Introduction
Contemporary human and animal viruses have a broad host range, including human and animal hosts (zoonotic viruses, ie, transmitted between human and animal hosts, and reverse zoonotic viruses, ie, transmitted from the human reservoir to animal hosts),1,2 or have a narrow host range, such as exclusively humans or animals. Two viral diseases have been eradicated worldwide, smallpox and rinderpest (German for “cattle plague”). The eradication was only possible because these viral diseases had an extremely narrow range of nonreservoir host species, smallpox (caused by variola virus, family Poxviridae) in humans3 and rinderpest (caused by rinderpest virus, family Paramyxoviridae) in domestic and wild artiodactyl species.4 However, in the case of smallpox, cattle were historically known to be reservoirs. Indeed, a smallpox-like disease continues to occur in several countries in Asia and South America.5 There is an urgent need to implement comprehensive one-health–approach6 global initiatives to monitor humans and terrestrial farmed, pet, and wild animals (and aquatic animals) for viruses naturally transmitted between humans and animals (Figure 1).
Continuous surveillance of humans, pets, livestock, and wildlife for viruses at the animal-human-environment interface, guided by the host range of zoonotic and reverse zoonotic viruses. Green arrows indicate human and terrestrial animal viruses evolved from aquatic vertebrate viruses. Contemporary human and animal viruses have a broad host range, including human and animal hosts (zoonotic viruses; ie, transmitted between human and animal hosts) or have a narrow host range, such as exclusively humans or animals. The blue arrow indicates reverse zoonotic viruses (ie, transmitted from the human reservoir to animal hosts), which is only possible in certain situations. For example, humans do not transmit the rabies virus to animal hosts because humans do not bite animals, or, in the case of eastern equine encephalitis virus or West Nile virus, humans are dead-end hosts because they do not develop high enough viremia to transmit the virus during a blood meal by an arthropod vector.
Citation: Journal of the American Veterinary Medical Association 261, 6; 10.2460/javma.23.03.0148
Carroll et al7 estimated that approximately 1.67 million unknown viruses from key zoonotic viral families exist in mammalian and avian hosts, and 631,000 to 827,000 of these viruses have zoonotic potential. A better understanding of viral zoonoses and viral reverse zoonoses is critical for the overall health of humans, animals, plants, and ecosystems. However, this continues to be a formidable undertaking.6 This review continues and compliments the companion Currents in One Health by Kibenge, AJVR, June 2023.
Coronaviruses
Coronaviruses are classified in the family Coronaviridae, in the order Nidovirales, which derives its name from the Latin word “nidus,” meaning “nest,” in reference to the unique strategy of genome expression of nidoviruses during replication. The virus particles are enveloped and contain long single-stranded positive-sense polycistronic RNA genomes ranging from 12 to 41 kb—the largest known RNA genomes.8 They are also among the most prone to homologous RNA recombination due to their unique use of random template switching during RNA replication and the innate infidelity of RNA replication.9 The vertebrate coronaviruses are classified in the subfamily Orthocoronavirinae, comprising 4 genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus.
Seven coronaviruses have been known to be zoonotic: HCoV-OC43 and HCoV-299 in 1966, SARS-CoV in 2003, HCoV-NL63 in 2004, HCoV-HKU1 in 2005, MERS-CoV in 2012, and SARS-CoV-2 in 2019. SARS-CoV and MERS-CoV have caused epidemics, whereas SARS-CoV-2 has caused the pandemic of the Coronavirus disease 2019 (COVID-19).10 HCoV-299 and HCoV-NL63 belonging to the genus Alphacoronavirus and HCoV-HKU1 of the genus Betacoronavirus are believed to have originated in either bats or rodents,11,12 whereas betacoronavirus HCoV-OC43 is assumed to have emerged from bovine coronavirus.13 SARS-CoV, MERS-CoV, and SARS-CoV-2, also of the genus Betacoronavirus, are highly pathogenic and lethal and likely originated in bats,14 reaching humans via intermediate animal hosts (farmed and wild-caught masked palm civets [Paguma larvata] and common raccoon dogs [Nyctereutes procyonoides] in the case of SARS-CoV, dromedary camels [Camelus dromedarius] in the case of MERS-CoV,14 and likely common raccoon dogs in the case of SARS-CoV-215).
Coronaviruses are known to readily mutate and give rise to new virulent or genetically divergent strains able to jump host species and adapt quickly to new ecological niches.9 For example, in the Alphacoronavirus genus, a novel canine coronavirus (CCoV) named CCoV-human pneumonia (HuPn)-2018 (CCoV-HuPn-2018), with evidence of recombination with a feline coronavirus, was associated with human pneumonia cases in Malaysia in 2017 to 2018.16 Furthermore, CCoV-HuPn-2018 is the major parent of HuCCoV_Z19Haiti, a novel CCoV isolated from a human case presenting with fever and malaise after traveling to Haiti in 2017.17 This virus is circulating in people at low levels in many parts of the world, making it the eighth coronavirus that has crossed the species barrier to affect humans,16 which also implies that it can be transmitted back to dogs.
In the Betacoronavirus genus, a novel preemergent bat MERS-like coronavirus similar to HKU4-CoV named Manis javanica HKU4-related coronavirus (MjHKU4r-CoV) has been identified circulating in Malayan pangolins.18 MjHKU4r-CoV-1 replicates in human cell lines Caco-2 and Huh-7. It uses human DPP4 as a receptor and bears a furin cleavage site that potentially broadens its host range; it is infectious in human organs and transgenic animals, suggesting that it might jump from pangolins to humans and cause disease.18 It has also been demonstrated that infection by MjHKU4r-CoV-1 can be mediated by DPP4 orthologs from pigs, goats, cats, rabbits, macaques, sheep, camels, marmosets, and cattle, indicating a wide host infection spectrum similar to that of MERS-CoV in terms of receptor usage.18 The study by Chen et al18 provided a novel insight that game animals such as pangolins could be more human-threatening reservoir hosts than bats because they are in closer contact with humans and carry more human-adapted CoVs.18 However, in contrast to MERS-CoV, MjHKU4r-CoV-1 only induced mild to moderate lung pathology in hDPP4-Tg mice, suggesting it is not highly pathogenic.18
SARS-CoV-2
SARS-CoV-2, the cause of the COVID-19 pandemic, has also spread internationally to several animal species as a result of close contact between infected humans and animals,19 with potential for the pandemic to evolve into a panzootic.14 As of December 31, 2022, 699 outbreaks in animals from 36 countries had been reported to the World Organisation for Animal Health, affecting 26 different animal species (cats, dogs, mink, otters, pet ferrets, lions, tigers, pumas, snow leopards, gorillas, white-tailed deer, fishing cat, Binturong, South American coati, spotted hyena, Eurasian lynx, Canada lynx, hippopotamus, hamster, mule deer, giant anteater, West Indian manatee, black-tailed marmoset, common squirrel monkey, mandrill, and red fox).19 Confirmed animal cases of SARS-CoV-2 in the US as of March 13, 2023, were 399 animals in human care (57.9% in cats and dogs), 18 mink farms, and 28 states with detections in wildlife (mink, mule deer, and white-tailed deer).20 Free-ranging white-tailed deer (Odocoileus virginianus) are highly susceptible to infection with the SARS-CoV-2 virus, exposed to a range of viral diversity from humans, and capable of sustaining transmission in nature, allowing the virus to acquire amino acid substitutions in the spike protein (including the receptor-binding domain) and ORF1 that are infrequently seen in humans.21 In addition, infected white-tailed deer in Canada were reported to have spread the virus back to humans,22 demonstrating their potential as reservoir hosts for SARS-CoV-2 viruses. Such reverse zoonosis events are likely to amplify mutations in SARS-CoV-2, which would reinfect humans with deadlier mutants.23 For example, it has been reported that the SARS-CoV-2 Omicron variant may have evolved in a mouse host.24 Some European countries have experienced a high prevalence of SARS-CoV-2 outbreaks in mink farms, and variant strains have been identified in mustelids,19 with evidence that close contact with infected animals can represent a potential source of infection in humans.19 Mink-to-human spread of SARS-CoV-2 has been reported in the Netherlands, Denmark, and Poland, and data suggest it might also have occurred in the US.25 Globally, most of the animals infected have been domestic cats and dogs,19,26 which is not surprising given their close interaction with humans and the high level of pet ownership, but pet-to-human transmission is not common. Cats show efficient viral replication and can transmit SARS-CoV-2 to each other via respiratory droplets.26 Human-to-dog transmission is well documented, but they often display mild symptoms, possibly accompanied by mild viral shedding when infected with the Wuhan strain of SARS-CoV-2.27
Orthopoxviruses
Poxviruses are large, brick-shaped viruses with a 130- to 360-kbp double-stranded DNA genome and replicate in the cytoplasm.28 These viruses have a wide natural host range that comprises mammals, birds, reptiles, fish, and insects. They are classified in the family Poxviridae, which is divided into 2 subfamilies, Chordopoxvirinae for poxviruses of mammals, birds, reptiles, and fish, and Entomopoxvirinae for poxviruses of insects.28 Among the Chordopoxvirinae, the genus Orthopoxvirus, with the prototype vaccinia virus as the most studied, played a historical role in smallpox eradication worldwide in 1980. The last endemic case of smallpox occurred in Somalia in 1977, and the smallpox vaccination was discontinued worldwide in 1980. The genus Orthopoxvirus is highly homogenous, allowing cross-transmission and high antigenic similarity. Consequently, before smallpox was eradicated, outbreaks of cowpox and smallpox were often directly related; smallpox in milkers would spread to cows and manifest as cowpox and vice versa,29 which was recognized by Edward Jenner in 1796 and used as the basis for vaccination against smallpox with vaccinia virus and would represent the first examples of viral reverse zoonosis events.
Vaccinia virus
There are several variants of vaccinia virus, named according to the species or location they were first identified in, including rabbitpox virus (New York 1932 and Utrecht 1941), buffalopox virus (northern India 1967), horsepox virus (Mongolia 1976), and Brazilian vaccinia virus (Brazil 1999), Aracatuba virus, or Cantagalo virus.5 The virus causes disease in several animals, including rodents, cattle, horses, monkeys, and humans.28 During the mass smallpox vaccination campaigns, vaccinia virus infections were occasionally transmitted from vaccinated humans to domestic animals, usually cattle. In turn, infected animals transmitted it back to susceptible humans, which was often misdiagnosed as cowpox.30 The indigenous vaccinia virus infections in dairy cattle and rural workers (milkers) in Brazil, Colombia, and India and Asian buffaloes in India, Pakistan, Bangladesh, Nepal, Iran, Egypt, Indonesia, Russia, and Italy5 are indicative of reverse zoonosis by vaccinia virus and its variants.
Mpox virus
Mpox virus belongs to the Orthopoxvirus genus. The virus is endemic in squirrels and other rodents in Africa,31 with sporadic transmissions to monkeys and humans. Human infections occur in remote villages near tropical rainforests in Central and West Africa through direct contact with wildlife killed for food.32 Mpox (human monkeypox) was given its name in 1970 (after the virus that causes the disease was discovered in captive monkeys in the Netherlands in 1958).31 In November 2022, WHO renamed it “mpox” following WHO best practices in naming diseases. The disease in humans resembles smallpox, albeit less contagious and less severe, and vaccination with smallpox vaccines ACAM2000, Dryvax, and JYNNEOS (Modified Vaccinia Ankara-Bavarian Nordic; MVA-BN) is protective.33 The mpox virus occurs in 2 distinct clades, which Happi et al,34 together with WHO, named Clade I (formerly Congo Basin [Central African]) and Clade II (formerly West African), with Clade II consisting of 2 subclades: Clade IIa and Clade IIb, with the latter referring primarily to the group of variants largely circulating in the 2022 global outbreak. Clade IIb consists of 2 lineages, B.1 and A.2, with the 2022–2023 mpox outbreak predominantly being lineage B.1.35 The first known human infections of mpox outside of Africa occurred in the US in 200336 in an outbreak that was linked to a shipment of small mammals from Ghana, West Africa, imported to Texas in April 2003.33,36 The virus spread to the prairie dogs (Cynomys ludovicianus) captured in Texas for use as pets and housed together with the Gambian pouched rats and dormice imports; all the human cases who contracted the virus had direct or close contact with recently purchased sick prairie dogs that had been infected after being housed near the infected imported animals.35 Because of this outbreak, the sale and display of North American prairie dogs and some African rodent species are now banned in the US, and an embargo was placed on importing rodents from Africa.37 Mpox was also reported in travelers from Nigeria to Israel in September 2018; the UK in September 2018, December 2019, and May 2021; Singapore in May 2019; and the US in July 2021 (Texas) and November 2021 (Maryland).33 Prior to this, other mpox outbreaks outside of Africa had only been reported in captive monkeys, with 2 outbreaks in Denmark in 1958, which led to the discovery of the mpox virus,31,38 and 2 times in the US in 1959 and 1962.31 In May 2022, a nontravel-associated cluster of mpox cases was reported in the UK and later spread to other European countries.39 The spread developed into a massive outbreak of human cases in different nonendemic countries without known epidemiological links to the endemic areas of West or Central Africa or animal sources. However, with a travel history to countries in Europe and North America, the cases have been concentrated in, but not exclusive to, men who have sex with men.40 The virus is believed to have been circulating via human-to-human transmission since April 2022.41 However, the earliest case identified through retrospective testing of a residual sample in the UK was on March 7, 2022, suggesting there had been undetected transmission for some time. In July 2022, WHO declared the mpox outbreak the seventh public health emergency of international concern.42 This outbreak continues to constitute a public health emergency of international concern.35 As of March 14, 2023, 86,516 laboratory-confirmed cases of mpox and 111 deaths have been reported in 110 countries.35 According to WHO, confirmation of 1 case of mpox in a country is considered an outbreak.35
In August 2022, the first case of human-to-dog transmission (reverse zoonosis of mpox) was reported in France.43 The case involved 2 men living in the same household with the dog (Italian Greyhound, 4 years old), with confirmed mpox in both men and confirmed mpox in the dog 12 days after their symptom onset. A single case of reverse transmission to a dog has also been reported in Brazil.44 The reported cases of mpox in dogs suggest the potential for reverse zoonosis transmission of the mpox virus (Clade IIb).45 However, combined surveillance and observations in the UK found no evidence of the mpox virus in pets, and the risk of mpox virus reverse zoonosis was assessed to be low.45 Moreover, because the first reported human-to-dog transmission of mpox virus was detected by PCR in a cutaneous swab, but the dog was negative by serology,43 it is unclear whether the dog was infected or the PCR just detected surface-contaminated virus. Regardless, mpox has a broad host range that might facilitate its adaptation to local susceptible animals in new geographical regions,46,47 much like the vaccinia virus becoming established in water buffalo in India and cattle in Brazil.32,48 Moreover, such a spillover event may be unrecognizable because animals infected with the mpox virus typically do not show the same clinical signs as humans and could potentially lead to the virus establishing in wildlife and the disease becoming an endemic zoonosis.40 Blagrove et al46 used a machine learning algorithm to predict several animal species potentially susceptible to the mpox virus. Approximately 80% of the newly predicted hosts were from the Rodentia and Primates orders. In Europe, the authors singled out the European red fox (Vulpes vulpes), the brown rat (Rattus norvegicus), the herb field mouse (Apodemus uralensis), Alpine marmot (Marmota marmota), the yellow-necked field mouse (Apodemus flavicollis), and domesticated cats and dogs as potentially susceptible to mpox virus with population numbers and behaviors that would sustain ongoing transmission and with opportunities for potential retransmission to humans.46 In China, the Tibetan macaque (Macaca thibetana), Himalayan marmot (Marmota himalayana), and Mongolian gerbil (Meriones unguiculatus) were predicted as potentially susceptible to the mpox virus. In North America, the striped skunk (Mephitis mephitis), Virginia opossum (Didelphis virginiana), and common raccoon (Procyon lotor) were predicted to be susceptible to mpox virus. All these animal species were suggested as surveillance priorities to help minimize the risk of the mpox virus becoming endemic in new regions.46 A one-health approach, including consideration of land-use change and the bushmeat and exotic pet trades, is required to prevent opportunities for the emergence of mpox, or diseases caused by other orthopoxviruses, and for a rapid and effective response to any outbreaks to limit their spread.49
Arboviruses
Arboviruses are viruses transmitted to humans or vertebrate animals by hematophagous arthropods, insects (mainly), and ticks. The arthropods serve as biological vectors since the viruses replicate in the vectors before transmission. In contrast, arthropod mechanical vectors are nonspecific, there is no virus replication, and the arthropod only serves as a syringe transmission. Moreover, whereas RNA viruses switch between hosts quite readily, the arthropod-borne property of viruses is conserved. Consequently, Babayan et al50 used machine learning algorithms to analyze genomic sequences from 12 taxonomic groups (11 families and 1 order) of single-stranded RNA (ssRNA) viruses that can infect humans (which is 80% of all human-infective groups) and was able to predict their animal reservoir hosts, whether they were arboviruses, and the identity of their arthropod vectors. The most important human arboviruses are in the tropical and subtropical areas worldwide and include yellow fever virus (YFV), dengue virus (DENV), zika virus (ZIKV), and chikungunya virus (CHIKV).51 Arboviral infections are among the greatest public health concerns in the Americas because of their increasing geographical spread and disease incidence.52 YFV, DENV, and ZIKV are classified in the family Flaviviridae, genus Flavivirus (previously Group B arboviruses), whereas CHIKV is classified in the family Togaviridae, genus Alphavirus (previously Group A arboviruses). Members of Flaviviridae and Togaviridae have enveloped virus particles with positive-sense ssRNA genomes.53,54 These families also include important veterinary viruses (eg, West Nile virus in the Flavivirus genus and the equine eastern/western/Venezuelan equine encephalitis viruses [EEEV/WEEV/VEEV] and Madariaga virus, EEEV lineages II, III, and IV, in Alphavirus genus).
As demonstrated by Figueiredo,51 YFV, DENV, ZIKV, and CHIKV can infect wild animals in the sylvatic (forest) cycle, causing epidemics of severe diseases whereby humans in the urban (or periurban) cycle are the source of viruses for the animals (Figure 2), which is consistent with viral reverse zoonosis. The most recent outbreak of yellow fever in Southeast Brazil from 2016 to 2018 killed at least 732 monkeys and was hypothesized to be of human origin.55 Humans infected in an urban cycle through Aedes aegypti mosquito bites can travel long distances over short periods, shuttling the disease from urban areas to forests where the sylvatic cycle occurs.56 The control of an arboviral sylvatic cycle is problematic since it is impossible to know where, when, or why a spillover would occur in wild animals, leaving it only possible to prevent the occurrence of an urban cycle as a spillover from the sylvatic cycle.51,55 Additionally, these arboviruses can be carried by infected travelers (imported cases) and may establish new areas of local transmission in the presence of vectors and a susceptible population.57 WHO recommends prevention efforts to be highly focused on the arbovirus surveillance in and control of Aedes spp mosquitoes (the most competent vector in the region).57 Arbovirus surveillance in wild animals and vaccination of humans against YFV and DENV are also important, as are the development of fast and reliable diagnostic methods for arbovirus infections in humans and animals, including genome surveillance for mutations, and development of efficacious antiviral drugs to treat human patients.51
Arbovirus jumping to the wild maintenance cycle from the urban cycle due to the Aedes aegypti vector infecting nonhuman primates or viremic individuals infecting the wild mosquito. From Figueiredo LTM. Human urban arboviruses can infect wild animals and jump to sylvatic maintenance cycles in South America. Front Cell Infect Microbiol. 2019;9:259. doi:10.3389/fcimb.2019.00259. Used under the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Citation: Journal of the American Veterinary Medical Association 261, 6; 10.2460/javma.23.03.0148
Venezuelan equine encephalitis virus
VEEV is endemic in Central and South America and causes sporadic outbreaks of equine and human encephalitis. Humans are usually dead-end hosts for equine alphavirus infections (EEEV and WEEV) except in VEEV, in which humans have a high enough viremia to be a source of virus for the arthropod vectors.58 VEEV occurs in 2 epidemiological groups: enzootic and epizootic virus strains. Enzootic VEEV strains (subtype 1, varieties D through F, and subtypes II through VI) use Culex spp vector and are generally avirulent for and incapable of amplification in equines. In contrast, humans are tangential spillover hosts and develop a severe febrile illness that can be fatal.58 Enzootic VEEV exists continuously in tropical regions, and there is a risk of the emergence of epizootic strains leading to equine and human outbreaks. Epizootic VEEV strains (subtype I, varieties A through C) are responsible for all major outbreaks in humans and equines, use several mosquito vectors, and use equines, dogs, and humans as highly efficient amplification hosts. They generate a sufficiently high-titer viremia to amplify the virus significantly and cause highly fatal encephalitis in equines; humans develop a severe febrile illness that can be fatal.58 Global warming may facilitate the emergence of VEEV epidemics by leading to longer transmission seasons and changes in rainy seasons, increasing mosquito populations and geographic distributions of tropical mosquito vectors.59 In endemic regions, surveillance programs for early detection and implementation of mosquito control and equine vaccination help control outbreaks.
Recent Examples of Viral Reverse Zoonoses in Endangered Species
Other recent examples of viral reverse zoonoses include human respiratory viruses in virus families Paramyxoviridae (human respirovirus 3, HRPV-3, and human respiratory syncytial virus), Pneumoviridae (human metapneumovirus [HMPV]), and Picornaviridae (human rhinovirus C) causing disease in endangered species. Köndgen et al60 reported transmission of human respiratory syncytial virus and HMPV from humans (most likely research personnel) to habituated chimpanzees at the Taï chimpanzee research project in Côte d’Ivoire. The data obtained suggested that humans had recently introduced the 2 viruses directly and repeatedly into wild chimpanzee populations.60 Palacios et al61 reported human transmission of HMPV to 2 wild mountain gorillas that died during a respiratory disease outbreak in Rwanda in 2009. Scully et al62 reported human rhinovirus C transmitted to wild chimpanzees in Uganda in 2013. Negrey et al63 reported HMPV and HRPV-3 transmitted to 2 chimpanzee communities in the same forest in Uganda in December 2016 and January 2017. The HMPV was closely related to a lethal 2009 variant from mountain gorillas, suggesting 2 independent and simultaneous reverse zoonotic origins, either directly from humans or via intermediary hosts.63 Kaur et al64 previously reported the detection of an HMPV in a habituated group of wild chimpanzees at the Mahale Mountains National Park, Tanzania; the virus was believed to have been transmitted by researchers and visitors to the national park where the chimpanzees resided.64
Control and Prevention of Reverse Zoonoses
The prevention and control of zoonotic diseases require the direct protection of humans within their environment (managed by the national public health agencies such as the CDC and Public Health Agency of Canada, and international organizations such as the WHO and United Nations Environment Program), reduction or elimination of the infection in the animal reservoir (managed by the national regulatory agencies such as USDA-APHIS and Canadian Food Inspection Agency and international organizations such as the Food and Agriculture Organization and World Organisation for Animal Health), and arthropod control measures (which is in the pervue of public health agencies).1 Regarding wildlife, Wallis and Lee65 reviewed the risks of transmitting human-carried diseases to nonhuman primates in natural settings and the strategies to prevent reverse zoonosis. Solutions require changing human behavior and policies at all levels—field researchers, veterinarians, human health-care providers, park personnel, government officials, local villagers, and tourists.65 Gryseels et al12 suggested guidelines to prevent the transfer of SARS-CoV-2 to wildlife during activities such as wildlife research, conservation activities, forestry work, pest control, management of feral populations, ecological consultancy work, management of protected areas and natural environments, wildlife tourism, and wildlife rehabilitation in animal shelters. These guidelines also apply where other viruses might be transferred from humans to animals. The same measures that prevent zoonotic diseases are also effective ways to reduce reverse zoonoses given that the human activities that facilitate viral zoonoses also facilitate environments that favor viruses with a broad host range, the main risk factor for the emergence of viral reverse zoonotic diseases. Most of these preventative measures aim to reduce the impact of diseases on humans and animals. For example, during the 2013–2016 West African Ebola outbreak, the largest and longest Ebola outbreak in history, the WHO developed an R&D Blueprint for action to prevent epidemics that aimed at averting and minimizing loss of human life and economic disruption due to an outbreak by reducing response time to availability of effective tests, vaccines, and medicines.66
There is an arguably critical need for a better understanding of the viral etiology as well to allow the design of robust predictive instruments to reduce and, where possible, eliminate the causes of zoonotic diseases,67 as was articulated in the One Health Joint Action Plan 2022–2026,6 WHO Blueprint,66 and Tripartite Zoonoses Guide.68 Considering the globalization of humans and animal products, termed the global express,69 a pathogenic virus anywhere can reach anywhere in a matter of hours, which occurred with the recent pandemics (2009 influenza A [H1N1] and SARS-CoV-2) and epidemics (SARS-CoV-1, MERS-CoV, Mpox, YFV, DENV, ZIKV, and CHIKV). There is, therefore, a need for continuous surveillance and monitoring at the animal-human-environment interfaces and key animal value-chain points (particularly wildlife [eg, bushmeat], livestock, and pets with direct contact or indirect contact [eg, via arthropods] with humans)70 for viruses known to have a wide host range (Figure 1), while also considering “Disease X,” caused by a yet-unknown zoonotic pathogen and with the potential to develop into a future epidemic/pandemic,6 and undertake viral genome sequencing (“genomic surveillance”)71 to catalog both zoonotic and reverse zoonotic mutations that could be used to identify potentially dangerous viruses rapidly. Machine learning algorithms are now available that can rapidly generate this information from sequence data.50 If this information is available, it would direct where effective preventative measures should be focused to mitigate human and animal health crises and eliminate potential delays. For example, Babayan et al,50 using machine learning algorithms to analyze genomic sequences of human ssRNA viruses, were able to predict animal reservoirs for viruses with previously unknown hosts (referred to as “orphan” viruses); O’nyong-nyong virus (family Togaviridae) and Bundibugyo and Tai Forest ebolaviruses were predicted to have primate reservoirs. Furthermore, machine learning algorithms can identify viruses with very limited research data for prioritized surveillance, facilitating quicker interventions that can limit future reemergences.50 Targeted one-health surveillance would include humans (with high levels of exposure to wild animals such as hunters, butchers of wild game, wildlife veterinarians, workers in wildlife trade, and zoo workers), livestock, pets, and wild animal die-offs not only providing a global early warning system70 but also exposing gaps in our knowledge of zoonotic viruses and their natural hosts,6 helping to fill in gaps in our understanding of the origin viruses (ie, the “origins initiative” proposed by Wolfe et al70) and generating prototypic vaccine candidates.
With the ongoing COVID-19 pandemic, several municipal and national programs have been initiated using wastewater-based epidemiology to assess and mitigate viral outbreaks involving human viruses shed in feces and urine (eg, SARS-CoV-2 and its emerging variants).72 Although these programs are not coordinated globally, wastewater-based epidemiology is considered a useful tool for monitoring in real-time the transfer of human viruses at the community level and across international borders and is recommended for monitoring and containing the spread of future human disease outbreaks.73 Perhaps the most comprehensive program in terms of large-scale sampling and viral discovery is the Global Virome Project (GVP), launched in 2018.7 The aim of GVP is to identify and characterize, within 10 years (ie, by 2028), 99% of all zoonotic viruses with epidemic/pandemic potential to better predict, prevent, and respond to future viral pandemic threats.7 The key deliverables of the GVP would provide a better understanding of the viral etiology of zoonoses and reverse zoonoses. Such a multifaceted undertaking requires a one-health approach and significant funding at a global scale.6
Ultimately, without any prospect of eradicating the recent viral reverse zoonoses, including those caused by members of the virus families Orthomyxoviridae, Coronaviridae, and Poxiviridae and arboviruses, and, for endangered nonhuman primate species, the human respiratory viruses, the best way to prevent animal infections transmitted from humans is to reduce contact with wildlife animal species and, where effective vaccines are available, to vaccinate the main reservoir—humans and susceptible farmed and pet animals.74 Such a strategy would protect farmed and pet animals against viral reverse zoonosis and prevent spillover into the human population.
Conclusion
Coronaviruses continue to emerge as new zoonotic agents, including a canine coronavirus, CCoV-HuPn-2018, circulating in people at low levels, and a pangolin coronavirus, MjHKU4r-CoV-1, circulating in Malayan pangolins. Moreover, the risk for SARS-CoV-2 variants to mutate in animal reservoirs like mink, white-tail deer, and mice and reinfect humans is ongoing. However, there are efficacious vaccines and antivirals for humans. In the case of mpox, the risk of reverse zoonosis is low and there are also vaccines and antivirals for use in humans at risk. The situation with arboviruses is as varied as the number of human arboviruses, and only YFV and DENV have licensed vaccines in the Americas. As for reverse zoonoses in endangered species, solutions require changing human behavior and policies at all levels impacting wildlife. Most preventative measures, which have always been after the occurrence of the disease events, have aimed at reducing the impact of diseases on humans and animals. However, there is an arguably critical need for a better understanding of the viral etiology of zoonoses and reverse zoonoses that would facilitate quicker interventions to prevent future reemergences. Overall, continuous surveillance and viral discovery in humans and animals remain a core component of a one-health approach to reduce and, where possible, eliminate zoonotic and reverse zoonotic diseases. Ultimately, without any prospect of eradicating the recent viral reverse zoonoses, the best way to prevent animal infections transmitted from humans is to reduce contact with wildlife animal species and, where effective vaccines are available, vaccinate the main reservoir—humans and susceptible farmed and pet animals.
Acknowledgments
No third-party funding or support was received in connection with the writing of the manuscript.
Dr. Kibenge serves as Associate Editor for the Journal of the American Veterinary Medical Association (JAVMA). He declares that he had no role in the editorial direction of this manuscript.
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