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Why Do Poxviruses Still Matter? Zhilong Yang1,2* , Mark Gray2 and Lake Winter2

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Why Do Poxviruses Still Matter? Zhilong Yang1,2* , Mark Gray2 and Lake Winter2 Yang et al. Cell Biosci (2021) 11:96 https://doi.org/10.1186/s13578-021-00610-8 Cell & Bioscience REVIEW Open Access Why do poxviruses still matter? Zhilong Yang1,2* , Mark Gray2 and Lake Winter2 Abstract Poxviruses comprise many members that infect both vertebrate and invertebrate animals, including humans. Despite the eradication of the historically notorious smallpox, poxviruses remain signifcant public health concerns and seri- ous endemic diseases. This short review briefy summarizes the present, historical, and future threats posed by pox- viruses to public health, wildlife and domestic animals, the role poxviruses have played in shaping modern medicine and biomedical sciences, the insight poxviruses have provided into complex life processes, and the utility of poxvi- ruses in biotechniques and in fghting other infectious diseases and cancers. It is anticipated that readers will appreci- ate the great merit and need for continued strong support of poxvirus research; research which benefts not only the expansion of fundamental biological knowledge but also the battle against diverse diseases. Keywords: Poxvirus, Vaccinia virus, Virology, Smallpox, Vaccine vector, Oncolytic therapy, Biodefense, Public health, Animal health Background of smallpox is unknown, it is believed that variola virus Te poxvirus family is a large family of double-stranded evolved from a rodent poxvirus [4]. While the lesions DNA viruses designated Poxviridae. Based on the Inter- found on the mummy of Egyptian Pharaoh Ramesses V national Committee on Taxonomy of Viruses (ICTV) (died 1145 BC) suggest that smallpox existed over Taxonomy 2019 release [1], Te Poxviridae comprises 3000 years ago [5, 6], the earliest written documenta- two subfamilies: Chordopoxvirinae (18 genera, 52 spe- tion of smallpox-like symptoms were from Ge Hong’s cies) and Entomopoxvarinae (4 genera, 30 species). Pox- (283–343, Eastern Jin Dynasty, China) book, Zhouhou viruses infect a range of animals including insects, birds, Beiji Fan, or, Handbook of Prescriptions for Emergency. reptiles, marsupials, and mammals [2, 3], and cause dis- Smallpox has likely caused more human deaths than all ease in many, including humans. In this review, we will other infectious diseases combined. According to an esti- briefy discuss the historical signifcance and research mation by Crosby et al., 10–15 million people had been endeavors pertaining to poxviruses. We will then focus infected with smallpox in the year of 1967 [7]. With a on why it is critical that we expand our understanding of mortality rate of 30–40%, smallpox killed approximately these viruses. 300 million people in the twentieth century alone [8]. Considering smallpox was eradicated in 1980, this esti- Poxviruses have historical, current, and future mation suggests approximately 5 million smallpox deaths signifcance to public health per year during the endemic phase in the early years of Smallpox, caused by variola virus of the orthopoxvirus the twentieth century. Notably, a negative correlation genera, is one of the most, if not the most, deadly and between human life expectancy and smallpox outbreaks dreaded diseases in human history. While the origin was observed in Sweden between year 1774 and 1843 (Fig. 1, data from https:// ourwo rldin data. org/ small pox) [9], when the date are available. Tis historic mortality *Correspondence: [email protected] 1 Department of Veterinary Pathobiology, College of Veterinary Medicine has resulted in Smallpox outbreaks reshaping the his- & Biomedical Sciences, Texas A&M University, College Station, TX, USA tory of many countries. For example, Emperor Kangxi Full list of author information is available at the end of the article (1654–1722), who ruled for over 60 years during the Qing © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Yang et al. Cell Biosci (2021) 11:96 Page 2 of 8 common in young people [23]. Te virus causes self-lim- iting benign tumors in healthy people but can cause seri- ous complications in immune-compromised individuals [23]. Besides these two human-specifc poxviruses, many animal poxviruses can cause severe diseases in humans, and some others may potentially be the pathogens for diseases with unidentifed causes. An ectromelia virus, erythromelalgia-associated poxvirus, or ERPV, was iso- lated from patients among school-age children in rural China. Te disease is characterized by pharyngitis fol- lowed by burning pain and infammation in the extremi- ties, with seasonal outbreaks occurring every few years in spring or winter [24–26]. While whether ERPV is the Fig. 1 Correlation coefciency of life expectancy and number of deaths from smallpox per 1000 population from 1774 to 1899 cause of the epidemic erythromelalgia is still unclear in Sweden. Shown data points are for years available. Data was and needs further investigation, some other poxviruses extracted from https:// ourwo rldin data. org/ small pox clearly cause human infections. For example, ORF virus causes sore mouth disease in goats and sheep, but can also infect humans. Cowpox virus can elicit serious ill- nesses in human hosts. A novel orthopoxvirus recently Dynasty, substantially infuenced Chinese history. After caused infections in humans in the state of Alaska and he sufered from smallpox and survived, his immunity is is believed to have been transmitted by animals [27, 28]. believed to have aided in him becoming emperor [10]. Monkeypox is endemic in Africa and has a 10% death While the World Health Organization (WHO) declared rate among the humans it infects [2]. A study pub- smallpox eradicated in 1980 following a world-wide vac- lished in 2010 showed that monkeypox virus cases have cination campaign [11], concerns persist that smallpox increased over 20-fold in the Democratic Republic of may re-emerge accidently from forgotten stocks of the Congo (DRC) during the 30 years following the termina- virus, from de novo synthesis, or from melting perma- tion of the smallpox vaccination campaign, as smallpox frost due to global warming [12, 13]. Tis is especially vaccine can protect humans from monkeypox infection. worrisome because of the low worldwide vaccination rate Individuals vaccinated against smallpox were at a 5.2-fold against smallpox since 1980, reducing rates of smallpox lower risk of contracting monkeypox compared to unvac- immunity in the population. Te US military considers cinated individuals [29]. New geographic areas reporting the risk of weaponized smallpox sufcient to justify the monkeypox cases have increased during recent years and continued vaccination of all its military personal against now include the Central African Republic, DRC, Libe- the disease [14]. While smallpox had caused count- ria, Nigeria, and Sierra Leone. In DRC, more than 1,000 less human lives historically and they continue to pose suspected cases have been reported each year since 2005 threats to public health, only recently did the U.S. FDA [30]. According to the WHO, a total of 4,594 suspected approved TPOXX as the frst specifc smallpox drug [15]. cases of monkeypox were reported in the DRC from 1 TPOXX targets a major viral protein that is important for January through 13 September 2020 (https:// www. who. morphogenesis (i.e. F13 in vaccinia virus) [16]. Cidofovir int/ csr/ don/ 01- octob er- 2020- monke ypox- drc/ en/). Te has of-label use for poxvirus infection and was originally numbers are likely underestimated due to a lack of reli- approved for AIDS-related retinal cytomegalovirus infec- able surveillance systems. Further spread of monkeypox tion [17–19]. Drug-resistance and side efects are still the is a real concern. In the last few years, several outbreaks concerns [20], promoting the necessity to search for new of monkeypox have occurred in Central and Western drugs. In fact, the U.S. Biomedical Advanced Research Africa, and travel-related monkeypox cases have been and Development Authority of the federal HHS Ofce of reported in the United Kingdom, Israel, and Singapore the Assistant Secretary for Preparedness and Response [30–34]. An outbreak occurred in the USA in 2003 that (BARDA) is actively seeking a second smallpox drug for was eventually traced to animals imported from Africa clinical development, according to a recommendation [35]. from the Institute of Medicine od the U.S. [21, 22]. Among the numerous poxviruses that can infect ani- Humans are the exclusive host of variola virus. Another mals, many have signifcant impacts on economically poxvirus, molluscum contagiosum virus, also exclusively important livestock and ecologically endangered wildlife. infects humans. Molluscum contagiosum accounts for Capripoxviruses cause lumpy skin disease (LSD) in cattle, 1 in 500 outpatient visits in the US and is particularly Yang et al. Cell Biosci (2021) 11:96 Page 3 of 8 sheep (sheeppox), and goats (goatpox), and can cause the most extensively studied virus in the Poxviridae fam- signifcant economic losses in commercial herds of these ily, contributing many critical concepts to the develop- animals. Recent outbreaks of capripoxviruses in Asia ment of modern virology and molecular biology.
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