Animal species susceptible to infection by SARS coronavirus*
| Animal | Mode of infection | Clinical signs | References | |
|---|---|---|---|---|
| Common name | Taxonomic name | |||
| Masked palm civet | Paguma larvata | Natural | None observed | (9) |
| Experimental | Fever, lethargy, reduced appetite | (11) | ||
| Racoon dog | Nyctereutes procyonoides | Natural | None observed | (9) |
| Chinese ferret badger | Melogale moschata | Natural | None observed | (9) |
| Cynomolgus macaque | Macaca facicularis | Experimental | Lethargy, skin rash, respiratory distress | (12) |
| Rhesus macaque | Macaca mulatta | Experimental | Fever, low appetite | (13,14) |
| African green monkey | Cercopithecus aethiops | Experimental | None observed | (15) |
| Ferret | Mustela furo | Experimental | Lethargy, mild pulmonary lesions | (16) |
| Golden hamster | Mesocricetus auratus | Experimental | None observed | (17) |
| Guinea pig | Cavia porcellus | Experimental | None observed | (18) |
| Mouse | Mus musculus | Experimental | Aged animal (12–14 mo): weight loss, hunched posture, ruffled fur, slight dehydration | (19) |
| Young animal (4–6 weeks): none observed | (20) | |||
| Rat | Rattus rattus | Experimental | None observed | B.T. Eaton et al., unpub. data |
| Domestic cat | Felis domesticus | Natural | Not reported | (16) |
| Experimental | None observed | (16) | ||
| Pig | Sus scrofa | Natural | Not reported | (21) |
| Experimental | None observed | (22) |
Severe acute respiratory syndrome (SARS) represents the 21st century’s first pandemic of a transmissible disease with a previously unknown cause. The pandemic started in November 2002 and was brought under control in July 2003, after it had spread to 33 countries on 5 continents, resulting in >8,000 infections and >700 deaths (1). The outbreaks were caused by a newly emerged coronavirus, now known as the SARS coronavirus (SARS-CoV).
In late 2003 and early 2004, sporadic outbreaks were reported in the region of the People’s Republic of China where the 2002–2003 outbreaks originated (2). However, molecular epidemiologic studies showed that the viruses responsible for the 2003–2004 outbreaks were not the same as those isolated during the 2002–2003 outbreaks (3). These findings indicate independent species-crossing events. They also indicate that a SARS epidemic may recur in the future and that SARS-like coronaviruses (SARS-like–CoVs) that originate from different reservoir host populations may lead to epidemics at different times or in different regions, depending on the distribution of the reservoirs and transmitting hosts. The recent discovery of a group of diverse SARS-like–CoVs in bats supports the possibility of these events and further highlights the need to understand reservoir distribution and transmission to prevent future outbreaks.
Animal Origin of SARS Coronaviruses
Because of the sudden and unpredictable nature of the SARS outbreaks that started in November 2002 in southern People’s Republic of China, structured and reliable epidemiologic studies to conclusively trace the origin of SARS-CoV were not conducted. However, accumulated studies from different groups, which used a variety of approaches, indicated an animal origin on the basis of the following findings. 1) Genome sequencing indicated that SARS-CoV is a new virus with no genetic relatedness to any known human coronaviruses (4,5). 2) Retrospective serologic studies found no evidence of seroprevalence to SARS-CoV or related viruses in the human population (6). 3) Serologic surveys among market traders during the 2002–2003 outbreaks showed that antibodies against SARS-CoV or related viruses were present at a higher ratio in animal traders than control populations (7–9). 4) Epidemiologic studies indicated that early case-patients were more likely than later case-patients to report living near a produce market but not near a farm, and almost half of them were food handlers with probable animal contact (7). 5) SARS-CoVs isolated from animals in markets were almost identical to human isolates (9). 6) Molecular epidemiologic analyses indicated that human SARS-CoV isolates could be divided into 3 groups from the early, middle, and late phases of the outbreaks and that early-phase isolates were more closely related to the animal isolates (10). 7) Human SARS-CoVs isolates from the 2003–2004 outbreaks had higher sequence identity to animal isolates of the same period than to human isolates from the 2002–2003 outbreaks (3).
Cross-species Transmission
Emergence of zoonotic viruses from a wildlife reservoir requires 4 events: 1) interspecies contact, 2) cross-species virus transmission (i.e., spillover), 3) sustained transmission, and 4) virus adaptation within the spillover species (34). These 4 transition events occurred during the SARS outbreaks and contributed to the rapid spread of the disease around the world.
The role of civets in directly transmitting SARS-CoV to humans has been well established. The most convincing case was the infection of a waitress and a customer in a restaurant where SARS-CoV–positive civets were housed in cages (25). Two key questions remain: What is the natural reservoir host for the outbreak SARS-CoV strains, and how were the viruses transmitted to civets or other intermediate hosts? Although not conclusive, the data obtained so far strongly suggest that bats (horseshoe bats in particular) are most likely the reservoir host of SARS-CoV. As indicated above, bat coronaviruses seem to be species-specific and SARS-like–CoVs discovered so far are exclusively associated with horseshoe bats. We hope that continued field study will eventually identify the direct progenitor of SARS-CoV among the 69 different known horseshoe species. The facts that the cross-species transmission of SARS-CoV seems to be a relatively rare event and that legal and illegal trading of wildlife animals between People’s Republic of China and other countries occurs raise the possibility that the natural reservoir species may not be native to People’s Republic of China. Thus, we should expand our search into regions other than Hong Kong and mainland People’s Republic of China. Another approach to search for the natural reservoir of SARS-CoV is to conduct infection experiments in different bat species. If we assume that the progenitor viruses come from bats, chances are high that the human/civet SARS-CoVs are still capable of infecting the original reservoir species.
Without knowing the natural reservoir of SARS-CoV, predicting the exact mechanism of transmission from reservoir host to intermediate host is difficult. However, the fecal-oral route represents the main mode of transmission among animals. Although mixing of live reservoir hosts (e.g., bats) and intermediate hosts (e.g., civets) would be an efficient means of transmission, the main source of cross-species transmission in the animal trading chain (including warehouses, transportation vehicles, markets) may come from contaminated feces, urine, blood, or aerosols. This may also be true for civet-to-human transmission. As shown in the case of the infected restaurant customer in 2004, the customer had no direct contact with civets and was sitting at a table ≈5 m from the civet cages (25).
Although at this stage we cannot rule out the possibility of direct transmission from the natural reservoir host to humans, molecular epidemiologic studies (2,10) and studies of the receptor-S protein interaction (35) indicate that the progenitor viruses are unlikely to be able to infect humans and that a rapid viral evolution in an intermediate host (such as civets) seems to be necessary to adapt the virus for human infection. Ability to efficiently use the receptor molecules (ACE2 for human and civet) seems to be a major limiting factor for animal-to-human and human-to-human transmission (35). This also explains why the SARS-CoV was able to cause the human pandemic but the closely related bat SARS-like–CoVs were not. For the SARS-like–CoVs to infect humans, substantial genetic changes in the S1 receptor-binding domain will be necessary. These changes may be achieved in 1 of 2 possible ways. They could be achieved by genetic recombination, as coronaviruses are known to be able to recombine. For example, bat SARS-like–CoVs and another yet unknown coronavirus could coinfect an intermediate host, and the bat viruses would gain the ACE2 binding site in the S1 domain by recombination. The alternative is continuous evolution independent of recombination. Coronaviruses in bats could have a spectrum sufficiently diverse to encompass the progenitor virus for SARS-CoVs. The progenitor virus’s ability to bind human ACE2 may be acquired or improved by adaptation (i.e., point mutations) in >1 intermediate host before it could efficiently infect humans. The existence of at least 3 discontinuous highly variable genomic regions between SARS-CoV and SARS-like–CoV indicates that the second mechanism is more likely.
In conclusion, the discovery of bat SARS-like–CoVs and the great genetic diversity of coronaviruses in bats have shed new light on the origin and transmission of SARS-CoV. Although the exact natural reservoir host for the progenitor virus of SARS-CoV is still unknown, we believe that a continued search in different bat populations in People’s Republic of China and neighboring countries, combined with experimental infection of different bat species with SARS-CoV, will eventually identify the native reservoir species. A positive outcome of these investigations will greatly enhance our understanding of spillover mechanisms, which will in turn facilitate development and implementation of effective prevention strategies. The discovery of SARS-like–CoVs in bats highlights the increasingly recognized importance of bats as reservoirs of emerging viruses (36). Moreover, the recent emergence of SARS-CoVs and other bat-associated viruses such as henipaviruses (37,38), Menangle, and Tioman viruses (36), and variants of rabies viruses and bat lyssaviruses (38,39) also supports the contention that viruses, especially RNA viruses, possess more risk than other pathogens for disease emergence in human and domestic mammals because of their higher mutation rates (40).
