Arbovirus Discovery in Central African Republic (1973-1993): Zika, Bozo, Bouboui, and More

The progressive research on yellow fever and the subsequent emergence of the field of arbovirology in the 1950s gave rise to the continued development of a global arbovirus surveillance network with a specific focus on human pathogenic arboviruses of the tropical zone. Though unknown at the time, some of the arboviruses studies would emerge within the temperate zone decades later (e.g.: West Nile, Zika, Chikungunya). However, initial research by the surveillance network was heavily focused on the discovery, isolation, and characterization of numerous arbovirus species. Global arboviral surveillance has revealed a cryptic circulation of several arboviruses, mainly in wild cycles of the tropical forest. Although there are more than 500 registered arbovirus species, a mere one third has proved to be pathogenic to humans (CDC, 2015). Indeed, most known arboviruses did not initially demonstrate a pathogenicity to humans or other vertebrates, and were considered “orphans” (i.e. without known of vertebrate hosts). As a part of this global surveillance network, the Institut Pasteur International Network has endeavored to understand the role played by arboviruses in the etiology of febrile syndromes of unknown origin as one of its research missions. Here, we report how The Pasteur Institute of Bangui (Institut Pasteur Bangui, or IPB) in the Central African Republic (CAR) actively participated in this mission and conducted an arbovirus survey from 1973 to 1993 that led to the isolation of 297 virus strains from 409,877 mosquitoes belonging to 78 different species. Ultimately, 24 new virus species were identified among these isolated strains, including two new orphan arboviruses Bozo, Bouboui, and two other unidentified arboviruses (ArB 11266 as a flavivirus-like virus and ArD28542 as a bunyavirus-like virus). The findings of this important, unpublished data from this survey are discussed here and give historical context to the recent global emergence and spread of Zika virus out of Africa. During its long journey from Africa emergence, into Asia, Oceania, and most recently to the Americas, the Zika virus has shown some significant genetic changes to its potential for pathogenicity. The original data presented here suggests that a significant number of other viruses, circulating in a hidden or discrete wild cycle with vertebrate hosts yet to be identified, represent a constant and undetermined risk of emergence among a nonimmune human population with the possibility for similar natural genetic changes. Jean François Saluzzo1, Tom Vincent2, Jay Miller3, Francisco Veas4 and Jean-Paul Gonzalez5* 1Fab’entech, Lyon, France 2O’Neill Institute for National and Global Health Law, Georgetown University Law Center, Washington, DC, USA 3Department of Infectious Disease, Health Security Partners, Washington, DC, USA 4Laboratoire d’Immunophysiopathologie Moléculaire Comparée-UMRMinistère de la Défense3, Institute de Recherche pour le Développement, Montpellier, France 5Center of Excellence for Emerging and Zoonotic Animal Disease, Kansas State University, Manhattan, KS, USA Jean-Paul Gonzalez, et al., Annals of Infectious Disease and Epidemiology Remedy Publications LLC. 2017 | Volume 2 | Issue 3 | Article 1022 2 of infected individuals. Non-human pathogenic viruses, mainly arboviruses, are considered to be orphaned or insect-specific viruses (i.e. without a permissive vertebrate host) [2]. Ultimately, those arboviruses usually pass unnoticed until the moment they emerge in a non-immune population, which reveals hitherto unknown and subsequently unexpected clinical and epidemic patterns. Arbovirus diseases are animal diseases (some are zoonotic), with a sylvatic cycle involving mosquitoes and wild animals [3]. The circulation of these viruses in their sylvatic cycle depends on the frequency of renewal of non-immune monkey populations. Humans are contaminated by penetrating these niches, which are shared with apes. Infections are rare and mainly affect children living in low population densities. The paucity of roads and the subsequent limits on travel help the virus remain confined to an endemic area more or less circumscribed. Once introduced into a non-immune human population, however, as was the case for the chikungunya virus on the island of la Réunion, the spread can be explosive [4]. Among the virus families to which arboviruses belong, it is within the Flaviviridae family (63 virus species) that most of viral species with human pathogenic potential are found. They are often responsible for a broad spectrum of clinical presentations, ranging from sub-clinical infection to deadly hemorrhagic syndrome. Most commonly, infected patients present a benign flu-like infection. These ignored arboviruses with mostly asymptomatic or mildly symptomatic infections can emerge unexpectedly, with improved methods of dispersion. These emergences are complex and difficult to anticipate, as exemplified by recent and original events: West Nile virus in North America; the establishment of a worldwide circulation of dengue viruses in less than a century; the re-emergence of yellow fever in Africa and South America; the recent emergence of the Alkhuma variant of Kyasanur Forest disease virus in Saudi Arabia; and Japanese encephalitis that emerged in Australia when wind-blown infected mosquitoes traveled from New Guinea to Australia, potentially introducing the virus to the continent in 1995 [5]. The Sindbis virus, an arbovirus transmitted between birds by ornithophilic mosquitoes, was isolated in Egypt and has been subsequently isolated in southern and central Europe and in several areas of Africa and in Asia and in Australia. Sindbis virus infection in humans causes a benign disease with arthralgia, rash, and occasional fever [6]. Chikungunya virus adapted quickly to a new environment and vectors among the non-immune populations of Indian Ocean island nations and presented unprecedented clinical severity after 50 years of silent circulation in Africa and Asia [7]. Usutu virus, after 40 years of a quasi-silent transmission in Africa among birds and mosquitoes, emerged in Europe, first appearing in Austria (2001) as a deadly virus for the Eurasian blackbird, but later showing a consistent prevalence among humans while few cases of men in goencephalitis in immune-compromised patients were reported in Italy [8]. Tembusu flavivirus, originating in China and later considered as a potential zoonosis [9], emerged in Southeast Asia, devastating layer and broiler duck farms in Thailand [10]. Recently and most notably is the global emergence of Zika virus. The first significant outbreak of Zika virus occurred in 2007, outside of the African continent on the tiny Micronesian island of Yap. This outbreak was accompanied by what remain the most severe clinical forms ever described for this virus [11]. A second major outbreak of Zika virus was declared in 2013-2014 across Oceania, in French Polynesia, New Caledonia, the Cook Islands, and Easter Island. Zika virus has since been making its mark in this millennium by settling in the Americas. As 2015 saw Ebola Virus Disease recede after devastating West Africa, the Zika virus made its way to the Western Hemisphere, and took its place at the forefront of the media scene [12]. The WHO is currently supporting national governments and communities in order to prevent and manage Zika and its complications. The WHO Zika strategic response will cost approximately $122 million, and will implement elements of detection, prevention, care and support, and research across 60 countries. [13]. Although long known to cause limited or mild infection until it arose in Yap state in 2007, Zika virus did not attract the attention of health authorities or arouse great interest in the fight against epidemics since its discovery in monkeys in 1947, or its subsequent identification in humans in 1952 [14]. This singular and unexpected intrusion, and spread, of Zika virus in the landscape outside of its traditional bounds is reminiscent of the role played by arboviruses in the history of infectious diseases [15].