key: cord-0682678-qkc748u7 authors: Opriessnig, Tanja; Huang, Yao‐Wei title: Third update on possible animal sources for human COVID‐19 date: 2021-01-21 journal: Xenotransplantation DOI: 10.1111/xen.12671 sha: a6efb8d4dd15130d87eb2bf195e13788cccd08c7 doc_id: 682678 cord_uid: qkc748u7 nan Approximately a year ago, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans was described for the first time in Wuhan, China. 1 Since, SARS-CoV-2 and its clinical manifestation, known as coronavirus disease 2019 (COVID- 19) , have dominated the news and varying restrictions to everyday life have been introduced in essentially all continents in an international effort to limit human-to-human spread as well as decrease hospitalization rates. 2 Updated information on confirmed high pathogenic CoV infections and fatalities in humans are provided in Table 1 . This synopsis represents the third update on recent findings on animal sources that could pose a risk for human SARS-CoV-2 infection. The information provided is intended to update people working closely with animals on new evidence of cross-species transmission of SARS-CoV-2 from humans. When assessing any new virus, it is essential to identify its origin as this could yield important data which could help in preventing future outbreaks. Further investigations into the origin of SARS-CoV-2 revealed that the virus itself likely originated from a bat sarbecovirus, a virus circulating in horseshoe bats. [3] [4] [5] Horseshoe bats can be found in tropical and temperate regions in Europe, Japan, Asia, and Africa. Divergence dates between SARS-CoV-2 and the bat sarbecovirus reservoir were estimated as 1948 and 1982, suggesting that the lineage which produced SARS-CoV-2 has been circulating unnoticed in bats for decades. 3, 6 Of note, the virus was introduced to humans via spillover or cross-species transmission but details still need to be estabilished. SARS-CoV-2 adapted quickly to its new human host resulting in rapid human-to-human transmission, with a mean reproductive number (R) estimated to be 3.28 (median 2.79), 7 which indicates that an infected person can potentially infect 3 to 4 others. In theory, it is possible that SARS-CoV-2 in its current form evolved directly from horseshoe bats, but an intermediate host, such as pangolins or another species, is also plausible. 3 SARS-CoV-2 emerged in Wuhan, China during the winter season, perhaps indicating that there was an intermediate host present at that time. 6 As we outlined in our previous commentary, 8 the pangolin has been proposed as the missing link bridging bats and humans in the context of SARS-CoV-2. Pangolins in some cases have developed natural disease associated with SARS-CoV-2 infection, perhaps indicating they may not be a natural reservoir. 3, 6 The current consensus is that more data is needed to conclusively determine the origin of SARS-CoV-2. Identifying intermediate host species capable of supporting SARS-CoV-2 replication is important as this could provide clues on future reservoir hosts. It has been determined that the likelihood of fish, birds, reptiles and amphibians to become a possible SARS-CoV-2 intermediate host in the future is low. 9,10 Among livestock species including ruminants, pigs and domestic poultry, reports of serious disease outbreaks, possibly suggesting a species jump of SARS-CoV-2, have not been reported to date. However, there is evidence that pigs 11 and ruminants 12 can be experimentally infected with SARS-CoV-2 at a low level, and livestock may pose a greater risk of serving as a reservoir in the future, when SARS-CoV-2 becomes more established in humans. 13 A potentially important role in cross-species transmission has been suggested for rodents including squirrels, rats, mice, hamster and others. 14 Rodents exist in sufficient numbers and densities for continuous transmission and are often in close proximity to humans, but so far experimental studies indicate a low probability or no risk of SARS-CoV-2 infection for mice and rats. 13 Interestingly, it has been found more recently that Chinese tree shrews, a squirrel-like mammal with a wide distribution in Southeast Asia, could not only be infected with SARS-CoV-2 but also developed clinical signs analogous to COVID-19 in humans. 15 Chinese tree shrews have been used as animal models in viral hepatitis, psychosocial and visual defect studies due to their phylogenetical closeness to primates. 16 Many research efforts focus on the animal-human interface of SARS-CoV-2. With the high rate of infections and the overall high virus load present in the human population today, it is likely that SARS-CoV-2 may enter other new hosts. This process is known as species jump or spillover and requires some level of adaption of the virus to the new host. Three stages of viral disease emergence leading to successful host switching have been defined previously. 17 During the first stage, a new host species becomes infected but there is no onward transmission. This scenario is likely true for dogs and cats: SARS-CoV-2-viremia or even clinical signs have occasionally been demonstrated in these pets, which were essentially always in close contact with COVID-19 infected humans and were the direct results of human-dog infection 18 or human-cat-infection. 19 However, to date, there have been no confirmed natural infections between dogs, between cats or from cats or dogs to humans and companion animals are unlikely to spread COVID-19 at a larger scale. 20 The second stage of viral disease emergence are spillovers that go on to cause local chains of transmission in the new host population before the epidemic fades out (outbreaks). The authors are not aware of any SARS-CoV-2 infections in domestic or wild animals that fall into this category. The third stage is development of an epidemic or sustained endemic the mink. 25, 27 During vaccine development, it is crucial to monitor any viral changes which may occur at vaccine target sites, as these may render a novel vaccination product ineffective. 28 At this point, scientists suggest that the mink-specific SARS-CoV-2 mutations identified so far will not jeopardize the effectiveness of potential The following information is an update on the current knowledge relevant to the susceptibility of different animal groups to SARS-CoV-2. Today pets often live in close contact with humans and are commonly considered part of the family. It comes as no surprise that SARS-CoV-2 has been detected in dogs and cats living in COVID-19 households. [33] [34] [35] Often SARS-CoV-2 in cats or dogs was only detected by PCR assays, occasionally the pet in question seroconverted, and in only a few cases, mild clinical signs were described. 8 Commonly, field assessments of the general cat and dog population using serology assays resulted in a low prevalence of antibody-positive animals. 36, 37 Overall, this has triggered a number of controlled experimental and observational studies. Since our last update, a few more experimental cat studies have been published ( virus shedding. To the authors' knowledge, there have been no reports of SARS-CoV-2 naturally infecting pet hamsters or ferrets. In general, it would appear pets are not easily infected. CoV-2 are very limited, while confirmed human infections have reached over 67 million cases, as outlined in Table 1 . Therefore, pets do not pose a major threat to humans at this point and human infection from cats, dogs, ferrets or Golden Syrian hamsters has not been reported. Fortunately, studies investigating the susceptibility of livestock species to SARS-CoV-2 have rarely resulted in finding viral infectivity (Table 3) . SARS-CoV-2 experimental infection trials in poultry using chickens, ducks, turkeys, quail and geese demonstrated these animals lacked susceptibility to the virus. 46, 47 For pigs, most available data points towards this species not being susceptible to SARS-CoV-2; however, there are some recent conflicting reports. A US study found no evidence of clinical signs, viral replication or SARS-CoV-2-specific antibody responses in 9 5-week-old pigs when infected through the oral, intranasal and intratracheal routes; however it was also found that porcine cell lines including a porcine kidney cell line and swine testicular (ST) cell line could be readily infected. 48 In a Spanish study, 20 SARS-CoV-2 in mink behaves differently compared to other animal species. It is commonly associated with severe clinical outbreaks including high morbidity and mortality in infected farms; however, subclinical disease can also occur. So far, outbreaks have been reported in several European countries and in the USA. As a consequence of the various outbreaks seen in mink farms, several culling interventions have been carried out, as outlined in Table 4 . Recently, a Chinese research group investigated the biological properties of SARS-CoV-2 in experimentally infected mink. 50 It was determined that SARS-CoV-2 replicates efficiently in the respiratory tract, as expected, and is transmitted among mink via respiratory droplets. As lesions in mink are similar to humans suffering from COVID-19, the mink model was proposed as a useful animal model to evaluate COVID-19 therapeutics or vaccines. 50 or pooled faecal samples from common areas such as freshwater reservoirs or feeding areas. Interestingly, in August 2020, China announced regular coronavirus tests at wholesale markets (weekly for major markets, monthly for smaller operations), with a focus on knives used at major stands, workers' clothing, surfaces, freezers, meat, seafood, sewage, restrooms, garbage trucks and offices (https://prome dmail.org/prome d-post/?id=20200 801.7635820). SARS-CoV-2 emerged in the human population towards the end of 2019 and has been spreading at an alarming rate and cases in humans continue to increase. This is predicted to continue until commercial vaccines, which recently became available in selected countries (https://www.bbc.co.uk/news/uk-55227325), are approved and have been distributed to a larger number of people, ensuring that a certain proportion of the global population is protected. Pet animals such as cats and dogs do not currently appear to pose a risk to humans; however, continuous monitoring of these animals is warranted. SARS-CoV-2 spillover into farm animals has not been Yao-Wei Huang https://orcid.org/0000-0001-9755-8411 Clinical features of patients infected with 2019 novel coronavirus in Wuhan Early epidemiological indicators, outcomes, and interventions of COVID-19 pandemic: a systematic review Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic Global epidemiology of bat coronaviruses Detection and characterization of bat sarbecovirus phylogenetically related to SARS-CoV-2 The origin of SARS-CoV-2 The reproductive number of COVID-19 is higher compared to SARS coronavirus Further information on possible animal sources for human COVID-19 Assessing the SARS-CoV-2 threat to wildlife: Potential risk to a broad range of mammals Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates Susceptibility of domestic swine to experimental infection with severe acute respiratory syndrome coronavirus 2 Experimental infection of cattle with SARS-CoV-2 Host range of SARS-CoV-2 and implications for public health Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection COVID-19-like symptoms observed in Chinese tree shrews infected with SARS-CoV-2 The tree shrews: adjuncts and alternatives to primates as models for biomedical research Cross-species virus transmission and the emergence of new epidemic diseases Infection of dogs with SARS-CoV-2 SARS-CoV-2 natural transmission from human to cat Companion animals likely do not spread COVID-19 but may get infected themselves Transmission of SARS-CoV-2 in Domestic Cats Experimental infection of domestic dogs and cats with SARS-CoV-2: pathogenesis, transmission, and response to reexposure in cats Transmission of SARS-CoV-2 on mink farms between humans and mink and back to humans Coronavirus rips through Dutch mink farms, triggering culls Mutated Covid-19 found in mink farms in Denmark The evolution and genetics of virus host shifts Transmission of SARS-CoV-2 on mink farms between humans and mink and back to humans Mutations in SARS-CoV-2 leading to antigenic variations in spike protein: a challenge in vaccine development COVID mink analysis shows mutations are not dangerous -yet Moderate mutation rate in the SARS coronavirus genome and its implications Genome evolution of SARS-CoV-2 and its virological characteristics The coronavirus is mutating -does it matter? 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Third update on possible animal sources for human COVID-19