viruses Review Here, There, and Everywhere: The Wide Host Range and Geographic Distribution of Zoonotic Orthopoxviruses Natalia Ingrid Oliveira Silva, Jaqueline Silva de Oliveira, Erna Geessien Kroon , Giliane de Souza Trindade and Betânia Paiva Drumond * Laboratório de Vírus, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais: Belo Horizonte, Minas Gerais 31270-901, Brazil; [email protected] (N.I.O.S.); [email protected] (J.S.d.O.); [email protected] (E.G.K.); [email protected] (G.d.S.T.) * Correspondence: [email protected] Abstract: The global emergence of zoonotic viruses, including poxviruses, poses one of the greatest threats to human and animal health. Forty years after the eradication of smallpox, emerging zoonotic orthopoxviruses, such as monkeypox, cowpox, and vaccinia viruses continue to infect humans as well as wild and domestic animals. Currently, the geographical distribution of poxviruses in a broad range of hosts worldwide raises concerns regarding the possibility of outbreaks or viral dissemination to new geographical regions. Here, we review the global host ranges and current epidemiological understanding of zoonotic orthopoxviruses while focusing on orthopoxviruses with epidemic potential, including monkeypox, cowpox, and vaccinia viruses. Keywords: Orthopoxvirus; Poxviridae; zoonosis; Monkeypox virus; Cowpox virus; Vaccinia virus; host range; wild and domestic animals; emergent viruses; outbreak Citation: Silva, N.I.O.; de Oliveira, J.S.; Kroon, E.G.; Trindade, G.d.S.; Drumond, B.P. Here, There, and Everywhere: The Wide Host Range 1. Poxvirus and Emerging Diseases and Geographic Distribution of Zoonotic diseases, defined as diseases or infections that are naturally transmissible Zoonotic Orthopoxviruses. Viruses from vertebrate animals to humans, represent a significant threat to global health [1]. 2021, 13, 43. https://doi.org/ Among the species recognized as pathogenic to humans, more than half originated in 10.3390/v13010043 animals, and some have been characterized as emerging or re-emerging pathogens [2,3]. Academic Editors: Jônatas Abrahão Most zoonotic pathogens originated in wild and domesticated mammalian hosts such as and Hermann Meyer bats, rodents, and primates [4]. The analysis of global trends indicates that new zoonotic Received: 14 November 2020 threats will continue to emerge at an accelerating rate, and are mainly associated with an Accepted: 24 December 2020 growthing population, changes in land use, climate changes, increased intercontinental Published: 30 December 2020 travel, and expanded trade networks [4,5]. Poxviruses are of great veterinary and human importance and infect numerous Publisher’s Note: MDPI stays neu- vertebrate and invertebrate animals, including humans. The Poxviridae family is di- tral with regard to jurisdictional clai- vided into two subfamilies, namely: Chordopoxvirinae, which infect vertebrates, and Ento- ms in published maps and institutio- mopoxvirinae (A–C), which infect invertebrates. The Chordopoxvirinae subfamily is further nal affiliations. divided into 18 genera (Avipoxvirus, Capripoxvirus, Centapoxvirus, Cervidpoxvirus, Crocodylid- poxvirus, Leporipoxvirus, Macropopoxvirus, Molluscipoxvirus, Mustelpoxvirus, Orthopoxvirus, Oryzopoxvirus, Parapoxvirus, Pteropopoxvirus, Salmonpoxvirus, Sciuripoxvirus, Suipoxvirus, Vespertilionpoxvirus, and Yatapoxvirus), distinguishable by their serological reactions [6,7]. Copyright: © 2020 by the authors. Li- The family Poxviridae comprises large, brick-shaped or ovoid enveloped viruses censee MDPI, Basel, Switzerland. This article is an open access article containing a linear, double-stranded DNA genome approximately 200 kilobase pairs in distributed under the terms and con- length [7,8]. Poxviruses are among mankind’s longest and best-known viruses mainly ditions of the Creative Commons At- because of their most feared and lethal representative, Variola virus (VARV), the causative tribution (CC BY) license (https:// agent of smallpox. Before its remarkable eradication in 1980, VARV represented a centuries- creativecommons.org/licenses/by/ old threat to humans worldwide and killed approximately 300–500 million people during 4.0/). the 20th century [9]. The global eradication of smallpox marked the culmination of an Viruses 2021, 13, 43. https://doi.org/10.3390/v13010043 https://www.mdpi.com/journal/viruses Viruses 2021, 13, 43 2 of 20 Viruses 2021, 13, x FOR PEER REVIEW 2 of 21 ofintensive an intensive vaccination vaccination program program and quarantine and quarantine measures measures promoted promoted by the by World the World Health HealthOrganization Organization (WHO) (WHO) [8,10,11 ].[8,10,11]. Although Although VARV was VARV eradicated was eradicated 40 years ago, 40 years many ago, chal- manylenges challenges regarding regarding poxvirus infectionspoxvirus infections persist, including persist, theincluding worrisome the worrisome possibility possibil- of VARV ityreintroduction of VARV reintroduction by accidental by release, accidental its use release, as a biological its use as weapon, a biological or the weapon, emergence or andthe emergencere-emergence and of re-emergence zoonotic orthopoxviruses of zoonotic orthopoxviruses worldwide [12, 13worldwide]. [12,13]. OrthopoxvirusesOrthopoxviruses are are remarkable remarkable for for their their wide wide host host spectrum, spectrum, ranging ranging from from humans humans toto domestic domestic and and wild wild animals animals (Figure (Figure 11).). OrthopoxvirusOrthopoxvirus isis the the most most important important and and well- well- characterizedcharacterized poxvirus poxvirus genus, genus, mainly mainly due due to to its its impact impact on on human human and and animal animal health health [7,8]. [7,8]. Here,Here, we we review review the the major major aspects aspects related related to to the the dynamics dynamics and and emergence emergence of of zoonotic zoonotic orthopoxvirusorthopoxvirus infections infections worldwide, worldwide, focusing focusing on on the the host host range range and and current current epidemio- epidemio- logicallogical situation situation relating relating to to monkeypox monkeypox (MPXV), (MPXV), cowpox cowpox (CPXV), (CPXV), vaccinia vaccinia (VACV), (VACV), and and VACV-likeVACV-like viruses. FigureFigure 1. 1. TheThe worldwide worldwide distribution distribution and and host host range range of of monkeypox, monkeypox, cowpox cowpox and and vaccinia vaccinia viruses. viruses. TheThe image image shows shows the the range range of of animal animal hosts hosts (represented (represented by by orders) orders) that that have have been been demonstrateddemonstrated to to be be natu naturallyrally infected byby somesomeOrthopoxvirus Orthopoxvirusspecies, species, according according to to different differ- entregions regions of theof the world world (except (except by Monkeypox by Monkeypox virus virus in the in United the United States States of America, of America, repre- representedsented by imported by imported cases). cases). Orthopoxvirus Orthopoxvirus infections infections have have been been demonstrated demonstrated in animals in an- imalsbelonging belonging to different to different orders, orders, using different using different methods methods (virus isolation, (virus isolation, molecular molecular detection detectionof viral genomes of viral orgenomes serological or screeningserological for screening antibodies for against antibodies orthopoxviruses). against orthopox- The oc- viruses).currence The of some occurrence zoonotic of orthopoxviruses some zoonotic orthopoxviruses has already been has confirmed already (by been virus confirmed isolation (byor molecularvirus isolation detection or molecular of the viral detection genome) of the in some viral geographicalgenome) in some regions geographical (indicated re- by gionscolored (indicated dots: blue: by colored vaccinia dots: virus blue: (including vaccinia buffalopox virus (including and rabbitpox buffalopox viruses) and rabbitpox in South America, Europe, Asia, and the Middle East; brown: monkeypox virus in Africa and North viruses) in South America, Europe, Asia, and the Middle East; brown: monkeypox virus America; orange: cowpox virus in Europe and Asia). in Africa and North America; orange: cowpox virus in Europe and Asia). Viruses 2021, 13, 43 3 of 20 2. Orthopoxvirus The Orthopoxvirus genus comprises VARV,VACV,CPXV,MPXV, camelpox virus, Akhmeta virus, and other species with zoonotic potential. All orthopoxviruses share significant DNA sequence similarity and are immunologically cross-reactive and cross-protective. Infection with any orthopoxvirus is considered to generate protection against exposure or re- expo- sure to any other member of the genus [14,15]. Orthopoxvirus species are named primarily according to the hosts from which they were first isolated and identified; however, the name does not necessarily represents its natural reservoir or complete host range [8,16–19]. Despite the large number of studies, little is known about the primary hosts and reservoirs of zoonotic orthopoxviruses in nature, or their transmission and maintenance cycles [20]. Regarding the host range, orthopoxviruses can be both highly specialized and host re- stricted or generalists with a broad host range. For instance, VARV is a highly specialized virus that infects only humans, whereas MPXV, CPXV, and VACV are examples of gener- alist zoonotic orthopoxviruses that can infect several mammalian host