirus antibody titers and patients with multiple sclerosis or other neurological diseases. Further studies are necessary to show if there is an association of coronaviruses SD and SK with multiple sclerosis.
3.3 AvianCoronaviruses 3.3.1 Infectious Bronchitis Virus Avian mv infects young chickens, causing an acute respiratory disease leading to high mortality and a decrease in yield and quality of egg production. The disease was fIrst described by Schalk and Hawn (1931) and is a very common and worldwide infection in poultry flocks. The virus spreads by both air and the fecal-oral route. At least eight mv serotypes have been described (Dawson and Gough 1971; Hopkins 1974). These serotypes fall into two main groups, the Massachusetts and Connecticut types, which differ in their antigenic relatedness (Sect 2). The virulence of many different isolates and attenuated vaccine strains differs widely. The primary target tissue for infection is the trachea (Purcell and McFerran 1972; Darbyshire et al. 1975). The virus replicates also in bronchial tissue, lung, kidneys, ovaries, and oviduct A strong tendency to produce a prolonged infection which results in shedding of virus of several months via the feces has been observed (Alexanderand Gough 1977). Per-
The Biology and Pathogenesis of Coronaviruses 177
sistent infection in the presence of high antibody titers is often accompanied by severe nephritis and infectious virus can be reisolated from cecal lymph nodes up to 8 months p.i. (Alexander et al. 1978). Both age and genetic factors influence the outcome of the diseases. In addition, infections by bacteria, mycoplasmas, or infectious bursal disease virus (Rosenberger and Gelb 1978) increase the susceptibility of chickens to my. Resistance to natural infection or experimental challenge after vaccination is probably mediated by the local immune response in the trachea, the nasal mucosa, and the Harderian gland. Detailed knowledge of the humoral or cellular immune mechanisms is not yet available (reviewed by Darbyshire 1981). No correlation between serumneutralizing antibodies and resistance to reinfection has been shown, but protection seems to be correlated to resistance of the tracheal epithelium to challenge virus and the presence of high titers of hemagglutinin-inhibiting serum antibodies (Gough and A lexander 1979). Secretion of local antibodies can also be demonstrated in organ cultures (Gomez and Raggi 1974; Darbyshire 1980). Cross-protection against challenge by homologous and heterologous virus strains can be measured by observation of the ciliary activity of tracheal explants from vaccinated chickens. The local antibody response is quite independent of the kinetics of the serum antibody development (Holmes 1973; Leslie and Martin 1973; Watanabe et al.1975; Chhabra and Goel 1980). Whereas antibodies were frrst detected 3 days p.i. in the trachea and the titers fall again several weeks later, serum antibodies maintain a persistently high titer. IgG, IgA, and IgM are all detectable in tracheal washings. However, it should be noted that the antibody patterns detected by neutralization tests and enzymelinked immunoassay (Mockett and Darbyshire 1981) are not identical, indicating that antibodies with different specificity and avidity might be detected by the two techniques. Cell-mediated immunity is demonstrable by specific lymphoblast transformation, but the role in pathogenesis is not yet known (Timms et at 1980). Maternal antibodies are transferred to chicks during development and may contribute to protection early after hatching (Darbyshire 1981). Under experimental conditions respiratory symptoms are observed between 2 and 8 days p.i, accompanied by complete absence of ciliary activity. Maximum virus titers are obtained 3 days p.i. The morphology of epithelial cells changes and thickening of mucosa, edema, and lylnphocytic infIltration are observed (Hawkes et at personal communication). Using immunofluorescence small groups of fluorescent cells can still be demonstrated 6 weeks p.i., but the regenerated tracheal epithelium seems to be restistant to destruction by virus infection. 3.3.2 Turkey Coronavirus
In the 1950s a virus was suspected to induce a transmissible enteritis of turkeys in Minnesota. By electron microscopic studies, a coronavirus-like agent was identifIed (Ritchie et al. 1973; Panigrahy et al. 1974) and characterized by physiochemical and morphological criteria (Deshmukh and Pomeroy 1974; Naqui et al. 1975). By immunoelectron-microscopy no cross-reaction of this virus to other coronaviruses was found (Ritchieetal.1973), but different isolates ofTCV are probably antigenically identical (Pomeroy et al. 1975). No tissue culture system is available for propagation of the virus but the virus grows in embryonated eggs (Adams and Hofstad 1971).
178 H. Wege et al.
The onset of the clinical disease caused by this virus is characterized by depression, loss ofappetite, weightloss, and watery diarrhea. The mortality, especially in older poults, is very low. The lesions in experimental and field cases are very similar to the changes caused by mammalian enterotropic coronaviruses and consist in a marked shortening of the villi, loss of microvilli, epithelial desquamation, and hemorrhage in the jejunum, ileum, and cecum. The number of goblet cells decreases, and the appearance of epithelial cells changes from columnar to cuboidal form (Adams et al. 1972; Desmukh et al. 1976; Gonder et al. 1976). The lesions appear within 1 day pj., and recovery and healing begins after about 5 days. No pathological changes are observed in other organs. The number of lymphoid cells in the lamina propria increases and the villus to crypt ratio remains depressed for 10 days. Despite an early regression of histopathological changes, viral antigen can be found by immunofluorescence up to 28 days pj. Turkeys that recover are immune throughout their lives (Pomeroy et al. 1975). This lifelong immunity is mediated by the secretory IgA antibody barrier (Nagaraja and Pomeroy 1978, 1980, 1981). Serum-neutralizing antibody titers are very low, but intestinal secretions and bile contain virusspecific IgA antibodies for at least 6 months p.i. By immunofluorescence, antibody-secreting cells can be localized in the intestines 4-5 months after recovery from disease. In addition to local immunity, peripherallymphocytes are specifically stimulated by virus antigen. These lymphocytes probably migrate from the intestinal lamina propria to the peripheral blood. Circulating IgA and IgM antibodies appear only during the acute phase of the disease (Carson et al. 1972).
3.4 Feline Coronaviruses 3.4.1 Feline Infectious Peritonitis Virus Feline infectious peritonitis virus (FIPV) normally causes widespread inapparent infections of wild and domestic cats, but the infection can also lead to a fatal disease. The disease syndrome was first described by Holzworth (1963) and experimentally transmitted from field cases to other cats by Wolfe and Griesemer (1966). A coronavirus was identified as the cause of this disease by both morphological and physiochemical criteria (Ward 1970; Osterhaus et al. 1976; Pedersen 1976a; HOlZinek et al. 1977). Serologically this agent reveals an antigenic relationship to the TGEV of pigs (Witte et al. 1977; Reynolds et al. 1977; Pedersen et al. 1978) and to CCV (Everman et al. 1981). Recently a tissue culture system was found which supports the growth of FIPV, and several isolates from field cases are now available (O'Reilly et al. 1979; Black etal.1980; Everman et al. 1981; McKeirnan et al. 1981). It is unknown, whether these isolates are serologically and biologically identical or represent different strains of FIPV. In nature the virus infects cats and other feline species. Randomly collected sera from wild cats and catteries are often up to 90% positive, indicating a wide distribution of the virus (Pedersen 1976b; Osterhaus et al. 1977; Loif.fler et al. 1978). However, the incidence of clinical disease is rather low, usually up to 10%. The virus probably causes a high rate of inapparent infections as coronavirus-like particles have been demonstrated in feces of normal cats. Furthermore, the virus replicates in organ cultures of both small intestines and trachea, causing only small ultrastructural changes of absorptive epithelial cells (Hoshino and Scott 1978, 1980a, b). Under epizootic conditions, the incubation time of clinical disease ranges from
The Biology and Pathogenesis of Coronaviruses 179
several weeks to 4 months (Hardy and Hurvitz 1971; Robison et al. 1971). Experimentally transmitted disease occurs after a much shorter incubation time, which may last only 2-3 days from oral inoculation (Pedersen and Boyle 1980; Everman et al. 1981). The clinical onset of disease is rather unspecific and characterized by fever, loss of appetite, and general depression. In typical cases swelling of the abdomen is observed as a result of peritonitis, but this effusive form is not always clinically detectable. In the noneffusive (dry) form localized granulomatous lesions are found. Both the effusive and noneffusive forms are caused by the same virus inoculum (Hayashi etal.1980; Everman et al. 1981). In addition, both neurological symptoms and pleuritis are observed. After onset of disease, several pathophysiological changes indicate damage to the reticuloendothelial system, liver, and kidneys (Gouffoux et al. 1975; Weiss et al. 1980). A depression of several plasma factors and an increase of fibrin-fibrinogen degradation products is accompanied by anemia, neutrophilia, and leukopenia. The amount of gammaglobulins increases significantly and the urine contains elevated levels of proteins, bilirubin, and urobilinogen. The level of liver-specific enzymes is very high. In the effusive form, fibrin is deposited on abdominal organs. Granulomatous inflammatory reactions, vasculitis, and plaques of focal necrosis are scattered through the parenchyma of the liver, kidneys, lung, spleen, and lymph organs. Central nervous system and ocular lesions can also occur, depending on the route of inoculation (Ward etal.1974). Virus can be isolated from peritoneal exudate, organ homogenates, and blood. Several observations support the concept that FIP might be an immunopathologically mediated disease (HolZinek et al. 1979). High levels of antibodies are often detected in field cases, but do not prevent disease (Pederson et al. 1976b; HOlZineket al. 1978). Experimentally infected seronegative kittens survive significantly longer and develop a less fulminant disease than seropositive kittens (Weiss et al. 1980; Pedersen and Boyle 1980). Moreover, treatment of seronegative kittens with purified anti-FIP IgG results in an aggravation of the disease. In addition, lesions in the liver and serosa of seropositive kittens contain viral antigen, IgG bound to antigen, and complement. In these animals immune complexes can be demonstrated in renal glomeruli tissue (Jacobse-Geels et al. 1980). These fmdings indicate that the immune response against FIPV infections does not have a protective but maybe a destructive effect. In this context it is of interest that the disease often occurs in association with other virus infections such as feline leukemia, feline panleukopenia (a parvovirus), and feline syncytial virus (Cotter et al. 1973; Black 1980; McKeiman et al. 1981). In such cases an enhancement of the FIPV-induced disease process is observed. It is possible that a preexisting persistent viral infection either leads to a higher susceptibility to FIPV or supports the manifestation of a disease state.
3.5 Other Coronaviruses 3.5.1 Bovine Coronavirus Rotaviruses, parvoviruses and coronaviruses are the main causes of bovine viral diarrhea. Mebus et al. (1973a, b) described a coronavirus-like agent associated with diarrhea in young calfs (neonatal calf diarrhea coronavirus), which was identified by morphological and physicochemical criteria (Stair et al. 1972; Sharpee et al. 1976; Dea et al. 1980a, b). This agent has been adapted to grow in tissue cultures and can easily be transmitted by the oral route.
180 H. Wege et al.
Other BCV strains cannot be grown on tissue culture and must be maintained by passage in vivo (Doughri et al. 1976; Doughri and StolZ 1977). Both these and the tissue-culture-adapted strains (Mebus et al. 1975) cause clinical signs of diarrhea within 24-30 h of inoculation. These symptoms last for 4-5 days and can be letha1. The most severe lesions develop in the small intestines, but the large intestines are also infected. The experimental observation that the addition of trypsin to culture media results in a significant enhancement of virus growth in vitro (Dea et al. 1980b; StolZ et al. 1981) suggests that the initiation of infection might be promoted by the action of proteolytic enzymes in the intestinal tract. Virions derived from such trypsin-treated in vitro cultures show shorter surface projections than usual (StolZ et al. 1981). The destruction of the intestinal absorptive epithelium leads rapidly to pathophysiological changes followed by extensive loss of water, sodium, chloride, bicarbonate, and potassium. Metabolism of glucose and lactate becomes severely disturbed and hypoglycemia, lactic acidosis, and an elevated effiux of potassium to the hypovolemic plasma consequently lead to acute shock, heart failure, and death (summarized by Lewis and Phillips 1978; Phillips and Case 1980). Maternal antibodies (IgA and IgM) are transmitted via colostrum to calves and reduce the severeness of disease (Mebus et a1. 1976). More than 50% of bovine sera contain antibodies againstthe BCV strain L Y -138 (Hajer and StolZ 1978; StolZ and Rott 1980). Furthermore, high percentages of human sera from different sources cross-react with BCV antigens in immunodiffusion, neutralization, and electron microscopic tests (StolZ and Rott 1981). The common reactive antigenes) responsible for neutralization is associated with the virion peplomers, but other studies indicate that additionally internal antigens may be responsible for cross-reactivity (Gema et a1. 1981). A single case of diarrhea caused in man by infection with a BCV has been observed (StolZ and Rott 1981), and could indicate that the high degree of reactive antibodies in human sera may result from infection with bovine strains. 3.5.2 Canine Coronavirus Canine coronaviruses usually induce a self-limiting mild gastroenteritis in dogs. CCV has been isolated during an epizootic outbreak of diarrheal disease in military dogs in 1971 (Binn et at. 1975) and during two outbreaks of a highly contagious vomiting and diarrheal disease in the USA (Appel et al. 1979). CCV often occurs in association with canine parvoviruses, which cause a similar but more severe enteric disease (Appel et a1. 1979; Helfer-Baker et al. 1980). Serologically, CCV is more predominant among kennel dogs than among family dogs (62%-87% vs 22%) and the incidence of animals seropositive against coronavirus in combination with parvovirus is also much higher in kennel dogs than in family dogs (55.6% vs 7.4%). Epizootic fatal canine enteritis caused by both viruses can also occur among captive coyote populations (Everman et al. 1980). Canine coronavirus cross-reacts strongly with the porcine TGEV, although it can be serologically differentiated (Reynolds et a1. 1980; Gmwes and Reynolds 1981). It is also serologically related to FIPV (Everman et al.1981). CCV cannot infect piglets, but TGEV can be transmitted to dogs without causing clinical signs (Larson et al. 1979). The oral inoculation of beagle pups leads within 1-7 days to enteritis and diarrhea (Keenan et a1. 1976; Takeuchi et a1. 1976; Nelson et al. 1979). The lesions, which consist of atrophy and fusion of intestinal villi, are most predominant in the ileum. Virus can be recovered from duodenum, jejunum, ileum, colon, and mesenteric lymph nodes, but no
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further spread of virus is detectable. Within 1-2 weeks the diarrhea and histopathological changes disappear and antibodies are detectable. The disease has a more severe course in very young pups than in older pups.
3.5.3 Hemagglutinating Encephalomyelitis Virus Hemagglutinating encephalomyelitis virus (HEV) selectively infects neuronal tissue of pigs and causes a vomiting and wasting disease. The disease was fIrst described as an epizootic outbreak in Canadian swine herds leading to high morbidity in suckling pigs (Roe and Alexander1958). Clinical symptoms consist of vomiting and depression which can lead to death after emaciation and starvation. Additionally, neurological signs of encephalomyelitis appear (Werdin et al.1976). The mortality in young pigs is very high: older litters often survive but remain permanently stunted. Clinical outbreaks are now not so predominant but high percentages of sera contain antibodies, indicating a wide distribution of the virus. The virus exists as a subclinical infection in the presence of maternal antibodies. After the weaning period an active immunity develops (Andries and Pen-
saert 1981). Greig et al. (1962) were the fIrst to isolate HEV. Mengeling and Cutlip (1976) demon-
strated that both the vomiting disease and encephalomyelitis are caused by the same virus. Pathogenetic studies reveal that after oronasal infection of newborn colostrum-deprived pigs the virus replicates in the respiratory tract, the tonsils, and small intestines and spreads via nerve tracts to the peripheral ganglia nearest to the sites of primary infection (Andries and Pensaert 1980a, b; Andries et al. 1978). Vomiting starts 4 days pj. at the time when the virus is detected in neurons of peripheral ganglia. In the central nervous system the viral antigen is fIrst detected in the sensory nuclei of the trigeminal and vagal nerve located in the medulla oblongata, and then spreads to the brain stem and occasionally to the cerebrum, cerebellum, and spinal cord. The infection of other organs or viremia doesnot play a signiftcant role in the pathogenesis of the disease. The local inoculation of the virus intragastrically, intraintestinally, intramuscularly, or into the cerebrosllinal fluid always leads to the same clinical signs. However, the distribution of viral antigens is very different depending on the route of inoculation. Thus it seems probable that infection of neurons in different locations could lead to vomiting due to a disturbance of regulatory mechanisms. A further consequence of the infection of neuronal cells is paralysis of the ileum, which leads to emaciation and death by starvation. 3.5.4 Transmissible Gastroenteritis Virus Transmissible gastroenteritis (TGE) is an acute disease affecting pigs of all ages. Especially in pigs under 2 weeks of age, the infection leads after a short incubation period to diarrhea and vomiting, resulting frequently in death within 3-6 days. Older pigs are less severely affected. The targets for virus replication after oral transmission are absorptive cells of the small intestine (Pensaert et al. 1970). However, respiratory infection can also occur, and viruses can persist for prolonged times in lung tissue of older pigs (Underthal et al. 1974, 1975; Watt 1978). In the infected intestinal cells necrotic lesions develop and lead to pro-
182 H. Wege et at.
gressive shortening of the villi. Replacement of the villous epithelial cells begins 18-72 h pj. by migration of undifferentiated cells from the crypts. These crypt cells are resistant against infection. The epithelial cells of microvilli are important for the digestion of disaccharides and the absorption ofmonosaccharides and contribute to osmoregulation. Their destruction leads consequently to diarrhea, acidosis, and dehydration (Moon et al. 1978; Shepherd et al. 1979a, b). A key role in the defence against TGE is played by the local immune response of secretory IgA and IgM production (Stone et at. 1977; Kodama et al. 1980). Recovery from infection might also be enhanced by a strong cell-mediated local immune response (Frederickand BohI1976; Shimizu and Shimizu 1979). Interferon (type 1) also appears early in the disease process and is probably secreted by local enterocytes. However, intestinal and serum interferon appear to have little protective effect, since up to 100% of newborn pigs die after infection (La Bonnardiere and Laude 1981). The transfer of antibodies via colostrum and milk is of practical importance for protection of suckling pigs. Several attenuated virus strains with low virulence are now available for vaccination of pregnant sows (Hess et al. 1977; Saifand BohI1979). IgA-secreting lymphocytes are locally stimulated in the lamina propria and invade the mammary glands. The pathological changes after oral infection are strongly dependent on the virulence of the TGEV inoculated, since attenuated strains infect only short parts of the intestines and cause only little atrophy of microvilli (Hess et al. 1977). However, the advantage of restricted growth of attenuated virus is counterbalanced by only a weak stimulation ofIgA-secreting cells. Recently, a coronavirus designated CV-777 was isolated in epizootic diarrhea outbreaks (Pensaert and Debouck 1978). No antigenic relationships to other coronaviruses were detected (Pensaert etal. 1981). The disease course is slower than in TGE andaccompanied by less cell destruction (Debouck and Pensaert 1980). CV-777 also replicates to a certain extent in the duodenum and colon and infects crypt cells without destroying their regenerative potential. Another porcine virus unrelated to TGEV was recently described by Horvath and Mocsori (1981). . 3.5.5 Rat Coronavims
Two different coronavirus strains have been isolated from rats. Parker's rat coronavirus (RCV) is pathogenic for the respiratory system of rats, whereas the sialodacryoadenitis virus (SDAV) has a pronounced tropism for salivary and lacrimal glands. These viruses replicate on primary rat kidney cells but not on cells susceptible to MHV infection. Isolation ofRCV was achieved by inoculation oflung tissue homogenates of rats into specific pathogen-free animals (Parker et al. 1970). Newborn rats infected intranasally with RCV develop respiratory disease and die within 6-U days pj. Rats older than 21 days remain clinically healthy. Histopathological lesions are typical for an interstitial pneumonitis. Virus replication is confmed to the mucosal epithelium and lungs. Virus was only exceptionally recovered from salivary and submaxillary glands (Bhatt and Jacoby 1977). Initially was SDAV detected by electron microscopy in the salivary glands of rats. Infectious virus was subsequently isolated by inoculation of organ homogenates into newborn mice (Jonas et al. 1969). The virus is pathogenic for newborn mice by intracerebral inoculation and causes neuronal degradation. Mouse passaged virus induces lesions
The Biology and Pathogenesis of Coronaviruses 183
of the salivary and lacrimal glands in rats (Bhatt et al. 1972). After intranasal inoculation the virus spreads from the respiratory tract via cervical lymph nodes to submaxillary and parotid salivary glands (Jacoby et al. 1975). Within 2 days a rhinitis develops and necrotic lesions spread, especially in the ductal epithelium of the affected glands. The disease is self-limiting and no spread to other organs is detectable. Antibodies are demonstrable within 7 days. In addition to the infection of salivary glands, a keratoconjunctivitis and ophthalmic lesions can be associated with the disease (Lai et al. 1976; Weisbroth and Peress 1977). These lesions may be a secondary phenomenon due to bacterial invasion and impediment of the lacrimal glands.
4 Pathogenetic Aspects The development of a disease process depends not only on the biological properties of the infectious agent but also on the host. Such factors as susceptibility, spread of virus through the body, type and severity of disease, and control and elimination of the infectious virus are all host-dependent. In this context, experiments carried out with MHVs have provided important information on the pathogenic mechanisms of coronavirus infections.
4.1 The Role of Resistance in The Development of Disease 4.1.1 Acute Infectious
22.214.171.124 Murine Hepatitis Virus Type 2 The fIrst evidence for an association of host genes with resistance to MHV infection was reported for MHV-2, which causes a fulminant hepatitis with high lethality in PRI mice but no clinical disease in adult C3H mice. Bang and Wmwick (1960) observed that peritoneal macrophages derived from PRI mice and cultured in vitro are able to replicate MHV-2, whereas novirus growth was detected in cultures ofC3H macrophages. Breeding experiments indicated that resistance is inherited by a single recessive gene. These observations suggested that the result of virus infection may depend on the genetically determined ability of cells from the macrophage lineage to replicate the virus. A difference in susceptibility of macro phages was also observed by Taguchi etal. (1976) who compared the mouse strains DDD and CDP 1. However, as the following experiments illustrate, a complex network of interactions with other cells of the immune system also influences and modifIes the outcome of infection (Bang 1981). Shif and Bang (1970a, b) demonstrated that macrophages of PRI and C3H mice absorb and take up the virus equally well although macrophage cultures derived from resistant C3H mice did not produce detectable amounts of infectious virus. The ability of macrophages from both strains to replicate equally well a variant virus which arose during high multiplicity of infection indicates, however, that this genetically determined resistance is not absolute and can be overcome by strain variation. Weiser and Bang (1976) bred a mouse strain (C3HSS) which contains the gene for MHV-2 susceptibility from PRI mice but is in all other respects congenic with the resistant C3H strain. Cotijl et al. (cit Bang 1981) used this new strain to show that whilst MHV-2 can replicate under single-
184 H. Wege et al.
cycle conditions in macrophage cultures from both resistant and susceptible strains, the virus produced in resistant macrophages is relatively much less infectious for the genetically incompatible system. Additional experiments have also shown that the resistance of adult C3H mice to hepatitis induced by MHV-2 can be modulated by procedures affecting T-cell functions. Whilst normal mice develop transitory hepatic lesions which do not lead to clinical signs, thymectomized animals are no longer resistant and die with an acute hepatitis (Sheets et a1. 1978). Macrophage cultures derived from thymectomized animals are, however, still relatively resistant This indicates that in addition to macrophage resistance, thymus-dependent functions are involved in preventing the disease. Also treatment of C3H mice with hydrocortisone, a steroid which suppresses T-cell functions, abolishes the resistance of C3H mice to MHV-2 (Gallily et al. 1964). On the other hand, polyclonal stimulation of lymphocytes by inoculation of concanavalin A into normally susceptible PRI mice induces resistance, again suggesting the involvement of T cell-mediated factors ( Weiser and Bang 1977). These in vivo observations were further supported by experiments with cultured macrophages in vitro (Weiser and Bang 1976, 1977; Taylor et al. 1981). These authors showed that macrophages from resistant mice can be modulated in their susceptibility by the addition of soluble mediators (lymphokines and interferon) which have been secreted by stimulated lymphocyte cultures. 126.96.36.199 Murine Hepatitis Virus Type 3 In the MHV-3 system, the resistance or susceptibility of animals is correlated with the degree of virus growth in macrophage cultures (Virelizierand Allison 1976; Macnaughton and Patterson 1980; reviewed by Virelizier 1981). Whilst little or no virus replication occurs in macrophage cultures from AIJ mice, a resistant strain (Table 6), the degree ofvirus replication in macrophage cultures from susceptible and semiresistant strains reflects the pathogenicity ofMHV-3 for the particular host Resistant and susceptible macrophage cultures absorb and incorporate virions to the same extend (Krzystyniak and Dupuy,
Table 6. Different diseases induced by MHV-3 in inbread strains of mice. (Virelizier et al. 1975; Le
Prevost et al. 1975a; Yamada et al. 1979) Type of disease
Mouse strain inoculated
Age at time of intraperitoneal infection
Lethal, fulminant hepatitis 5-8 days pj., systemic infection Lethal hepatitis 6-10 days pj., selective destruction of T cells Chronic vasculitis 2-12 months pj. Chronic chorioependyrnitis 2-12 months pj. Clearance of virus within 7 days, survival Inapparent hepatitis, clearance of virus within 7 days pj.
C57 BLl6, Balb/c, DBA2, and others C3H1He
C3H1He A2G AlJ DDD
5-8 months 6-8 weeks Over 10 weeks 4 weeks
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1981). The restriction may affectlater stages in virus replication. LelYetal. (1981) observed that infection of macrophages from susceptible mouse strains leads to a significant stimulation of the blood coagulation system. This may be an additional parameter which contributes to the development of disease. The genetically determined degree of susceptibility is not only restricted to peritoneal macrophages, since hepatocyte cultures obtained by perfusion ofliver also reveal the same type of genetic restriction (A mheiter and Haller 1981). LeIY-Leblond et al. (1979) have shown that at least two recessive genes are responsible for resistance and that they are associated with the histocompatibility (H2) genes. This suggests that antigen recognition by T -lymphocytes plays a role in virus elimination. Further evidence that impairment of virus replication in macrophages and cooperation with cells of the T-cell lineage are both required for resistance is the observation that resistance can only be transferred if peritoneal cells and adherent spleen cells are inoculated together (LeIY-Leblond and Dupuy 1977). Additionally, bone marrow cells enhance the protection transferred by spleen cells (Tardieu et al. 1980). The host-cell gene functions which regulate the susceptibility for MIN-3 are apparently not important for the replication of other viruses (Amheiter and Haller 1981). The interferon system represents another important line of defence against MIN-3 infection. Interferon is released by macrophages during the fIrst cycles of virus replication and is induced in both resistant and susceptible mouse strains, with peak titers 1-2 days pj. (Virelizieret al.1976). Application of an antiserum against virus-induced (type 1) interferon amplifles the disease course in susceptible mice and abolishes resistance if inoculated into resistant strains shortly before virus infection (Virelizierand Gresser 1978). No enhancement of disease by anti-interferon globulin can be found in chronically diseased animals (Sect 4.1.2). As in the MIN-2 system, inlrnunosuppressive treatments such as thymectomy or treatment with anti Thy-1 serum aggravate the disease - induced b-y MIN-3 and indicate that T cell-mediated immune mechanisms contribute to resistance (Dupuy et al. 1975). SpecifIc antibodies are not of major importance, since transfer of serum from immunized, resistant mice to susceptible mice gives no protection (LePrevostetal.1975). It should also be noted, however, that immunosuppressive treatments impair not only T-cell functions but also the production of virus-induced interferon (Virelizieretal.1979). Interperitoneal inoculation of inactivated Corynebacterium parvum together with MIN-3 suppresses the development of disease (Schindleret al. 1981). This type of resistance may be due to a nonspecifIc immune stimulation and activation of macrophages. This situation is still further complicated by the influence of age of the mouse at the time ofMIN-3 infection. For example, in young C3H mice T cells and not macrophages are the primary target for MIN-3 replication (Yamada et al. 1979). Thus although C3H mice infected at 4 weeks of age are susceptible, whilst D D D mice are relatively resistant, (Table 6), peritoneal macrophages from both strains support virus growth to the same extent and serum interferon titers are very similar. However, in cultured spleen cells ofC3H mice virus growth is associated only with Thy-1-antigen-positive cells.
188.8.131.52 Murine Hepatitis Virus JHM The third MIN strain that has been studied in some detail is MIN-JHM. Stohlman and Frelinger(1978) showed that resistance to JHM virus is a recessive genetic trait, not strongly associated with the H2 complex. The interaction of at least two host genes may be re-
186 H. Wege et a1.
quired. A similar result was reported by Knobler et al. (1981b). It seems most important that in infections with MHV-JHM the development of resistance correlates with the maturation of the macrophage cell population. This is indicated by the results of cell transfer experiments (Stohlman et al. 1980, Stohlman and Frelinger 1981). SJL/J mice at an age of6 weeks are relatively susceptible compared to older mice ofthe same strain and resistance can be transferred from old to young mice by peritoneal exudate cells. Depletion of cells bearing markers for Tor B cells does not influence the transfer ofprotection. Virus replication in macrophage cultures ofboth young and old mice is poor, andmacrophages have the ability to suppress virus growth in another susceptible cell culture which is permissive for the virus. This type of suppression is not mediated by interferon. When comparing resistant and susceptible strains, Knobleretal. (1981b) found a correlation between virus replication in cultured macrophages and the outcome of disease in vivo. A similar age-dependent resistance associated with the IIl8;turation of macrophages was observed by Taguchi et al. (1977, 1979b, c, 1980) for MHV-S. Pickel etal. (1981) also studied the development of resistance to MHV-JHM infection during host maturation and found that a mature immune system is not the only requirement for protection. Intraperitoneal infection ofC3H mice withJHM virus up to 20 days of age results in an acute fatal disease, whilst mice older than 20 days rapidly acquire resistance. Suckling mice can be rendered resistant by transferring spleen cells from adult mice immunized against JHM virus. Nonimmune spleen cells from adult mice, however, cannot protect after transfer. The transferred normal spleen cells were able to mediate a normal immune response in the immature host 4.1.2 Chronic Infections
The infection ofsemiresistant strains (C3H1He andA2G) withMHV-3 results ina persistent infection associated with a chronic neurological disease (Virelizier et al. 1975; LePrevost et al. 1975b). The majority of animals survive the acute stage of infection and develop a progressive chronic disease characterized by incoordination and paresis ofone or more limbs (Table 6). The pathological fmdings in A2G mice consist mainly of a chronic chorioependymitis resulting in hydromelia and hydrocephalus, whereas C3H mice reveal a diffuse vasculitis in kidney, liver, spleen, brain, and spinal cord. Perivascular infiltrations by polymorphonuclear lymphocytes and fibrinoid necrosis develop around veins and arteries. In the central nervous system destruction of myelin and axons can be found, but in contrast to neurotropic MHV strains virus antigen has never been demonstrated in neuronal cells. Antigens and immunoglobulin are, however, detectable in the walls of affected vessels. Inoculation of susceptible mouse strains with organ suspensions from chronically diseased animals induces a fatal acute hepatitis in the recipient Therefore, persistency in semisusceptible mice is a consequence of the host response and not due to the biological properties of the virus. The infection of host macrophages by MHV-3 results in modification of the immune response (Virelizier et al. 1976; Lahmy and Virelizier 1981). Application of antigen (sheep red blood cells) at the time of virus infection results in an immunostimulation against this antigen. However, an immunosuppression occurs if the antigen is inoculated later in infection. In persistent infection, a chronic immunosuppression is observed and may be associated with the continuous release of circulating (type 2) interferon. Furthermore,
The Biology and Pathogenesis of Coronaviruses 187
prostaglandin(s) produced by stimulated macrophages contribute to immunosuppression. This modification might be one of the mechanisms in the pathogenesis of chronic disease in semisusceptible mice. Athymic nude mice are another host in which a chronic MHV infection occurs. Several MHVs have been isolated from nude (nu/nu) mice (Table 5). The strain termed MHV-NuU is oflow virulence and causes a persistent infection with progressive necrotizing hepatitis and perivascular infiltrations in the lung (Furuta et a1.1979). It is not pathogenic for heterozygote nul+ mice with a Balbic background. Interestingly, Tamura et al. (1977, 1978, 1980) found in infected athymic nulnu mice an immune response normally not detectable in these animals. After inoculation with thymus-dependent antigen (sheep red blood cells), chronically infected nulnu mice produce neutralizing antibodies (lgM and IgG) and also produce a secondary response (Tamura and Fujiwara 1979). This immunostimulation is thought to involve the differentiation ofT-cell precursors. Humoral immunity alone however is not sufficient to prevent disease. Especially the functions ofT cells are required for protection (Kai et al. 1981). Additionally, during the early phase of disease; the phagocytic activity and number of macrophages is enhanced. Impairment of macrophage functions by the toxic effects of silica inoculation aggravates the disease course and leads to a lethal acute hepatitis (Tamura et al. 1979, 1980).
4.2 Pathogenicity Associated with Viral Gene Sequences In the preceeding sections the importance of both viral and host factors in determining the outcome of coronaviral infection have been discussed. As a flrst step in attempting to defme the viral gene sequences which might playa major role in the pathogenicity of a particular virus strain, Lai and co-workers have compared the genomes of several MHV strains and variants by oligonucleotide fmgerprinting (Lai and Stohlman 1981ab; Lai et al. 1981). Most interesting is their comparison oflarge- and small-plaque variants ofMHVJHM (Stohlman et al. 1981). The large-plaque variant (DL) is highly virulent for mice, whereas the small-plaque variant is less virulent and might induce a more extensive demyelination (Fleming et al., personal communication). Each variant contains one unique oligonucleotide sequence which is missing in its counterpart. The unique oligonucleotide of the large-plaque variant is located on the genome about 14-15 kb from the 3' end, whilst the small-plaque variant oligonucleotide maps about 3-5 kb from the 3' end. The respective mRNAs for these oligonucleotides have been tentatively identifled. Assuming that the same genes are associated with tropism in tissue culture and pathogenicity in animals, these studies, in conjunction with biochemical studies on viral replication (see Siddell et al. pp 131-165), could eventually indicate which protein(s) are important for the different biological properties of such mutant pairs. A similar approach is based on the observation that MHV-3 is more hepatotropic in comparison to MHV-A59. The genomic RNAs of these two virus strains have been compared by T 1 oligonucleotide mapping and are very similar except for two oligonucleotide sequences. The mRNAs encoded by these sequences are known. Consequently, when the proteins encoded by these mRNAs are identilled it may be possible to determine the proteins which are associated with the different pathogenicity of these virus strains.
188 H. Wege et aI.
5 Conclusions It is evident that the framework of host age and genetic background, biological properties of the virus strain, and dose and route of inoculation are the major factors which determine the result of coronavirus infection. The respiratory and intestinal tract may be the site of primary replication for all coronavirus infections under natural conditions, although the involvement of other target organs is important for the manifestation of disease in most cases. These target cells are hepatocytes and macrophages in the case of different MHV strains and FIPV, ependymal and endothelial cells for MHV-3 in semiresistant hosts, T cells in MHV-3 infection of young C3H mice, ductus cells in the salivary glands for SDAV infection, neurons in the case of infections with HEV and some MHV strains, and oligodendroglia cells for infection with MHV-JHM mutants. For most viruses causing enteric diseases (BCV, CCV, some MHV strains, TGEV, and TCV) and respiratory diseases (!BV, HCV, and RCV) the pathophysiological events leading to clinical symptoms are almost certainly due to the acute cytocidal infection of the target cells (epithelial cells of intestines or respiratory epithelium). These infections can be limited by the local immune response resulting in production of secretory antibodies. In enteric infections, maternal antibodies supplied by colostrum and milk are an additional important defence mechanism. In contrast, many coronaviruses are maintained and spread in the population as inapparent and subclinical infections. Many murine strains have been isolated from clinically healthy animals, and chronic infection by mv can result in prolonged virus shedding. TGEV can also be carried for a prolonged time. In the case ofFIPV, although only a low percentage of animals develop disease there is good reason to believe that many more animals may be infected. In central nervous system infections with MHV-JHM a clinically silent acute encephalitis develops, which may later become a subacute to chronic demyelinating disease. The sequence of events leading to chronic diseases is unknown. During the pathogenesis of chronic and acute diseases stages of viral persistency can be involved. The result depends on the expression of viral genes, the functional impairment of host cells and the interaction with the host immune response. At the present stage, no experimental data are available on the molecular mechanisms important in the development and maintenance of persistent infections. However, the use of permanent cultures of differentiated cells may be of great use in this respect. For example, neurotropic and nonneurotropic MHV viruses behave very differently in certain neuroblastoma lines (Lucas et al. 1977) and viral mutants exist which selectively replicate in oligodendroglia cells (Knobler et al. 1981a). Also, persistent infected neuroblastoma cell lines can harbor the virus without any indication of viral antigen expression and other lines can shed virus variants with altered pathogenicity (Stahlman et al. 1979a, b; Holmes and Behnke 1981; Hirano et al. 1981b). Such systems will be of value in investigating the physiological impairment of cell functions by virus persistence and as model systems to evaluate mechanisms of viral persistence. For several murine systems the host genetic background is an essential parameter determining resistance and the outcome of disease. A valuable system for investigating the mechanism of genetic resistance is formed by inbred mice, which are congenic with the exception of the gene(s) responsible for different susceptibility. Many results indicate
The Biology and Pathogenesis of Coronaviruses 189
that macrophages playa key role in this genetic restriction. The detailed mechanisms for this restriction are as yet difficult to defme and cannot be generalized, and the effect of genes which influence the susceptibility may change during host maturation. Mutations within the virus population also have to be considered during prolonged virus-host relationships. Additionally, infection of macrophages and other cells of the immune system clearly modulates the host immune response and influences the outcome of the infection. The ftrst attempts to defme viral genes which influence pathogenicity have been reported. If strain differences are defmed in biochemical terms, it may be possible to describe the role of these gene products in pathogenesis. Further work on variants which differ in only few mutations and show clear differences in biological properties can help to elucidate the function of viral genes in pathogenesis. Coronaviruses are pathogens of economic and clinical importance. Defmed experimental systems have been established, especially for murine coronaviruses, which are valuable disease models representative for coronaviral and other diseases of man and animals. We may expect rapid progress to be made in the next few years. Acknowledgements. We gratefully acknowledge the help of many colleagues who provided manuscripts and information. Data were also made available by the WHO Collaborating Centre for Collection and Evaluation of Data on Comparative Virology, University of Munich, Germany. We thank Helga Kriesinger for typing the manuscript The authors were supported by the Deutsche Forschungsgemeinschaft
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