Genetic Diversity and Geographic Distribution of Bat-borne Hantaviruses Satoru Arai1* and Richard Yanagihara2* 1Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Shinjuku, Tokyo, Japan. 2Pacifc Center for Emerging Infectious Diseases Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, USA. *Correspondence: [email protected] and [email protected] htps://doi.org/10.21775/cimb.039.001 Abstract as well as the pathogenic potential, of bat-borne Te recent discovery that multiple species of viruses of the family Hantaviridae. shrews and moles (order Eulipotyphla, families Soricidae and Talpidae) from Europe, Asia, Africa and/or North America harbour genetically distinct Introduction viruses belonging to the family Hantaviridae (order As recently as a decade ago, the single exception Bunyavirales) has prompted a further exploration to the strict rodent association of hantaviruses of their host diversifcation. In analysing thousands was Totapalayam virus, a long-unclassifed virus of frozen, RNAlater®-preserved and ethanol-fxed originally isolated from the Asian house shrew tissues from bats (order Chiroptera) by reverse (Suncus murinus) (Carey et al., 1971). Analysis of transcription polymerase chain reaction (RT-PCR), the genome of Totapalayam virus strongly sup- ten hantaviruses have been detected to date in bat ported an ancient non-rodent host origin and an species belonging to the suborder Yinpterochirop- early evolutionary divergence from rodent-borne tera (families Hipposideridae, Pteropodidae and hantaviruses (Song et al., 2007a; Yadav et al., 2007). Rhinolophidae) and the suborder Yangochiroptera Equipped with this information and employing (families Emballonuriade, Nycteridae and Vesper- reverse transcription polymerase chain reaction tilionidae). Of these, six hantaviruses are from Asia (RT-PCR), genetically distinct hantaviruses were (Xuân Sơn virus and Đakrông virus in Vietnam; detected in multiple species of shrews (order Euli- Láibīn virus in China and Myanmar; Huángpí virus potyphla, family Soricidae) from widely separated and Lóngquán virus in China; and Quezon virus in geographic regions in Asia, Europe, Africa and the Philippines); three are from Africa (Mouyassué North America. In addition to challenging the con- virus in Côte d’Ivoire and Ethiopia; Magboi virus ventional view that rodents are the sole or principal in Sierra Leone; and Makokou virus in Gabon); reservoirs of hantaviruses, the discovery of soricid- and one from Europe (Brno virus in the Czech borne hantaviruses suggested that moles (order Republic). Molecular identifcation of many more Eulipotyphla, family Talpidae) might also harbour bat-borne hantaviruses is expected. However, thus hantaviruses, and as predicted, several talpid-borne far, none of these newfound viruses has been iso- hantaviruses have been found in Europe, Asia and lated in cell culture and it is unclear if they cause North America (Yanagihara et al., 2014). infection or disease in humans. Future research Acquisition of new knowledge about the spatial must focus on myriad unanswered questions about and temporal distribution, host range and genetic the genetic diversity and geographic distribution, diversity of hantaviruses in shrews and moles, and caister.com/cimb 1 Curr. Issues Mol. Biol. Vol. 39 Arai and Yanagihara more recently in bats, has been made possible insights into their evolutionary origins and future largely through the generosity of museum curators risk and disease emergence. and feld mammalogists, who willingly granted access to their archival tissue collections. Te avail- ability of such well-curated specimens provides Taxonomy strong justifcation for the continued long-term Previously classifed in an unassigned order and in maintenance and near-term expansion of archival the genus Hantavirus of the family Bunyaviridae, tissue repositories for future investigations and hantaviruses have been recently reclassifed and innovative applications (Dunnum et al., 2017). reassigned to a new family, designated Hantaviridae, Phylogenetic analyses of these newfound han- in the order Bunyavirales (Adams et al., 2017; Maes taviruses indicate at least four distinct clades, with et al., 2018). Viruses belonging to the four other the most divergent lineage comprising hantaviruses genera formerly in the family Bunyaviridae (namely, harboured by the European mole (Talpa euro- Nairovirus, Orthobunyavirus, Phlebovirus, and paea) (Kang et al., 2009c) and several bat species Tospovirus) are now members of new viral families: (Sumibcay et al., 2012; Weiss et al., 2012; Arai et Feraviridae, Fimoviridae, Jonviridae, Nairoviridae, al., 2013; Guo et al., 2013; Gu et al., 2014c; Xu et Peribunyaviridae, Phasmaviridae, Phenuiviridae, and al., 2015; Arai et al., 2016b; Witkowski et al., 2016; Tospoviridae. Straková et al., 2017; Těšíková et al., 2017; Arai et Te family Ha n t a v i r i d a e has been further classifed al., 2019a; Arai et al., 2019b). On the basis of inten- into four subfamilies (Actantavirinae, Agantavirinae, sive phylogenetic analysis of the full-length S- and Mammantavirinae and Repantavirinae) (Table 6.1). M-genomic segments, a new taxonomic classifca- Te subfamily Mammantavirinae comprises four tion has been proposed, which includes four newly genera (Loanvirus, Mobatvirus, Orthohantavirus and defned subfamilies in the family Hantaviridae Totimvirus), based on DEmARC analysis, using (Maes et al., 2019). In addition, the realization that concatenated complete S and M amino acid-coding these Eulipotyphla- and Chiroptera-borne hantavi- regions (Maes et al., 2019). Virus members of each ruses are more genetically diverse than those found genus in the subfamily Mammantavirinae, with in rodents, as well as the discovery of hantavirus- their mammalian reservoir host category (rodent, like sequences in fsh and reptile hosts, suggests that shrew, mole and bat), are summarized in Table the evolutionary history of the Hantaviridae is far 6.1. In addition, recently published hantavirus-like more complex than previously conjectured. Tus, sequences from fsh and reptile, which are closely the dawn of a new era in hantavirology is focused related and ancestral to hantaviruses harboured by on exploring the inconvenient evidence that mammals (Shi et al., 2018), have been classifed rodents may not be the original mammalian hosts into the newly created subfamilies of Actantavirinae of primordial hantaviruses. Also, the once-growing and Agantavirinae and Repantavirinae, respectively complacency and indiference towards rodent- (Table 6.1). borne hantaviruses is being replaced by renewed All rodent-borne hantaviruses belong to the zeal to fll major gaps in our understanding about genus Orthohantavirus, which also comprises the ecology, transmission dynamics and pathogenic nearly all of the genetically distinct hantaviruses potential of these newly discovered, still-orphan recently detected in shrews and moles (Table 6.1). hantaviruses, before the emergence of the next new Te exceptions are members of the genus Tot- hantavirus disease outbreak occurs (Yanagihara et timvirus: Totapalayam virus in the Asian house al., 2015). shrew (Suncus murinus) (Carey et al., 1971; Song Te history of research on this once-obscure et al., 2007a; Kang et al., 2011c) and Imjin virus in group of rodent-borne viruses has been marked by the Ussuri white-toothed shrew (Crocidura lasiura) rediscovery and new beginnings (Yanagihara et al., (Song et al., 2009), as well as probably Uluguru 2014). In this brief review, the genetic diversity and virus in the Geata mouse shrew (Myosorex geata) geographic distribution of hantaviruses from bats (Kang et al., 2014) and Kilimanjaro virus in the will be summarized in the context of hantaviruses Kilimanjaro mouse shrew (Myosorex zinki) (Kang harboured by rodents, shrews and moles to provide et al., 2014). By contrast, all newfound hantaviruses caister.com/cimb 2 Curr. Issues Mol. Biol. Vol. 39 Bat-borne Hantaviruses Table 6.1 Taxonomic classifcation of viruses belonging to the family Hantaviridae and their reservoir host category Subfamily Genus Host Virus namea Actantavirinae Actinovirus Fish Hagfsh Agantavirinae Agnathovirus Fish Batfsh, Goosefsh, Spikefsh Mammantavirinae Loanvirus Bat Brno, Huángpí, Lóngquán, Magboi, Mouyassué Mobatvirus Bat Đakrông, Láibīn, Makokou, Quezon, Xuân Sơn Mole Nova Orthohantavirus Rodent Andes, Bayou, Black Creek Canal, Cano Delgadito, Choclo, Dàbiéshān, Dobrava, El Moro Canyon, Fugong, Hantaan, Khabarovsk, Laguna Negra, Lúxī, Maporal, Montano, Necocli, Prospect Hill, Puumala, Sangassou, Seoul, Sin Nombre, Thailand, Tigray, Tula Shrew Ash River, Asikkala, Azagny, Boginia, Bowé, Cao Bằng, Jeju, Jemez Springs, Kenkeme, Qian Hu Shan, Seewis, Tanganya, Yákèshí Mole Asama, Bruges, Oxbow, Rockport Thottimvirus Shrew Imjin, Kilimanjaro, Thottapalayam, Uluguru Mole Dahonggou Creek Repantavirinae Reptillovirus Reptile Gecko aVirus names shown in italics indicate the presumptive taxonomic placement in the absence of full-length S- and M-segment sequences. The names for the viruses in the genera Actinovirus, Agnathovirus and Reptillovirus are tentative. harboured by bats belong to the genera Loanvirus caused by a few rodent-borne orthohantaviruses and Mobatvirus (Table 6.1). in Europe, Asia and the Americas (Lee et al., 1979; To minimize unnecessary confusion, the viruses Brummer-Korvenkontio et al., 1980; Nichol et newly classifed in the family Hantaviridae will be al., 1993; Jonsson et