3
Microbiology, Ecology, and Natural History of Coronaviruses

OVERVIEW

Coronaviruses cause a substantial fraction of human colds and a host of common respiratory infections in many other animals, including economically important diseases of livestock, poultry, and laboratory rodents. Moreover, although these viruses were not known for producing more than mild infections in humans prior to the SARS epidemic, veterinary coronavirologists have long been aware of their potential for producing lethal infections in animals, as Linda Saif describes in this chapter’s first paper. For this reason, there is already an extensive amount of research on animal coronaviruses that can be drawn from for understanding the life cycle and pathogenicity of the SARS virus, and veterinary scientists are now being called on to join the research response to the epidemic and share their knowledge of coronaviruses with a broader audience. Mark Denison’s paper describes the current state of research on animal coronaviruses and discusses how results from these animal models suggest promising directions for future research on SARS and other emerging zoonoses.

Animal coronaviruses tend to follow one of two basic pathogenic models, producing either enteric or respiratory infections. Both models show parallels to the clinical features of SARS patients, the majority of whom presented with respiratory infections but in some cases also suffered from enteric complications. In adult animals, coronavirus infections of a respiratory nature have shown increased severity in the presence of several factors, including high exposure doses, respiratory coinfections, stress related to shipping or commingling with animals from different farms, and treatment with corticosteroids. In young, seronegative animals, enteric coronaviruses can cause fatal infections. Although coronaviruses



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary 3 Microbiology, Ecology, and Natural History of Coronaviruses OVERVIEW Coronaviruses cause a substantial fraction of human colds and a host of common respiratory infections in many other animals, including economically important diseases of livestock, poultry, and laboratory rodents. Moreover, although these viruses were not known for producing more than mild infections in humans prior to the SARS epidemic, veterinary coronavirologists have long been aware of their potential for producing lethal infections in animals, as Linda Saif describes in this chapter’s first paper. For this reason, there is already an extensive amount of research on animal coronaviruses that can be drawn from for understanding the life cycle and pathogenicity of the SARS virus, and veterinary scientists are now being called on to join the research response to the epidemic and share their knowledge of coronaviruses with a broader audience. Mark Denison’s paper describes the current state of research on animal coronaviruses and discusses how results from these animal models suggest promising directions for future research on SARS and other emerging zoonoses. Animal coronaviruses tend to follow one of two basic pathogenic models, producing either enteric or respiratory infections. Both models show parallels to the clinical features of SARS patients, the majority of whom presented with respiratory infections but in some cases also suffered from enteric complications. In adult animals, coronavirus infections of a respiratory nature have shown increased severity in the presence of several factors, including high exposure doses, respiratory coinfections, stress related to shipping or commingling with animals from different farms, and treatment with corticosteroids. In young, seronegative animals, enteric coronaviruses can cause fatal infections. Although coronaviruses

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary generally cause disease in a single animal species, some have been demonstrated to cross species barriers. Considerable effort has already been applied toward uncovering an animal source of the SARS virus. This has been sought primarily through the genetic characterization of viral isolates from suspected animal sources and comparison with human SARS coronavirus samples. In the past, however, epidemiological detective work has identified the source of many outbreaks of infectious disease, and one workshop participant suggested that a case control study of the first 50 to 100 SARS patients from China’s Guangdong Province, where the earliest cases of the disease were detected, might prove similarly fruitful. While a natural reservoir for the SARS virus has not yet been identified, the combination of such genomic and epidemiological techniques is already yielding suggestive results. For example, the last paper in this chapter by Yi Guan et al. describes the presence of coronaviruses closely related to SARS among live animals sold in Guangdong markets. Similar epidemiological principles may yet provide valuable direction for further laboratory surveys of animal viruses aimed at finding the original source and reservoir of the SARS coronavirus. Coronaviruses have been classified into three major categories based on their genetic characteristics. While the SARS virus has been linked with Group II coronaviruses, whose members include human and bovine respiratory viruses and the mouse hepatitis virus, there is still some debate over whether its genetic features might be sufficiently distinct to warrant classification within a separate, fourth class of coronaviruses. Studies of coronavirus replication at the molecular level reveal several mechanisms that account for the repeated, persistent infections typical of coronaviral disease. High rates of mutation and RNA-RNA recombination produce viruses that are able to adapt to acquire and regain virulence. Although researchers have identified several potential targets for antiviral therapies, the ability of the virus to mutate and recombine represents a major challenge to vaccine development. A vaccine that can provide highly effective, long-term protection against respiratory coronavirus infections has not yet been developed, nor have appropriate animal models been developed to test potential vaccines against SARS. It was noted by several workshop participants that a coordinated, multidisciplinary research effort, drawing on expertise in both the veterinary and biomedical sciences, will likely be needed to meet these goals. ANIMAL CORONAVIRUSES: LESSONS FOR SARS Linda J. Saif Department of Food Animal Health Research Program, Ohio Agricultural Research and Development Center The emergence of severe acute respiratory syndrome (SARS) illustrates that coronaviruses (CoVs) may quiescently emerge from possible animal reservoirs and

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary can cause potentially fatal disease in humans, as previously recognized for animals. Consequently the focus of this review will be on the emergence of new CoV strains and the comparative pathogenesis of SARS CoV with those CoVs that cause enteric and respiratory infections of various animal hosts. A review of animal CoV vaccines recently has been compiled (Saif, in press), so this topic will not be addressed. Emergence of New Coronaviruses The medical community was amazed by the emergence of a new coronavirus associated with SARS in healthy adults in 2003 (Drosten et al., 2003; Ksiazek et al., 2003; Peiris et al., 2003b; Poutanen et al., 2003). Historically human CoV infections (229E and OC43 CoV strains) were mild and associated with only common cold symptoms although reinfections, even with the same strain, occur (Callow et al, 1990; Holmes, 2001). However, veterinary coronavirologists had previously recognized the potential for coronaviruses to cause fatal enteric or respiratory infections in animals and for new CoV strains to emerge from unknown reservoirs, often evoking fatal disease in naïve populations. For example, the porcine epidemic diarrhea CoV (PEDV) first appeared from an unknown source in Europe and Asia in the 1970s and 1980s, causing severe diarrhea and widespread deaths in baby pigs before becoming endemic in swine (Pensaert, 1999). The PEDV is absent in U.S. swine. Interestingly, PEDV is genetically more closely related to human CoV 229E than to the other animal group I CoV (Duarte et al., 1994), and unlike the other group I CoV, it grows in Vero cells like SARS CoV (Hoffman and Wyler, 1988). These observations raise intriguing, but unanswered, questions about its origin. Alternatively new CoV strains differing in tissue tropism and virulence may arise from existing strains. The less virulent porcine respiratory coronavirus (PRCV) evolved as a spike (S) gene deletion mutant of the highly virulent enteric CoV, transmissible gastroenteritis virus (TGEV) ( reviewed in Laude et al., 1993; Saif and Wesley, 1999). Curiously, differences in the sizes of the 5′ end S gene deletion region (621–681 nucleotides) between European and U.S. PRCV strains provided evidence for their independent origin on two continents within a similar time frame (1980s). Deletion of this region (or in combination with deletions in ORF 3a) presumably accounted for altered tissue tropism from enteric to respiratory and reduced virulence of the PRCV strains (Ballesteros et al., 1997; Sanchez et al., 1999). The ability of certain CoVs to persist in their host also provides a longer opportunity for new mutants to be selected with altered tissue tropisms and virulence from among the viral RNA quasispecies (or swarm of viruses). An example is the virulent systemic variant, the feline infectious peritonitis virus (FIPV), which likely arises from persistent infection of cats with the less virulent feline enteric CoV (Herrewegh et al., 1997; Vennema et al., 1995). Furthermore, animal CoVs may acquire new genes via recombination, as exemplified by the acquisition of an influenza C-like hemagglutinin by bovine

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary CoV or its ancestor CoV (Brian et al., 1995). Recombination events among CoVs may also generate new strains with altered tissue or host tropisms. For example, targeted recombination between feline and mouse S proteins enables feline CoV to infect mice (Haijema et al., 2003). Recent phylogenetic analysis suggests that SARS CoV may have evolved from a past recombination event between mammalian-like and avian-like parent strains with the S gene representing a mammalian (group 1)–avian origin mosaic (Stavrinides and Guttman, 2004). This recognition that CoVs can further evolve in a host population to acquire new tissue tropisms or virulence via mutations or recombination suggests that similar events may occur if SARS CoV persists in humans. Interspecies Transmission of Coronaviruses The genus coronavirus is composed of at least three genetically and autigenically distinct groups of CoV that cause mild to severe enteric, respiratory, or systemic disease in domestic and wild animals, poultry, rodents, and carnivores and mild colds in humans (Table 3-1) The SARS CoV is genetically distantly related to known CoVs and comprises a provisional new group (IV) (Drosten et al., 2003; Marra et al., 2003; Rota et al., 2003) or alternatively, using rooted tree phylogenetic analysis, belongs to a subgroup of group II (Snijder et al., 2003). Coronaviruses from two wild animal species (civet cats and raccoon dogs) recently have been characterized genetically as members of the SARS CoV group (Guan et al., 2003). Coronaviruses within each group share various levels of genetic and antigenic relatedness and several show cross-species transmission. Thus the likelihood that SARS CoV is a zoonotic infection potentially transmitted from wild animals to humans is not unprecedented based on previous research on interspecies transmission of animal CoV and wildlife reservoirs for CoV. As examples, the porcine CoV, TGEV, and canine and feline CoVs can cross-infect pigs, dogs, and cats with variable disease expression and levels of cross-protection in the heterologous host (Saif and Wesley, 1999; Saif and Heckert, 1990). These three related CoVs appear to be host range mutants of an ancestral CoV. Wildlife reservoirs for CoVs were recognized prior to SARS. Captive wild ruminants harbor CoVs antigenically closely related to bovine CoV and CoV isolates from the wild ruminants experimentally infected domestic calves (Tsunemitsu et al., 1995; Majhdi et al., 1997). The promiscuousness of bovine CoV is evident by infection of dogs and also humans by genetically similar (>97 percent identity) CoV strains (Erles et al., 2003; Zhang et al., 1994). Even more dramatic than infection of mammalian hosts by bovine CoV is the finding that bovine CoV can experimentally infect and cause disease (diarrhea) in phylogenetically diverse species such as avian hosts, including baby turkeys, but not baby chicks (Ismail et al., 2001b). It is notable that in the latter study, the bovine CoV-infected baby turkeys also transmitted the viruses to unexposed contact control birds. The reasons for the broad host range of bovine CoV are unknown, but may relate to the

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary TABLE 3-1 Coronavirus Groups, Target Tissues, and Diseases       Disease/Infection Site Genetic Group Virus Host Respiratory Enterica Otherb I HCoV-229E Human X upper       TGEV Pig X upper X S1     PRCV Pig X upper/lung   Vitremia   PEDV Pig   X SL, colon     F1PV Cat X upper X Systemic   FCoV Cat   X S1     CCOV Dog   X S1     RaCoV Rabbit     Systemic 11 HCoV-OC43 Human X upper ?? (BCoV?)     NUN Mouse   X Hepatitis, CNS, systemic   RcoV Rat X       (sialodocryadenitis) Pig X   Eye, salivary glands CNS   BEV Cattle X upper/lung X S1, colon     BCoV         III IBV Chicken X upper X Kidney, oviduct   TCoV (TECoV) Turkey   X S1   IV?? SARS Human X lung X (?) Viremia, kidney? IIA? Civet cat CoV Himalayan palm civet X X Subclinical?     Raccoon dog         Raccoon dog CoV   ? X Subclinical? aSl = small intestine; ?? = BCoV-Iike CoV from a child, Zhang et al. (1994); ? = unknown. bCNS = central nervous system.

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary presence of a hemagglutinin on bovine CoV and its possible role in binding to diverse cell types. Recent data suggest that SARS CoV may also have a broad host range besides humans. Genetically similar CoVs were isolated from civet cats and raccoon dogs (Guan et al., 2003). In experimental studies, the SARS CoV infected and caused disease in macaques and ferrets and infected cats subclinically (Fouchier et al., 2003; Martina et al., 2003). In the latter two species, the SARS CoV was further transmitted to exposed contacts, documenting transmission within the new host species. Consequently, although previous data document the emergence of new animal CoV strains and the broad host range of several CoVs, the determinants for host range specificity among CoVs are undefined. In addition, we understand little about CoVs circulating in wildlife and relatively few animal CoV strains have been fully sequenced for comparative phylogenetic analysis to trace their evolutionary origins. Pathogenesis of Animal Enteric and Respiratory Coronaviruses Pathogenesis of Group I TGEV and PRCV CoV: Models of Enteric and Respiratory Infections Because both pneumonia and diarrhea occur in SARS patients, an understanding of the tissue tropisms and pathogenesis of respiratory and enteric animal CoVs should contribute to our understanding of similar parameters for SARS. The TGEV targets the small intestinal epithelial cells leading to severe villous atrophy, malabsorptive diarrhea, and a potentially fatal gastroenteritis (Table 3-1). The virus also infects the upper respiratory tract with transient nasal shedding (Van Cott et al., 1993), but infection or lesions in the lung are less common. In adults, TGEV is mild with transient diarrhea or inappetence, but pregnant or lactating animals develop more severe clinical signs and agalactia (Saif and Wesley, 1999). The PRCV, an S gene deletion mutant of TGEV, has an altered tissue tropism (respiratory) and reduced virulence (Laude et al., 1993; Saif and Wesley, 1999). Like SARS, PRCV spreads by droplets and has a pronounced tropism for the lung, replicating to titers of 107-108 TCID50 and producing interstitial pneumonia affecting 5 to 60 percent of the lung (Cox et al., 1990; Halbur et al., 1993; Laude et al., 1993; Saif and Wesley, 1999). Although many uncomplicated PRCV infections are mild or subclinical, lung lesions are invariably present. Like SARS, clinical signs of PRCV include fever with variable degrees of dyspnea, polypnea, anorexia, and lethargy, and less coughing and rhinitis (Cox et al., 1990; Halbur et al., 1993; Hayes, 2000; Laude et al., 1993; Saif and Wesley, 1999). Further resembling SARS, PRCV replicates in lung epithelial cells, although viral antigen is also detected in type I and II pneumocytes and alveolar macrophages. In lungs, bronchiolar infiltration of mononuclear cells, lymphohistiocytic exudates, and epithelial cell necrosis leads to interstitial pneumonia. PRCV induces transient

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary viremia with virus also detected from nasal swabs and in tonsils and trachea, similar to SARS (Drosten et al., 2003; Ksiazek et al., 2003; Peiris et al., 2003b). The PRCV further replicates in undefined cells in the gut lamina propria, but without inducing villous atrophy or diarrhea and with limited fecal shedding (Cox et al., 1990; Saif and Wesley, 1999). Recently, however, fecal isolates of PRCV were detected with consistent, minor point mutations in the S gene compared to the nasal isolates from the same pig (Costantini et al., in press). Such observations suggest the presence of CoV quasispecies in the host with some strains more adapted to the intestine, a potential corollary for the fecal shedding of SARS CoV (Drosten et al., 2003; Ksiazek et al., 2003; Peiris et al., 2003a). Of further relevance to SARS was the displacement of the virulent TGEV infections by the widespread dissemination of PRCV in Europe and the disappearance of PRCV from swine herds in summer with its reemergence in older pigs in winter (Laude et al., 1993; Saif and Wesley, 1999). Group II Bovine CoV (BCoV): Models of Pneumoenteric Infections The shedding of SARS in feces of many patients and the occurrence of diarrhea in 10 to 27 percent of patients (Peiris et al., 2003a), but with a higher percentage (73 percent) in the Amoy Gardens, Hong Kong, outbreak (Chim et al., 2003) suggests that SARS may be pneumoenteric like BCoV. BCoV causes three distinct clinical syndromes in cattle: calf diarrhea; winter dysentery with hemorrhagic diarrhea in adults; and respiratory infections in cattle of various ages, including cattle with shipping fever (Table 3-1) (Clark, 1993; Lathrop et al., 2000a; Lathrop et al., 2000b; Saif and Heckert, 1990; Storz et al., 1996, 2000a, Tsunemitsu et al., 1995). Based on BCoV antibody seroprevalence, the virus is ubiquitous in cattle worldwide. All BCoV isolates from both enteric and respiratory infections are antigenically similar in virus neutralization (VN) tests, comprising a single serotype, but with two to three subtypes identified by VN or using monoclonal antibodies (MAbs) (Clark, 1993; Hasoksuz et al., 1999a; Hasoksuz et al., 1999b; Saif and Heckert, 1990; Tsunemitsu and Saif, 1995). In addition, genetic differences (point mutations but not deletions) have been detected in the S gene between enteric and respiratory isolates, including ones from the same animal (Chouljenko et al., 2001; Hasoksuz et al., 2002b). Nevertheless, inoculation of gnotobiotic or colostrum-deprived calves with calf diarrhea, winter dysentery, or respiratory BCoV strains led to both nasal and fecal CoV shedding and cross-protection against diarrhea after challenge with a calf diarrhea strain (Cho et al., 2001b; El-Kanawati et al., 1996). However, subclinical nasal and fecal virus shedding detected in calves challenged with the heterologous BCoV strains (Cho et al., 2001b; El-Kanawati et al., 1996) confirmed field studies showing that subclinically infected animals may be a reservoir for BCoV (Heckert et al., 1990, 1991). Cross-protection against BcoV-induced respiratory disease has not been evaluated.

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary Calf Diarrhea and Calf Respiratory BCoV Infections Calf diarrhea BCoV strains infect the epithelial cells of the distal small and large intestine and superficial and crypt enterocytes of the colon, leading to villous atrophy and crypt hyperplasia (Saif and Heckert, 1990; Van Kruiningen et al., 1987). One- to 4-week-old calves develop a severe, malabsorptive diarrhea, resulting in dehydration and often death. Concurrent fecal and nasal shedding often occur. BCoV are also implicated as a cause of mild respiratory disease (coughing, rhinitis) or pneumonia in 2- to 24-month-old calves and are detected in nasal secretions, lungs, and often the intestines (Clark, 1993; Heckert et al., 1990; Heckert et al., 1991; Saif and Heckert, 1990). In studies of calves from birth to 20 weeks of age, Heckert and colleagues (1990, 1991) documented both fecal and nasal shedding of BCoV, with repeated respiratory shedding episodes in the same animal with or without respiratory disease, and subsequent increases in their serum antibody titers consistent with these reinfections. These findings suggest a lack of long-term mucosal immunity in the upper respiratory tract after natural CoV infection, confirming similar observations for human respiratory CoV (Callow et al., 1990; Holmes, 2001). Winter Dysentery BCoV Infections Winter dysentery (WD) occurs in adult cattle during the winter months and is characterized by hemorrhagic diarrhea, frequent respiratory signs, and a marked reduction in milk production in dairy cattle (Saif, 1990; Saif and Heckert, 1990; Van Kruiningen et al., 1987). Intestinal lesions and BCoV-infected cells in the colonic crypts resemble those described for calf diarrhea. The BCoV isolates from WD outbreaks at least partially reproduced the disease in BCoV seropositive nonlactating cows (Tsunemitsu et al., 1999) and in BCoV seronegative lactating cows (Traven et al., 2001). Interestingly, in the later study, the older cattle were more severely affected than similarly exposed calves, mimicking the milder SARS cases seen in children versus adults (Kamps and Hoffmann, 2003a). Shipping Fever BCoV Infections More recent studies done in 1995 have implicated BCoV in association with respiratory disease (shipping fever) in feedlot cattle (Lathrop et al., 2000a, Storz et al., 1996). BCoV was isolated from nasal secretions and lungs of cattle with pneumonia and from feces (Hasoksuz et al., 1999a, 2002a; Storz et al., 2000a, b). In a subsequent study, a high percentage of feedlot cattle (45 percent) shed BCoV both nasally and in feces by ELISA (Cho et al., 2001a). Application of nested RT-PCR detected higher BCoV nasal and fecal shedding rates of 84 percent and 96 percent, respectively (Hasoksuz et al., 2002a).

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary Cofactors That Exacerbate CoV Infections, Disease, or Shedding Underlying disease or respiratory coinfections, dose and route of infection, and immunosuppression (corticosteroids) are all potential cofactors related to the severity of SARS. These cofactors can also exacerbate the severity of BCoV, TGEV, or PRCV infections. In addition, these cofactors may play a role in the superspreader cases seen in the SARS epidemic (Kamps and Hoffmann, 2003b) by enhancing virus transmission. Impact of Respiratory Co-Infections on CoV Infections, Disease, and Shedding Shipping fever is recognized as a multifactorial, polymicrobial respiratory disease complex in young adult feedlot cattle with several factors exacerbating respiratory disease, including BCoV infections (Lathrop et al., 2000a,b; Storz et al., 1996; Storz et al., 2000a; Storz et al., 2000b). Shipping fever can be precipitated by several viruses, alone or in combination, including viruses similar to common human respiratory viruses (BCoV, bovine resiratory syncytial virus, parainfluenza-3 virus), bovine herpesvirus, and viruses capable of mediating immunosuppression (bovine viral diarrhea virus, etc.). The shipping of cattle long distances to feedlots and the commingling of cattle from multiple farms creates physical stresses that overwhelm the animal’s defense mechanisms and provides close contact for exposure to new pathogens or strains not previously encountered. Such factors are analogous to the physical stress of long airplane trips with close contact among individuals from diverse regions of the world, both of which may play a role in enhancing an individual’s susceptibility to SARS. For shipping fever, various predisposing factors (viruses, stress) allow commensal bacteria of the nasal cavity (Mannheimia haemolytica, Pasteurella spp., Mycoplasma spp., etc.) to infect the lungs, leading to fatal fibrinous pneumonia (Lathrop et al., 2000a,b; Storz et al., 1996, 2000a,b). Like PRCV or SARS infections, it is possible that antibiotic treatment of such individuals with massive release of bacterial lipopolysaccharides (LPS) could precipitate induction of proinflammatory cytokines, which may further enhance lung damage. For example, Van Reeth et al. (2000) showed that pigs infected with PRCV followed by a subclinical dose of E. coli LPS within 24 hours developed enhanced fever and more severe respiratory disease compared to each agent alone. They concluded that the effects were likely mediated by the significantly enhanced levels of proinflammatory cytokines induced by the bacterial LPS. Thus there is a need to examine both LPS and lung cytokine levels in SARS patients as possible mediators of the severity of SARS. Bacteria (Chlamydia spp.) have been isolated from SARS patients, but their role in enhancing the severity of SARS is undefined (Poutanen et al., 2003). Interactions between PRCV and other respiratory viruses may also parallel the potential for concurrent or preexisting respiratory viral infections to interact with SARS CoV (such as metapneumoviruses, influenza, reoviruses, respiratory

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary syncytial virus [RSV], OC43 or 229E CoV). Hayes (2000) showed that sequential dual infections of pigs with the arterivirus (order Nidovirales, like CoV) PRRSV followed in 10 days by PRCV significantly enhanced lung lesions and reduced weight gains compared to each virus alone. The dual infections also led to more pigs shedding PRCV nasally for a prolonged period and surprisingly, to fecal shedding of PRCV. The lung lesions observed resembled those in SARS victims (Nicholls et al., 2003). In another study, Van Reeth and Pensaert (1994) inoculated pigs with PRCV followed in 2 to 3 days by swine influenza A virus (SIV). They found that SIV lung titers were reduced in the dually compared to the singly infected pigs, but paradoxically the lung lesions were more severe in the dually infected pigs. They postulated that the high levels of IFN-alpha induced by PRCV may mediate interference with SIV replication but may also contribute to the enhanced lung lesions. Such studies are highly relevant to potential dual infections with SARS CoV and influenza virus and potential treatments of SARS patients with IFN alpha. Impact of Route (Aerosols) and Dose on CoV Infections Experimental inoculation of pigs with PRCV strains showed that administration of PRCV by aerosol compared to the oronasal route, or in higher doses, resulted in higher virus titers shed and longer shedding (Van Cott et al., 1993). In other studies, high PRCV doses induced more severe respiratory disease. Pigs given 108.5 TCID50 of PRCV had more severe pneumonia and deaths than pigs exposed by contact (Jabrane et al., 1994), and higher intranasal doses of another PRCV strain (AR310) induced moderate respiratory disease whereas lower doses produced subclinical infections (Halbur et al., 1993). By analogy, hospital procedures that could potentially generate aerosols or exposure to higher initial doses of SARS CoV may enhance SARS transmission or lead to enhanced respiratory disease (Kamps and Hoffman, 2003a,b). Impact of Treatment with Corticosteroids on CoV Infections of Animals Corticosteroids are known to induce immunosuppression and reduce the numbers of CD4 and CD8 T cells and certain cytokine levels (Giomarelli et al., 2003). Many hospitalized SARS patients were treated with steroids to reduce lung inflammation, but there are no data to assess the outcome of this treatment on virus shedding or respiratory disease. A recrudescence of BCoV fecal shedding was observed in one of four winter dysentery BCoV infected cows treated with dexamethasone (Tsunemitsu et al., 1999). Similarly, treatment of older pigs with dexamethasone prior to TGEV challenge led to profuse diarrhea and reduced lymphoproliferative responses in the treated pigs (Shimizu and Shimizu, 1979). These data raise issues for corticosteroid treatment of SARS patients re-

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary lated to possible transient immunosuppression leading to enhanced respiratory disease or increased and prolonged CoV shedding (superspreaders). Alternatively, corticosteroid treatment may be beneficial in reducing proinflammatory cytokines if found to play a major role in lung immunopathology (Giomarelli et al., 2003). Group I Feline CoV (FCoV): Model for Systemic and Persistent CoV Infection The spectrum of disease evident for FCoV (feline infectious peritonitis virus) exemplifies the impact of viral persistence and macrophage tropism on CoV disease progression and severity. Historically, two types of FCoVs have been recognized: feline enteric CoV (FECoV) and FIPV. Current information suggests that the FECoV that causes acute enteric infections in cats establishes persistent infections in some cats, evolving into the systemic virulent FIPV in 5 to 10 percent of cats (deGroot and Horzinek, 1995; Herrewegh et al., 1997; Vennema et al., 1995). The relevance of this model to SARS is whether similar persistent CoV infections might occur in some patients, leading to the emergence of macrophage-tropic mutants of enhanced virulence and precipitating systemic or immune-mediated disease. The initial site of FCoV replication is in the pharyngeal, respiratory, or intestinal epithelial cells (deGroot and Horzinek, 1995; Olsen, 1993), and clinical signs include anorexia, lethargy, and mild diarrhea. The prolonged incubation period for FIPV and its reactivation upon exposure to immunosuppressive viruses or corticosteroids suggested that FCoVs could cause chronic enteric infections in cats (deGroot and Horzinek, 1995; Olsen, 1993). Recent reports of chronic fecal shedding and persistence of FCoV mRNA or antigen in infected cats confirm this scenario (Herrewegh et al., 1997). A key pathogenetic event for development of FIPV is productive infection of macrophages followed by cell-associated viremia and systemic dissemination of virus (deGroot and Horzinek, 1995; Olsen, 1993). Stress (immunosuppressive infections, transport to new environments, cat density) leading to immune suppression may trigger FIP in chronically infected cats, similar to its role in shipping fever CoV infections of cattle. Two major forms of FIP occur: (1) effusive, with a fulminant course and death within weeks to months, and (2) noneffusive, progressing more slowly (deGroot and Horzinek, 1995; Olsen, 1993). The effusive form is characterized by fibrin-rich fluid accumulation in peritoneal, pleural, pericardial, or renal spaces, with fever, anorexia, and weight loss. Noneffusive FIP involves pyogranulomatous lesions with thrombosis, central nervous system, or ocular involvement. Fulminant FIP with accelerated early deaths appears to be immune mediated in FCoV seropositive cats. At least two mechanisms implicating IgG antibodies to FCoV S protein in FIP immunopathogenesis have been described. In the first, circulating immune complexes (IC) with C’ depletion in sera and IC in lesions are evident in cats with terminal FIP (deGroot and Horzinek, 1995). In the second, antibody dependent enhancement (ADE) of FCoV infection of macrophages in vitro is mediated by neutralizing IgG MAbs to the S protein of

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary FIGURE 3-2 Phylogenetic analysis of the nucleotide acid sequence of the spike gene of SCoV-like viruses. Nucleotide sequences of representative SCoV Sgenes (Sgene coding region 21477 to 25244, 3768 bp) were analyzed. The phylogenetic tree was constructed by the neighbor-joining method with bootstrap analysis (1000 replicates) using MEGA 2 (Kumar et al., 2001). Number at the nodes indicates bootstrap values in percentage. The scale bar shows genetic distance estimated using Kimura’s two-parameter substitution model (Kimura, 1980). In addition to viruses sequenced in the present study, the other sequences used in the analysis could be found in GenBank with accession number: from AY304490 to AY304495, AY278741, AY278554, AY278491, AY274119, and AY278489. Tor-2, HKU-39848, and Urbani) differed by only 14 nucleotides (nt). Nevertheless, animal virus SZ13 (raccoon dog) and SZ16 (palm civet) were genetically almost identical, and transmission or contamination from one host to the other within the market cannot be excluded. When the full genome of the animal (n = 2) and human (n = 5, see above) virus groups were compared, the most striking difference was that these human viruses have a 29-nt deletion (5'-CCTACTGGTTACCAACCTGAATGGAATAT-3', residue 27869 to 27897) that is 246 nt upstream of the start codon of the N gene (see Figure 3-3). Of human SCoV sequences currently available in GenBank, there was only one (GZ01) with this additional 29-nt sequence. In addition to that, there were 43 to 57 nucleotide differences observed over the rest of the genome. Most of these differences were found in the S gene coding region. The existence of the additional 29-nt sequence in the animal viruses results in demolishing the open reading frames (ORFs) 10 and 11 (Marra et al., 2003) and merging these two ORFs into a new ORF encoding a putative protein of 122

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary amino acids (see Figure 3-3). This putative peptide has a high homology to the putative proteins encoded by ORF10 and ORF11. Because ORF11 does not have a typical transcription regulatory sequence for SCoV (Marra et al., 2003), the putative ORF11 reported by others may just be the direct result of the deletion of the 29-nt sequence. BLAST search of this peptide yields no significant match to any other known peptide. Further investigation is required to elucidate the biological significance of this finding. When the S-gene sequences of the four animal viruses were compared with 11 human SCoV viruses, 38 nucleotide polymorphisms were noted, and 26 of them were nonsynonymous changes (see Table 3-4). The S genes among the four FIGURE 3-3 A 29-nt deletion in the human SCoV genome. (A) Genetic organization of SCoV-like viruses found in humans and animals. ORFs 1a and 1b, encoding the nonstructural polyproteins, and those encoding the S, E, M, and N structural proteins are indicated (green boxes). (B) Expanded view of the SCoV genomic sequence (27700 nt to 28200 nt, based on AY278554 numbering). ORFs for putative proteins and for N in human isolates are indicated as brown and green boxes, respectively (Marra et al., 2003). An extra 29-nt sequence is present downstream of the nucleotide of 27868 of the animal SCoV (based on AY278554 numbering). The presence of this 29-nt sequence in animals isolates results in fusing the ORFs 10 and 11 (top) into a new ORF (bottom; ORF10', light blue box). (C) Protein sequence alignment of ORF10 and 11 from human isolates and ORF 10' from animal isolates.

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary TABLE 3-4 Nucleotide Sequence Variation of the S Gene of Animal and Human SCoV Nucleotide residue   2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2   1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 3 3 3 3 3 3 3 3 3 3 4 4 4 4 4 4 5   6 6 6 6 7 7 1 1 1 2 2 2 4 5 5 5 6 9 9 9 0 1 2 2 4 5 6 7 7 8 8 1 1 3 5 8 9 0   2 9 9 9 0 0 3 5 9 0 0 5 0 0 0 5 4 1 3 7 0 4 0 9 7 7 1 0 3 0 5 5 9 6 5 5 6 1 Virus 2 0 1 2 0 6 0 7 2 5 7 8 7 2 7 5 6 3 6 8 3 8 5 5 0 8 7 3 7 8 6 6 7 8 1 7 3 2 SZ3 C A T T C A T A T T C A G G G C A A G T G T T C C T C G T G C G C G C T G T SZ16 C A T T C A T A T C C A G G G C G A G T G A T C C T C G T G C G C T C T G T SZ1 C A T T C A T A T T C A G G G C G A G T T A T C C T T G T G C G T T T T G T SZ13 C A T T C A T A T T C A G G G C G A G T G A T C C T C G T G C G C T C T G T GZ01 C A T T C A C C T C C C A G G T G T C A G T T T T C C A C G T A C G C T A T GZ43 C – – – G A T C T C C C A G G T G T C T G T T T C C C A C G C A C G C T A C GZ60 C – – – G A T C T C C C A G G T G T C T G T T T C C C A C G C A C G C T A C GZ50 T A T T C A T C C C C C G A A T G T C T G T T T T C C A C G C A C G T T A T CUHK-W1 C A T T C A T C C C C C G A A T G T C T G T T T T C C A C T C A C G T T A T HKU-36871 C A T T C A T C C C C C G A A T G T C T G T T T T C C A C T C A C G T T A T HKU-39848 C A T T C G T C C C T C G A A T G T C T G T T T T C C A C T C A C G T T A T HKU-66078 C A T T C G T C C C T C G A A T G T C T G T T T T C C A C T C A C G T T A T HKU-65806 C A T T C G T C C C T C G A A T G T C T G T T T T C C A C T C A C G T T A T Urbani C A T T C G T C C C T C G A A T G T C T G T T T T C C A C T C A C G T C A T Tor2 C A T T C G T C C C T C G A A T G T C T G T G T T C C A C T C A C G T T A T NOTE: The nucleotide residues are based on AY278554 numbering. Nonsilent mutations are highlighted in bold. Dash indicates a nu cleotide deletion.

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary animal viruses had eight nucleotide differences, whereas there were 20 nucleotide differences among 11 human viruses. Thus, the animal viruses, although isolated from one market, are no less divergent than the human viruses isolated from Hong Kong, Guangdong, Canada, and Vietnam. However, whereas 14 (70 percent) of the 20 polymorphisms among the human viruses were nonsynonymous mutations, only two (25 percent) of the eight nucleotide substitutions within the animal viruses were. An amino acid deletion (nucleotide positions 21690 to 21692) was observed in two of the human viruses (GZ43 and GZ60). Of the 38 polymorphisms, there were 11 consistent nucleotide signatures that appeared to distinguish animal and human viruses. The observation that the human and animal viruses are phylogenetically distinct (see Figure 3-2) makes it highly unlikely that the SCoV-like viruses isolated in these wild animals is due to the transmission of SCoV from human to animals. Our findings suggest that the markets provide a venue for the animal SCoV-like viruses to amplify and to be transmitted to new hosts, including humans, and this is critically important from the point of view of public health. However, it is not clear whether any one or more of these animals are the natural reservoir in the wild. It is conceivable that civets, raccoon dog, and ferret badgers were all infected from another, as yet unknown, animal source, which is in fact the true reservoir in nature. However, because of the culinary practices of southern China, these market animals may be intermediate hosts that increase the opportunity for transmission of infection to humans. Further extensive surveillance on animals will help to better understand the animal reservoir in nature and the interspecies transmission events that led to the origin of the SARS outbreak. REFERENCES Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R. 2003. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science 300(5626):1763-7. Anonymous. 2003. Severe acute respiratory syndrome (SARS). Weekly Epidemiological Record78:81-3. Ballesteros ML, Sanchez CM, Enjuanes L. 1997. Two amino acid changes at the N-terminus of transmissible gastroenteritis coronavirus spike protein result in the loss of enteric tropism. Virology 227(2):378-88. Baric RS, Fu K, Chen W, Yount B. 1995. High recombination and mutation rates in mouse hepatitis virus suggest that coronaviruses may be potentially important emerging viruses. Advances in Experimental Medicine and Biology 380:571-6. Baric RS, Sullivan E, Hensley L, Yount B, Chen W. 1999. Persistent infection promotes cross-species transmissibility of mouse hepatitis virus. Journal of Virology 73(1):638-49. Baric RS, Yount B, Hensley L, Peel SA, Chen W. 1997. Episodic evolution mediates interspecies transfer of a murine coronavirus. Journal of Virology 71(3):1946-55. Bonilla PJ, Gorbalenya AE, Weiss SR. 1994. Mouse hepatitis virus strain A59 RNA polymerase gene ORF 1a: heterogeneity among MHV strains. Virology 198(2):736-40. Bost AG, Carnahan RH, Lu XT, Denison MR. 2000. Four proteins processed from the replicase gene polyprotein of mouse hepatitis virus colocalize in the cell periphery and adjacent to sites of virion assembly. Journal of Virology 74(7):3379-87.

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary Bost AG, Prentice E, Denison MR. 2001. Mouse hepatitis virus replicase protein complexes are translocated to sites of M protein accumulation in the ERGIC at late times of infection. Virology 285(1):21-9. Brian DA, Hogue BG, Kienzle TE. 1995. The Coronavirus Hemagluttinin Esterase Clycoprotein. In: Siddell SG, ed., The Coronaviridae. New York: Plenum Press. Pp. 165-79. Brockway SM, Clay CT, Lu XT, Denison MR. 2003. Characterization of the expression, intracellular localization, and replication complex association of the putative mouse hepatitis virus RNA-dependent RNA polymerase. Journal of Virology 77(19):10515-27. Callow KA, Parry HF, Sergeant M, Tyrrell DA. 1990. The time course of the immune response to experimental coronavirus infection of man. Epidemiology and Infection 105:435-46. Campanacci V, Egloff MP, Longhi S, Ferron F, Rancurel C, Salomoni A, Durousseau C, Tocque F, Bremond N, Dobbe JC, Snijder EJ, Canard B, Cambillau C. 2003. Structural genomics of the SARS coronavirus: cloning, expression, crystallization and preliminary crystallographic study of the Nsp9 protein. Acta Crystallographica. Section D, Biological Crystallography 59(Pt 9):1628-31. Casais R, Thiel V, Siddell SG, Cavanagh D, Britton P. 2001. Reverse genetics system for the avian coronavirus infectious bronchitis virus. Journal of Virology 75(24):12359-69. CDC. 2003. Update: outbreak of severe acute respiratory syndrome-Worldwide, 2003. MMWR52:241-8. Chen W, Baric RS. 1995. Evolution and persistence mechanisms of mouse hepatitis virus. Advances in Experimental Medicine & Biology 380:63-71. Chen W, Baric RS. 1996. Molecular anatomy of mouse hepatitis virus persistence: coevolution of increased host cell resistance and virus virulence. Journal of Virology 70(6):3947-60. Chim SS, Tsui SK, Chan KC, Au TC, Hung EC, Tong YK, Chiu RW, Ng EK, Chan PK, Chu CM, Sung JJ, Tam JS, Fung KP, Waye MM, Lee CY, Yuen KY, Lo YM. 2003. Genomic characterisation of the severe acute respiratory syndrome coronavirus of Amoy Gardens outbreak in Hong Kong. Lancet 362(9398):1807-8. Cho KO, Hasoksuz M, Nielsen PR, Chang KO, Lathrop S, Saif LJ. 2001. Cross-protection studies between respiratory and calf diarrhea and winter dysentery coronavirus strains in calves and Rt-Pcr and nested Pcr for their detection. Archives of Virology 146(12):2401-19. Cho KO, Hoet AE, Loerch SC, Wittum TE, Saif LJ. 2001. Evaluation of concurrent shedding of bovine coronavirus via the respiratory tract and enteric route in feedlot cattle. American Journal of Veterinary Research 62(9):1436-41. Chouljenko VN, Lin XQ, Storz J, Kousoulas KG, Gorbalenya AE. 2001. Comparison of genomic and predicted amino acid sequences of respiratory and enteric bovine coronaviruses isolated from the same animal with fatal shipping pneumonia. Journal of General Virology 82(12):2927-2933. Clark MA. 1993. Bovine coronavirus. British Veterinary Journal. 149(1):51-70. Cook J, Mockett APA. 1995. Epidemiology of infectious bronchitis virus. In: Siddell SG, ed., The Coronaviridae. New York: Plenum Press. Pp. 317-35. Costantini V, Lewis P, Alsop J, Templeton C, Saif LJ. In press. Respiratory and enteric shedding of porcine respiratory coronavirus (PRCV) in sentinel weaned pigs and sequence of the partial S gene of the PRCV isolates. Archives of Virology. Cox E, Hooyberghs J, Pensaert MB. 1990. Sites of replication of a porcine respiratory coronavirus related to transmissible gastroenteritis virus. Research in Veterinary Science 48(2):165-9. deGroot RJ, Horzinek MC. 1995. Feline infectious peritonitis. In: Siddell SG, ed., The Coronaviridae. New York: Plenum Press. Pp. 293-315. de Haan CA, Masters PS, Shen X, Weiss S, Rottier PJ. 2002. The group-specific murine coronavirus genes are not essential, but their deletion, by reverse genetics, is attenuating in the natural host. Virology 296(1):177-89. de Jong JC, Claas EC, Osterhaus AD, Webster RG, Lim WL. 1997. A pandemic warning? Nature 389:544.

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary de Vries AAF, Horzinek MC, Rottier PJM, de Groot RJ. 1997. The genome organization of the nidovirales: similarities and differences between arteri-, toro-, and coronaviruses. Seminars in Virology 8(1):33-47. Denison MR, Spaan WJ, van der Meer Y, Gibson CA, Sims AC, Prentice E, Lu XT. 1999. The putative helicase of the coronavirus mouse hepatitis virus is processed from the replicase gene polyprotein and localizes in complexes that are active in viral RNA synthesis. Journal of Virology 73(8):6862-71. Domingo E, Holland JJ. 1997. RNA virus mutations and fitness for survival. Annual Review of Microbiology 51:151-78. Drosten C, Gunther S, Preiser W, van der Werf S, Brodt HR, Becker S, Rabenau H, Panning M, Kolesnikova L, Fouchier RA, Berger A, Burguiere AM, Cinatl J, Eickmann M, Escriou N, Grywna K, Kramme S, Manuguerra JC, Muller S, Rickerts V, Sturmer M, Vieth S, Klenk HD, Osterhaus AD, Schmitz H, Doerr HW. 2003. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. New England Journal of Medicine 348(20):1967-76. Duarte M, Tobler K, Bridgen A, Rasschaert D, Ackermann M, Laude H. 1994. Sequence analysis of the porcine epidemic diarrhea virus genome between the nucleocapsid and spike protein genes reveals a polymorphic ORF. Virology 198(1):466-476. Dveksler GS, Gagneten SE, Scanga CA, Cardellichio CB, Holmes KV. 1996. Expression of the recombinant anchorless N-terminal domain of mouse hepatitis virus (MHV) receptor makes hamster of human cells susceptible to MHV infection. Journal of Virology 70(6):4142-5. Dveksler GS, Pensiero MN, Cardellichio CB, Williams RK, Jiang GS, Holmes KV, Dieffenbach CW. 1991. Cloning of the mouse hepatitis virus (MHV) receptor: expression in human and hamster cell lines confers susceptibility to MHV. Journal of Virology 65(12):6881-91. El-Kanawati ZR, Tsunemitsu H, Smith DR, Saif LJ. 1996. Infection and cross-protection studies of winter dysentery and calf diarrhea bovine coronavirus strains in colostrum-deprived and gnotobiotic calves. American Journal of Veterinary Research 57(1):48-53. Enjuanes L, Smerdou C, Castilla J, Anton IM, Torres JM, Sola I, Golvano J, Sanchez JM, Pintado B. 1995. Development of protection against coronavirus induced diseases: a review. Advances in Experimental Medicine and Biology 380:197-211. Erles K, Toomey C, Brooks HW, Brownlie J. 2003. Detection of a group 2 coronavirus in dogs with canine infectious respiratory disease. Virology 310(2):216-23. Fouchier RA, Kuiken T, Schutten M, van Amerongen G, van Doornum GJ, van den Hoogen BG, Peiris M, Lim W, Stohr K, Osterhaus AD. 2003. Aetiology: Koch’s Postulates Fulfilled for Sars Virus. Nature 423(6937):240. Gallagher TM, Escarmis C, Buchmeier MJ. 1991. Alteration of the pH dependence of coronavirus-induced cell fusion: effect of mutations in the spike glycoprotein. Journal of Virology 65(4):1916-28. Gonzalez JM, Almazan F, Penzes Z, Calvo E, Enjuanes L. 2001. Cloning of a transmissible gastroenteritis coronavirus full-length cDNA. Advances in Experimental Medicine and Biology 494:533-6. Gosert R, Kanjanahaluethai A, Egger D, Bienz K, Baker SC. 2002. RNA replication of mouse hepatitis virus takes place at double-membrane vesicles. Journal of Virology 76(8):3697-708. Guan Y, Peiris JM, Lipatov AS, Ellis TM, Dyrting KC, Krauss S, Zhang LJ, Webster RG, Shortridge KF. 2002. Emergence of multiple genotypes of H5N1 avian influenza viruses in Hong Kong SAR. Proceedings of the National Academy of Sciences 99:8950-5. Guan Y, Zheng BJ, He YQ, Liu XL, Zhuang ZX, Cheung CLLSW, Li PH, Zhang LJ, Guan YJ, Butt KM, Wong KLCKW, Lim W, Shortridge KF, Yuen KY, Peiris JSM, Poon LLM. 2003. Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science 302(5643):276-8. Guangdong Public Health Office. January 21, 2003. Summary report of investigating an atypical pneumonia outbreak in Zhongshan, Document No 2.

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary Haijema BJ, Volders H, Rottier PJM. 2003. Switching species tropism: an effective way to manipulate the feline coronavirus genome. Journal of Virology 77(8):4528-38. Hayes JR. 2000. Evaluation of dual infection of nursery pigs with U.S. strains of porcine reproductive and respiratory syndrome virus and porcine respiratory coronavirus. Master’s Thesis, Food Animal Health Research Program, OARDC/The Ohio State University. Herrewegh AA, Mahler M, Hedrich HJ, Haagmans BL, Egberink HF, Horzinek MC, Rottier PJ, de Groot RJ. 1997. Persistence and evolution of feline coronavirus in a closed cat-breeding colony. Virology 234(2):349-63. Heusipp G, Harms U, Siddell SG, Ziebuhr J. 1997. Identification of an ATPase activity associated with a 71-kilodalton polypeptide encoded in gene 1 of the human coronavirus 229E. Journal of Virology 71(7):5631-4. Hoffmann C, Kamps BS. 2003. Clinical presentation and diagnosis. In: Kamps BS, Hoffmann C, eds., SARS Reference. 3rd ed. Pp. 124-43. [Online] Available: http://www.SARSreference.com. Hoffmann M and Wyler R. 1988. Propagation of the virus of porcine epidemic diarrhea in cell culture. Journal of Clinical Microbiology (26):2235-9. Holland JJ, de la Torre JC, Clarke DK, Duarte E. 1991. Quantitation of relative fitness and great adaptability of clonal populations of RNA viruses. Journal of Virology 65(6):1960-2967. Holmes KV. 2001. Coronaviruses. In: Knipe DM, Howley PM, eds. Field Virology, 4th ed. Philadelphia: Lippincott Williams and Wilkins. Pp. 1187-203. Holmes KV. 2003. SARS coronavirus: a new challenge for prevention and therapy. Journal of Clinical Investigation 111(11):1605-9. Holmes KV, Lai MMC. 1996. Coronaviridae: the viruses and their replication. In: Fields BN, Knipe DM, Howley PM, eds., Virology. Vol. 1. 3rd ed. Philadelphia: Lippincott-Raven. Pp. 1075-93. Ismail MM, Cho KO, Hasoksuz M, Saif LJ, Saif YM. 2001. Antigenic and genomic relatedness of turkey-origin coronaviruses, bovine coronaviruses, and infectious bronchitis virus of chickens. Avian Diseases 45(4):978-84. Ismail MM, Cho KO, Ward LA, Saif LJ, Saif YM. 2001. Experimental bovine coronavirus in turkey poults and young chickens. Avian Diseases 45(1):157-63. Kamps BS, Hoffmann C. 2003a. Pediatric SARS. In: Kamps BS, Hoffmann C, eds., SARS Reference. 3rd ed. Pp. 49-60. [Online] Available: http://www.SARSreference.com. Kamps BS, Hoffmann C. 2003b. Transmission. In: Kamps BS, Hoffmann C, eds., SARS Reference. 3rd ed. Pp. 49-60. [Online] Available: http://www.SARSreference.com. Kim JC, Spence RA, Currier PF, Lu X, Denison MR. 1995. Coronavirus protein processing and RNA synthesis is inhibited by the cysteine proteinase inhibitor E64d. Virology 208(1):1-8. Kimura M. 1980. A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. Journal of Molecular Evolution 16(2):111-20. Klumperman J, Locker JK, Meijer A, Horzinek MC, Geuze HJ, Rottier PJ. 1994. Coronavirus M proteins accumulate in the Golgi complex beyond the site of virion budding. Journal of Virology 68(10):6523-34. Krijnse-Locker J, Ericsson M, Rottier PJ, Griffiths G. 1994. Characterization of the budding compartment of mouse hepatitis virus: evidence that transport from the RER to the Golgi complex requires only one vesicular transport step. Journal of Cell Biology 124(1-2):55-70. Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, Emery S, Tong S, Urbani C, Comer JA, Lim W, Rollin PE, Dowell SF, Ling AE, Humphrey CD, Shieh WJ, Guarner J, Paddock CD, Rota P, Fields B, DeRisi J, Yang JY, Cox N, Hughes JM, LeDuc JW, Bellini WJ, Anderson LJ, SARS Working Group. 2003. A novel coronavirus associated with severe acute respiratory syndrome. New England Journal of Medicine 348(20):1953-66. Kumar S, Tarnura K, Jakobsen IB, Nei M. 2001. MEGA2: molecular evolutionary genetics analysis software. Bioinformatics 17:1244-5. Kuo L, Godeke GJ, Raamsman MJ, Masters PS, Rottier PJ. 2000. Retargeting of coronavirus by substitution of the spike glycoprotein ectodomain: crossing the host cell species barrier. Journal of Virology 74(3):1393-406.

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary Lai MM, Cavanagh D. 1997. The molecular biology of coronaviruses. Advances in Virus Research 48:1-100. Laude H, Van Reeth K, Pensaert M. 1993. Porcine respiratory coronavirus: molecular features and virus-host interactions. Veterinary Research 24(2):125-50. Lee N, Hui D, Wu A, Chan P, Cameron P, Joynt GM, Ahuja A, Yung MY, Leung CB, To K, Lui SF, Szeto CC, Chung S, Sung JJ. 2003. A major outbreak of severe acute respiratory syndrome in Hong Kong. New England Journal of Medicine 348:1986-94. Lee HJ, Shieh CK, Gorbalenya AE, Koonin EV, La Monica N, Tuler J, Bagdzhadzhyan A, Lai MM. 1991. The complete sequence (22 kilobases) of murine coronavirus gene 1 encoding the putative proteases and RNA polymerase. Virology 180(2):567-82. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. 2003. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426(6965):450-4. Lu Y, Lu X, Denison MR. 1995. Identification and characterization of a serine-like proteinase of the murine coronavirus MHV-A59. Journal of Virology 69(6):3554-9. Majhdi F, Minocha HC, Kapil S. 1997. Isolation and characterization of a coronavirus from elk calves with diarrhea. Journal of Clinical Microbiology 35(11):2937-42. Marra MA, Jones SJ, Astell CR, Holt RA, Brooks-Wilson A, Butterfield YS, Khattra J, Asano JK, Barber SA, Chan SY, Cloutier A, Coughlin SM, Freeman D, Girn N, Griffith OL, Leach SR, Mayo M, McDonald H, Montgomery SB, Pandoh PK, Petrescu AS, Robertson AG, Schein JE, Siddiqui A, Smailus DE, Stott JM, Yang GS, Plummer F, Andonov A, Artsob H, Bastien N, Bernard K, Booth TF, Bowness D, Czub M, Drebot M, Fernando L, Flick R, Garbutt M, Gray M, Grolla A, Jones S, Feldmann H, Meyers A, Kabani A, Li Y, Normand S, Stroher U, Tipples GA, Tyler S, Vogrig R, Ward D, Watson B, Brunham RC, Krajden M, Petric M, Skowronski DM, Upton C, Roper RL. 2003. The genome sequence of the SARS-associated coronavirus. Science 300(5624):1399-404. Masters PS, Koetzner CA, Kerr CA, Heo Y. 1994. Optimization of targeted RNA recombination and mapping of a novel nucleocapsid gene mutation in the coronavirus mouse hepatitis virus. Journal of Virology 68(1):328-37. Navas S, Seo SH, Chua MM, Das Sarma J, Hingley ST, Lavi E, Weiss SR. 2001. Role of the spike protein in murine coronavirus induced hepatitis: an in vivo study using targeted RNA recombination. Advances in Experimental Medicine and Biology 494:139-44. Navas S, Weiss SR. 2003. Murine coronavirus-induced hepatitis: JHM genetic background eliminates A59 spike-determined hepatotropism. Journal of Virology 77(8):4972-8. Opstelten DJ, Raamsman MJ, Wolfs K, Horzinek MC, Rottier PJ. 1995. Envelope glycoprotein interactions in coronavirus assembly. Journal of Cell Biology 131(2):339-49. Ortego J, Sola I, Almazan F, Ceriani JE, Riquelme C, Balasch M, Plana J, Enjuanes L. 2003. Transmissible gastroenteritis coronavirus gene 7 is not essential but influences in vivo virus replication and virulence. Virology 308(1):13-22. Peiris JS, Lai ST, Poon LL, Guan Y, Yam LY, Lim W, Nicholls J, Yee WK, Yan WW, Cheung MT, Cheng VC, Chan KH, Tsang DN, Yung RW, Ng TK, Yuen KY, SARS study group. 2003a. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 361(9366):1319-25. Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF, Poon LL, Law KI, Tang BS, Hon TY, Chan CS, Chan KH, Ng JS, Zheng BJ, Ng WL, Lai RW, Guan Y, Yuen KY, HKU/UCH SARS Study Group. 2003b. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet 361(9371):1767-72. Peng GW, He JF, Lin JY, Zhou DH, Yu DW, Liang WJ, Li LH, Guo RN, Luo HM, Xu RH. 2003. Epidemiological study on severe acute respiratory syndrome in Guangdong province. Chinese Journal of Epidemiology 24:350-2. Pensaert MB. 1999. Porcine epidemic diarrhea. In: Straw BE, D'Allaire S, Mengeling WL, Taylor D. eds., Diseases of Swine. 8th ed. Ames, IA: Iowa State Press. Pp. 179-85.

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary Perlman S, Ries D, Bolger E, Chang LJ, Stoltzfus CM. 1986. MHV nucleocapsid synthesis in the presence of cycloheximide and accumulation of negative strand MHV RNA. Virus Research 6(3):261-72. Poutanen SM, Low DE, Henry B, Finkelstein S, Rose D, Green K, Tellier R, Draker R, Adachi D, Ayers M, Chan AK, Skowronski DM, Salit I, Simor AE, Slutsky AS, Doyle PW, Krajden M, Petric M, Brunham RC, McGeer AJ, National Microbiology Laboratory Canada, Canadian Severe Acute Respiratory Syndrome Study Team. 2003. Identification of severe acute respiratory syndrome in Canada. New England Journal of Medicine 348(20):1995-2005. Prentice E, Denison MR. 2001. The cell biology of coronavirus infection. In: Lavi E, Weiss SR, Hingley S, eds., The Nidoviruses. Philadelphia, PA: Plenum. Rao PV, Gallagher TM. 1998. Mouse hepatitis virus receptor levels influence virus-induced cytopathology. Advances in Experimental Medicine and Biology 440:549-55. Rota PA, Oberste MS, Monroe SS, Nix WA, Campagnoli R, Icenogle JP, Penaranda S, Bankamp B, Maher K, Chen MH, Tong S, Tamin A, Lowe L, Frace M, DeRisi JL, Chen Q, Wang D, Erdman DD, Peret TC, Burns C, Ksiazek TG, Rollin PE, Sanchez A, Liffick S, Holloway B, Limor J, McCaustland K, Olsen-Rasmussen M, Fouchier R, Gunther S, Osterhaus AD, Drosten C, Pallansch MA, Anderson LJ, Bellini WJ. 2003. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 300(5624):1394-9. Rottier PJ, Rose JK. 1987. Coronavirus E1 glycoprotein expressed from cloned cDNA localizes in the Golgi region. Journal of Virology 61(6):2042-5. Saif LJ. In press. Comparative biology of coronaviruses: Lessons for SARS. In: Peiris M, ed., SARS: The First New Plague of the 21st Century. Oxford, UK: Blackwell. Saif L, Wesley R. 1999. Transmissible gastroenteritis virus. In: Straw BE, D'Allaire S, Mengeling WL, Taylor D. eds., Diseases of Swine. 8th ed. Ames, IA: Iowa State University Press. Saif LJ, Heckert RA. 1990. Enteric coronaviruses. In: Saif LJ, Thiel KW. Viral Diarrheas of Man and Animals. Boca Raton, FL: CRC Press. Pp. 185-252. Salanueva IJ, Carrascosa JL, Risco C. 1999. Structural maturation of the transmissible gastroenteritis coronavirus. Journal of Virology 73(10):7952-64. Sanchez CM, Izeta A, Sanchez-Morgado JM, Alonso S, Sola I, Balasch M, Plana-Duran J, Enjuanes L. 1999. Targeted recombination demonstrates that the spike gene of transmissible gastroenteritis coronavirus is a determinant of its enteric tropism and virulence. Journal of Virology 73 (9):7607-18. Sarma JD, Scheen E, Seo SH, Koval M, Weiss SR. 2002. Enhanced green fluorescent protein expression may be used to monitor murine coronavirus spread in vitro and in the mouse central nervous system. Journal of Neurovirology 8(5):381-91. Sawicki SG, Sawicki DL. 1986. Coronavirus minus-strand RNA synthesis and effect of cycloheximide on coronavirus RNA synthesis. Journal of Virology 57(1):328-34. Sawicki SG, Sawicki DL. 1998. A new model for coronavirus transcription. Advances in Experimental Medicine and Biology 440:215-9. Shi ST, Schiller JJ, Kanjanahaluethai A, Baker SC, Oh JW, Lai MM. 1999. Colocalization and membrane association of murine hepatitis virus gene 1 products and De novo-synthesized viral RNA in infected cells. Journal of Virology 73(7):5957-69. Shortridge KF, Stuart-Harris CH. 1982. An influenza epicentre? Lancet 2:812-13. Sims AC, Ostermann J, Denison MR. 2000. Mouse hepatitis virus replicase proteins associate with two distinct populations of intracellular membranes. Journal of Virology 74(12):5647-54. Snijder EJ, Bredenbeek PJ, Dobbe JC, Thiel V, Ziebuhr J, Poon LL, Guan Y, Rozanov M, Spaan WJ, Gorbalenya AE. 2003. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. Journal of Molecular Biology 331(5):991-1004. Stalcup RP, Baric RS, Leibowitz JL. 1998. Genetic complementation among three panels of mouse hepatitis virus gene 1 mutants. Virology 241(1):112-21.

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary Stavrinides J, Guttman DS. 2004. Mosaic evolution of the severe acute respiratory syndrome coronavirus. Journal of Virology 78(1):76-82. Subbarao K, Klimov A, Katz J, Regnery H, Lim W, Hall H, Perdue M, Swayne D, Bender C, Huang J, Hemphill M, Rowe T, Shaw M, Xu X, Fukuda K, Cox N. 1998. Characterisation of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 279:393-6. Thiel V, Herold J, Schelle B, Siddell SG. 2001. Infectious RNA transcribed in vitro from a cDNA copy of the human coronavirus genome cloned in vaccinia virus. Journal of General Virology 82(Pt 6):1273-81. Thiel V, Ivanov KA, Putics A, Hertzig T, Schelle B, Bayer S, Weissbrich B, Snijder EJ, Rabenau H, Doerr HW, Gorbalenya AE, Ziebuhr J. 2003. Mechanisms and enzymes involved in SARS coronavirus genome expression. Journal of General Virology 84(Pt 9):2305-15. Tresnan DB, Levis R, Holmes KV. 1996. Feline aminopeptidase N serves as a receptor for feline, canine, porcine, and human coronaviruses in serogroup I. Journal of Virology 70(12):8669-74. Tsang KW, Ho PL, Ooi GC, et al. 2003. A cluster of cases of severe acute respiratory syndrome in Hong Kong. New England Journal of Medicine 348:1977-85. Tsunemitsu H, El-Kanawati ZR, Smith DR, Reed HH, Saif LJ. 1995. Isolation of coronaviruses antigenically indistinguishable from bovine coronavirus from wild ruminants with diarrhea. Journal of Clinical Microbiology 33(12):3264-9. Tsunemitsu H, Saif LJ. 1995. Antigenic and biological comparisons of bovine coronaviruses derived from neonatal calf diarrhea and winter dysentery of adult cattle. Archives of Virology 140(7):1303-11. van der Meer Y, Snijder EJ, Dobbe JC, Schleich S, Denison MR, Spaan WJ, Locker JK. 1999. Localization of mouse hepatitis virus nonstructural proteins and RNA synthesis indicates a role for late endosomes in viral replication. Journal of Virology 73(9):7641-57. Vennema H, Poland A, Floyd Hawkins K, Pedersen NC. 1995. A comparison of the genomes of FECVs and FIPVs and what they tell us about the relationships between feline coronaviruses and their evolution. Feline Practice 23:40-4. WHO (World Health Organization). 2003a. Cumulative number of reported probable cases of severe acute respiratory syndrome (SARS). [Online] Available: http://www.who.int/csr/sarscountry/2003_07_11/en [accessed July 16, 2003]. WHO. 2003b. Case definitions for surveillance of severe acute respiratory syndrome (SARS) [Online] Available: http://www.who.int/csr/sars/casedefinition/en/ [accessed May 1, 2003]. WHO [Online] Available: www.who.int/csr/sars/en/. WHO. Cumulative Number of reported probable cases of severe acute respiratory syndrome (SARS). [Online] Available: www.who.int/csr/sars/country/2003_05_20/en/. Xiao X, Chakraborti S, Dimitrov AS, Gramatikoff K, Dimitrov DS. 2003. The SARS-CoV S glycoprotein: expression and functional characterization. Biochemincal and Biophysical Research Communucations 312(4):1159-64. Yeager CL, Ashmun RA, Williams RK, Cardellichio CB, Shapiro LH, Look AT, Holmes KV. 1992. Human aminopeptidase N is a receptor for human coronavirus 229E. Nature 357(6377):420-2. Yokomori K, Lai MM. 1992. Mouse hepatitis virus utilizes two carcinoembryonic antigens as alternative receptors. Journal of Virology 66(10):6194-9. Yount B, Curtis KM, Baric RS. 2000. Strategy for systematic assembly of large RNA and DNA genomes: transmissible gastroenteritis virus model. Journal of Virology 74(22):10600-11. Yount B, Curtis KM, Fritz EA, Hensley LE, Jahrling PB, Prentice E, Denison MR, Geisbert TW, Baric RS. 2003. Reverse genetics with a full-length infectious cDNA of severe acute respiratory syndrome coronavirus. Proceedings of the National Academy of Sciences 100(22):12995-3000. Yount B, Denison MR, Weiss SR, Baric RS. 2002. Systematic assembly of a full-length infectious cDNA of mouse hepatitis virus strain A59. Journal of Virology 76(21):11065-78.

OCR for page 137
Learning From Sars: Preparing for the Next Disease Outbreak - Workshop Summary Zhang XM, Herbst W, Kousoulas KG, Storz J. 1994. Biological and genetic characterization of a hemagglutinating coronavirus isolated from a diarrhoeic child. Journal of Medical Virology 44 (2):152-61. Zhong NS, Zheng BJ, Li YM, Poon, Xie ZH, Chan KH, Li PH, Tan SY, Chang Q, Xie JP, Liu XQ, Xu J, Li DX, Yuen KY, Peiris, Guan Y. 2003. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People’s Republic of China. Lancet 362(9393):1353-8. Ziebuhr J, Snijder EJ, Gorbalenya AE. 2000. Virus-encoded proteinases and proteolytic processing in the Nidovirales. Journal of General Virology 81(Pt 4):853-79. Ziebuhr J, Thiel V, Gorbalenya AE. 2001. The autocatalytic release of a putative RNA virus transcription factor from its polyprotein precursor involves two paralogous papain-like proteases that cleave the same peptide bond. Journal of Biological Chemistry 276(35):33220-32.