The current outbreak of coronavirus disease COVID-19 is showing up vulnerabilities in many aspects of the globalised world we live in. The suggestion that it may have originated in the endangered pangolin also puts animal trafficking in the spotlight. The human–wildlife interface remains an important risk factor for further disease outbreaks. Michael Gross reports.

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By Thursday February 20th, as this article went into production, there have been more than 75,000 confirmed cases and more than 2,000 deaths from the novel coronavirus disease COVID-19. The vast majority of the cases and deaths were recorded within mainland China, but other accumulations of cases have emerged in the South Korean city of Daegu and on the cruise ship Diamond Princess docked at Yokohama, Japan. The World Health Organization (WHO) is issuing daily situation reports, with a risk assessment of ‘very high’ for China and ‘high’ at the global level. Both travel and manufacturing industries are already feeling the effects of the outbreak.

Like other virus infections that have caused concern in the last two decades, COVID-19 has crossed the species barrier from an animal reservoir and demonstrated the ability to spread between humans, making it a further example of a zoonosis. Many zoonotic diseases that have established themselves in the human population, such as today’s childhood infections like chickenpox, have evolved to become relatively harmless, enabling them to spread without endangering the survival of their host population.

This relatively peaceful co-evolution between some zoonotic pathogens and human populations is thought to have originated when agriculture enabled people to live in larger communities, creating effective population sizes big enough to sustain a permanent equilibrium with a weakened pathogen. By contrast, viruses that have made the transition more recently may still be more lethal. Thus, Ebola virus disease, which occasionally causes outbreaks in tropical Africa, where its natural reservoir is in bats, typically causes a very high rate of mortality among those infected and therefore has to be confined at all costs (Curr. Biol. (2018) 28, R51–R54).

A few outbreaks of severe respiratory disease caused by coronaviruses have caused concern since the beginning of this century. They came from different animal sources and the course of the epidemics has highlighted problems in the response systems.

Caves to markets Coronaviruses, a group of spherical RNA viruses with an envelope that in the electron microscope can appear like a star’s corona, were discovered in the 1960s in the context of human respiratory diseases like the common cold. They were also found to cause respiratory disease in some animal species, diarrhoea in others. Point made: The 2019–2020 outbreak of coronavirus disease has highlighted the vulnerability of the increasingly connected world population to newly emerging zoonotic diseases. (Photo: zhizhou deng/Flickr (CC BY 2.0).) The first major outbreak of a new and dangerous zoonotic disease linked to a coronavirus was the epidemic of severe acute respiratory syndrome (SARS) in 2002–2003. Starting in November 2002 in southern China, the disease affected more than 8,000 people, with a mortality rate of just under 10%. After spreading to 17 countries, the outbreak could be contained and no cases of SARS have been reported since 2004. Initial studies into the source of the SARS version of the coronavirus identified the Asian palm civet (Paradoxurus hermaphroditus) as a carrier. This small mammal of the tropical forests was on sale for its meat at the local meat markets in Yunnan province. Further studies indicated that the civets may have been infected by bats. In 2017, the teams of Shi Zheng-Li and Cui Jie at the Wuhan Institute of Virology, China, discovered a mixed population of several species of horseshoe bats in a cave in the Yunnan province carrying a coronavirus variant with precisely the same genetic elements that were found in the pathogen of the SARS outbreak (PLoS Pathog. (2017) 13, e1006698). Animal wrongs: Markets in Asia selling a wide variety of wild and domesticated animals have been identified as a risk factor for the spread of zoonotic diseases such as SARS and COVID-19. (Photo: Daniel Case/Wikimedia Commons (CC BY-SA 3.0).) Bats are known to have a remarkable tolerance of viruses that may cause serious disease in other species. This feature has been linked to the dampened inflammation response to stress factors such as DNA present in the cytosol, which can be an indicator of viral infection but in the case of bats can also be linked to the stress caused by the high amount of energy needed for powered flight (Curr. Biol. (2019) 29, R1163–R1165). Keeping the inflammation response under control enables the bats to mount a robust immune reaction against the virus while avoiding the side effects such as swelling and fever. In a recent study of bat resistance to viral disease, Cara Brook from the University of California at Berkeley, USA, and colleagues analysed and modelled these effects in detail using cell cultures derived from two different species of bats (eLife (2020) 9, e48401). The authors conclude that viruses respond to robust bat immunity by establishing more rapid cell-to-cell transmission rates than do comparable viruses in other groups of mammals. Therefore, when they transfer to humans, they may become more deadly than established human viruses. People don’t often mingle with bats, but Brook and colleagues note that the diseases are often transferred from bats to humans via another mammalian host, like the palm civet in the case of SARS. Moreover, they note that disturbing bat habitat may stress the bats and make them shed more viruses via their saliva and excretions. Their Bat One Health field project, currently operating in Madagascar, Bangladesh, Ghana and Australia, explores the link between the loss of bat habitat and the transfer of their viruses into other animals and humans.

Camel connections The next significant outbreak of coronavirus disease was the Middle East respiratory syndrome (MERS), first identified in Saudi Arabia in 2012. Like SARS, this disease is caused by a virus of the genus Betacoronavirus, but of a clearly distinct lineage from that pathogen. Compared with SARS, it is more deadly but less infectious in the transmission between humans. According to WHO figures from January 2020, there have been just over 2,500 cases so far, causing 862 deaths. In spite of the high mortality of 34%, this virus is not regarded as a major global health threat, as its spread can be contained relatively well. Virus strains identical to the one in MERS patients were discovered in dromedary camels. The virus appears to have passed from camels to humans on several occasions, causing further outbreaks in 2015 and 2018. Following the first outbreak in 2012, government advice to avoid close contact with camels has led to a backlash among farmers in Saudi Arabia. The BBC reported in 2014 that farmers kissed their camels in defiance of health advice. This kind of resistance to medical advice might explain the later recurrence of the disease. As recently as November 2019, several new cases of MERS were reported from Saudi Arabia, and in each of these cases the infected people were known to have had contact with camels, but not with other patients infected with the virus. In a recent study, Sohail Hassan from the University of Veterinary and Animal Sciences at Lahore, Pakistan, and colleagues tested for MERS-specific antibodies in camel handlers and their families in Pakistan, where no cases of MERS infection have been reported (Emerg. Infect. Dis. (2019) 25, 2307–2309). Of 91 ELISA tests, more than half were positive for MERS-CoV antibodies. With a 50% reduction plaque-reduction neutralization test (PRNT 50 ), 12 participants tested positive for exposure to the coronavirus, and 10 of these were confirmed by immunofluorescence. While the authors interpret the high ELISA result as possible cross-reaction from other coronaviruses, they consider the ten positive tests obtained by the other two methods as an indication that exposure to MERS-like coronaviruses is widespread among camel handlers in Pakistan. A separate study conducted in Sudan detected MERS-CoV antibodies in nearly all of the dromedary camels tested but not in humans exposed to them (Emerg. Infect. Dis. (2019) 25, 2333–2335). As transmission between humans mainly occurs within healthcare environments, Emmie de Wit and colleagues at the National Institute of Allergy and Infectious Diseases at Hamilton, USA, have tested the prophylactic use of the antiviral drug remdesivir (Proc. Natl. Acad. Sci. USA (2020) 117, https://doi.org/10.1073/pnas.1922083117 ). In a study using rhesus macaques, the researchers found that the compound, if given before infection with the virus, protects the animals from becoming ill. The researchers conclude that its usefulness for the protection of healthcare professionals in the current coronavirus outbreak should be tested.

A pangolin pandemic? The current outbreak of coronavirus disease is, according to the results available so far, less deadly than MERS and SARS, but also more infectious. Even with a death rate below one percent, it could kill millions if it establishes itself in the global human population. This fear motivates the dramatic protection and quarantine measures that have been taken since the disease was first identified. This new outbreak emanated from the city of Wuhan, the capital of the Hubei province in China, and has been traced back to the Huanan Seafood Market, where numerous animals ranging from fish, chickens, and pheasants to wild animals such as bats, marmots, venomous snakes, and deer are on sale. At this point it appears certain that the outbreak, like SARS and MERS, is a new zoonotic transfer, but the animal source remains to be confirmed. Sequencing of virus genomes from five of the first cases identified established that the same virus was present in all five patients, that it was new in that it had limited similarity to the SARS virus (79%) and to the MERS one (52%), and that it may have originated in bats, as it showed higher similarity (87%) to viruses found in Chinese horseshoe bats, ZC45 and ZXC21 (Chinese Medical Journal (2020) https://doi.org/10.1097/CM9.0000000000000722 ). The connection between horseshoe bats and humans may again have passed through another carrier species. A new zoonotic connection emerged in the shape of the endangered Asian pangolin. In October 2019, Ping Liu, Wu Chen and Jin-Ping Chen from the Guangdong Institute of Applied Biological Resources, Guangzhou, China, reported that they had discovered high loads of coronavirus in blood samples of 21 Malayan pangolins (Manis javanica) that had been confiscated from wildlife traffickers (Viruses (2019) 11, 979). Many of these animals were ill and 16 of them died despite rescue efforts. Although the motivation of the study was rooted in conservation concerns, as the Malayan pangolin is critically endangered, the discovery of the viruses led the researchers to conclude: “Malayan pangolins could be another host with the potential of transmitting the SARS coronavirus to humans. As a consequence, the viral metagenomic study of Malayan pangolin is meaningful both for the conservation of rare wild animals and public health.” th, researchers Shen Yongyi and Xiao Lihua from the South China Agricultural University in Guangzhou reported that they compared the coronavirus sequences from the pangolins to those of the recent outbreak and found them virtually identical. This work, currently submitted for publication, might assign the pangolin a role as an intermediate host between a bat reservoir and the human outbreak, in analogy to the role that palm civets played in the SARS epidemic. Curling up: The four endangered Asian pangolin species are widely poached and trafficked. As yet unpublished analyses of coronaviruses in pangolins confiscated from traffickers suggest they may have been carriers in the transmission of the new coronavirus from bats to humans. (Photo: Shukran888/Wikimedia Commons (CC BY-SA 4.0).) At a press conference held on February 7, researchers Shen Yongyi and Xiao Lihua from the South China Agricultural University in Guangzhou reported that they compared the coronavirus sequences from the pangolins to those of the recent outbreak and found them virtually identical. This work, currently submitted for publication, might assign the pangolin a role as an intermediate host between a bat reservoir and the human outbreak, in analogy to the role that palm civets played in the SARS epidemic. The suggestion casts a spotlight on one of the most endangered and most trafficked groups of mammals. Pangolins, which are armoured with tough scales like armadillos, have the defence strategy of curling up into a ball like a hedgehog. Unfortunately, this makes them vulnerable to human hunters who can just pick them up and take them home. Hunted both for their meat and for the use of their keratin scales in traditional medicine, the four species of Asian pangolins are all endangered, three of them critically. The four African species (two of genus Phataginus, two of Smutsia) are listed as vulnerable or endangered. The critically endangered Asian pangolin species Manis pentadactyla and Manis javanica are featured on the EDGE of existence list of unique and endangered mammals (Curr. Biol. (2018) 28, R1283–R1286). The Zoological Society of London (ZSL), UK, which compiled this ranking, has championed the case of pangolin conservation, which until 2012 didn’t find much attention. One might hope that the news of pangolins carrying coronaviruses might help deter the poachers and traffickers, but then again the reports of farmers kissing their potentially virus-infested camels suggest that rational arguments don’t always win at the human–animal interface.