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Institute of Medicine (US) Forum on Microbial Threats; Knobler S, Mahmoud A, Lemon S, et al., editors. Learning from SARS: Preparing for the Next Disease Outbreak: Workshop Summary. Washington (DC): National Academies Press (US); 2004.

Cover of Learning from SARS

Learning from SARS: Preparing for the Next Disease Outbreak: Workshop Summary.

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CORONAVIRUS RESEARCH AND SARS

The SARS coronavirus (SCoV) appears to be zoonotic and to have originated in wild mammals in southern China. A coronavirus comprises single-stranded RNA inside a lipid envelope. Coronaviruses cause a substantial fraction of human colds and a number of common respiratory infections in other animals, including livestock and poultry (Holmes, 2003). Since its emergence, several veterinary and biomedical scientists have been called on to share their considerable knowledge of coronaviruses with a vast new audience and to join the research response to the epidemic. This experience—and the high value evident in available knowledge and understanding of coronavirus biology and molecular biology, gained at a time when coronaviruses were not recognized to be the causative agent of any severe infectious disease—attests to the value of basic research.

Based on their genetic sequences, the 14 previously known coronaviruses have been divided into three major groups. While SCoV 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.

Although coronaviruses generally cause disease in a single species, it has been demonstrated that some coronaviruses can cross species barriers. Moreover, RNA viruses are more likely to be zoonotic than DNA viruses. These findings lend credence to the hypothesis that SCoV is a zoonosis. Viruses resembling human SCoV reportedly have been detected in wild mammals of southern China that were brought to marketplaces where they were sold as exotic food. Immunological and genetic tests of these SCoV-like viruses suggest that human SCoV may be an animal virus transmitted to humans in the recent past (Guan et al., 2003).

Understanding the Biology and Epidemiology of SARS

As one would expect of a newly characterized disease, much knowledge about the microbiology, pathogenesis, natural history, and epidemiology of SARS remains to be discovered. For example, scientists have not yet identified the animal source of the infectious agent and have not determined whether a persistent animal reservoir of the infectious agent exists. It is also unclear whether SARS, like influenza, is a seasonal disease that would have receded on its own. Along the same lines, it remains to be seen whether SARS will reemerge on a seasonal basis, and if so, how virulent future manifestations of SCoV will be. These and other unanswered scientific questions, listed in Box S-1, were a prominent theme of workshop presentations and discussions. Answers to these questions would certainly advance the world’s ability to predict and prepare for a resurgence of SARS.7

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BOX S-1

Scientific Unknowns About SARS. What is the natural animal host of SCoV? How was the virus transmitted to humans, and under what circumstances might transmission across species recur?

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Considerable effort already has been applied to finding the animal source of SCoV. For example, viral isolates from suspected animal sources were genetically characterized and compared with samples of SCoV (see Guan et al. in Chapter 3). However, recalling previous investigations of outbreaks of Legionnaire’s disease, Schistosomiasis, and E. coli 0157, workshop participants noted the crucial role played by epidemiological “detective work” in developing hypotheses that led ultimately to the source of transmission (Zhong et al., 2003).8 To this end, it was suggested at the workshop that a case control study of the first 50 to 100 SARS patients be conducted using epidemiological data collected in Guangdong Province. Such an endeavor may provide direction to further laboratory surveys of animal viruses to reveal the source of SCoV and, perhaps, its animal reservoir.9

SARS researchers benefit from the wealth of literature on coronaviruses in general. Presentations by two coronavirus experts at the workshop summarized the current understanding of coronavirus biology and pathogenesis and suggested promising directions for research on SARS and other emerging zoonoses (see Saif and Denison in Chapter 3).

The pathogeneses of animal coronaviruses conform to a basic model of either intestinal (enteric) or respiratory infection. Enteric coronaviruses can cause fatal infections in young, seronegative animals. Respiratory coronavirus infections in adult animals 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. It is unknown whether SCoV is a respiratory virus or a pneumoenteric virus. This knowledge gap will stymie efforts to develop a vaccine or drug against SCoV.

Studies of coronavirus replication 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 extremely adaptable and capable of acquiring or regaining virulence. The relatively large coronavirus genome tolerates deletions, mutations, and substitutions and can recover from deleterious mutations. Molecular biological studies have also identified several potential targets for antiviral drug discovery, including viral binding and uncoating, replication, protein expression and processing, assembly, and release. Cellular functions on which the virus depends, such as cholesterol synthesis, membrane trafficking, and autophagy, also present opportunities for antiviral design (see Matthews et al. in Chapter 4).

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The tendency of coronaviruses to undergo mutation and recombination represents a significant challenge for vaccine development. To date, no vaccine has been produced that can provide highly effective, long-term protection against respiratory coronavirus infections. Genetic approaches represent the best hope of overcoming this propensity for mutability, according to workshop presenters.10 For example, it might be possible to find ways to limit RNA-RNA homologous recombination, or to identify areas in the genome that are more or less prone to survive mutation. Promising approaches to these challenges include the use of reverse molecular genetics to make specific mutations in the virus genome and test their functional effects.

Workshop presenters emphasized that appropriate animal models are needed immediately to advance the development of a SARS vaccine. Participants also noted that studies in existing animal models of coronavirus infection could play a role in the development of antiviral therapies against SARS. Ultimately, a range of natural and transspecies disease models will be critical to understanding the pathogenesis of this and other emerging zoonoses. Coordinated, multidisciplinary research drawing on expertise in veterinary sciences, medicine, molecular biology, and virology will be needed to meet these goals. However, the coronavirus experts who presented at the workshop lamented that there is little encouragement or support for such critical cross-disciplinary research at present.

Footnotes

7

The recent reemergence of human SARS infections in 2004 would indicate both an animal reservoir and a seasonality to disease emergence, but further investigation will be required for conclusive evidence.

8

Workshop presentation by Robert Breiman, Centre for Health and Population Research, Dhaka, Bangladesh, October 1, 2003.

9

Workshop presentation by Yi Guan, University of Hong Kong, September 30, 2003.

10

Workshop presentation by Alan Shaw, Merck Vaccine Co., October 1, 2003.

Copyright © 2004, National Academy of Sciences.
Bookshelf ID: NBK92490

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