The Evolution of Viruses - Zhdanov, V. M. 1990

Special Section
Bunyaviruses

The family Bunyaviridae encompasses A large number of Viruses transmitted by Blood-sucking Arthropods. Within this extensive family, several genera are distinguished: Bunyavirus, which contains numerous groups of serologically related viruses; Phlebovirus, which includes the causative agents of sandfly fevers; Nairovirus, comprising the causative agents of hemorrhagic fevers and other diseases; Uukuvirus, whose prototype is the Uukuniemi virus; Hataanvirus, which includes the causative agents of hemorrhagic fever with renal syndrome, as well as A number of unclassified viruses.

This very large group of bunyaviruses possesses several properties that set them apart from other viruses, even within the category of negative-sense single-stranded RNA viruses (Lvov D.K., 1982; Bishop D. et al., 1980; Matthews R., 1982]. Virions are spherical in shape and consist of an outer envelope and a circular nucleocapsid with helical Symmetry containing three RNA segments. The diameter of the nucleocapsid is 2–2.5 nm, the length of its fragments is 0.2–3.0 µm, and the virion diameter is 90–100 nm. The Genome consists of 3 fragments of single-stranded negative-polarity RNA with molecular weights of 3×10⁶–5×10⁶ (L), 10⁶–2×10⁶ (M), and 0.4×10⁶–0.8×10⁶ (S). The fragment sizes vary significantly among different genera. The L fragment encodes the Synthesis of the putative RNA-dependent RNA polymerase (transcriptase L), M encodes the synthesis of Glycoproteins G1 and G2 and the nonstructural protein NS_M, and S encodes the synthesis of two Proteins in an overlapping reading frame (N and NS_s). All RNAs are characterized by a conserved decanucleotide at the 3' end and a complementary sequence at the 5' end of the molecule. The molecular weights of the RNA and proteins vary among the viruses of the 4 genera (Table 12).

Table 12. Molecular weights of RNA fragments (×10⁶) and proteins (×10³)

Note. — molecular weight unknown.

It is interesting to compare the sequences at the 3' end of the RNA molecule across different viral genera: bunyaviruses — UCA UCA CAU G..., phleboviruses — UGU GUU UCG..., nairoviruses — AGA GUU UCU..., uukuviruses — UGU GUU UCU GGA G..., hantaviruses — AUC AUC AUC UG...

The reproduction of bunyaviruses is similar to that of other negative-sense RNA viruses. The virus enters The Cell via receptor-mediated endocytosis followed by membrane fusion. A partially deproteinized nucleocapsid is released into the Cytoplasm, where genomic RNA METABOLISM/31.html">Transcription takes place, with the primer originating from the host cell, much like in Influenza Viruses. Nucleocapsids are assembled in the cytoplasm, and viral particle maturation occurs at cellular membranes, with progeny exiting via budding into cytoplasmic vacuoles.

Studies of the Punta Toro phlebovirus revealed a novel genome strategy (ambisense genomic RNA); the S segment encodes the synthesis of the nucleoprotein N from the 3' half of the complementary mRNA, whereas the synthesis of the nonstructural protein NS_s is encoded by the 5' half of the virion RNA. Thus, phleboviruses, which comprise 36 recognized species, are ambisense viruses [Ihara T. et al., 1984].

The genus Bunyavirus includes 145 viruses grouped into the Anopheles A (11), Anopheles B (2), Bunyamwera (23), Bwamba (2), C (14), California encephalitis (14), Capim (9), Gamboa (7), Guamá (12), Kongolo (10), Olifantsvlei (3), Patois (6), Simbu (25), Tete (5), Turlock (6) groups, alongside unassigned viruses (2). Among these, Bunyamwera and Bwamba fevers, as well as California encephalitis, stand out due to their high incidence or clinical severity in humans. The genus Phlebovirus contains 31 viruses, including the causative agents of sandfly fevers and Rift Valley fever. The genus Nairovirus includes 28 viruses grouped into the Crimean-Congo hemorrhagic fever (3), Dera Ghazi Khan (6), Hughes (8), Nairobi sheep disease (3), Qalyub (2), and Sakhalin (6) serological groups, with hemorrhagic fevers being of paramount importance. Most nairoviruses exhibit complex serological cross-reactivities among themselves [Casals J., Tesh R.B., 1980]. The genus Uukuvirus includes 8 viruses, of which Uukuniemi virus is of the greatest significance. An additional 4 groups have been delineated, including the Bakau (2), Kaisodi (3), Mapuri (4), and Togoto (2) viruses, plus unclassified ones (11), totaling 22 viruses. Thus, we are dealing with an extensive group of arboviruses with a well-established ecology (natural foci, warm-blooded vertebrate hosts, blood-sucking arthropods). Arboviruses have spread to all continents and every climatic and geographical zone on Earth. Following these observations, we will attempt to provide an ecological analysis of bunyaviruses and trace their potential evolutionary pathways.

The genus Bunyavirus comprises over 100 representatives belonging to 16 complexes. Many members of this genus, especially those from the California encephalitis virus complex, are pathogenic to humans. The overwhelming majority of viruses in this genus are ecologically associated with mosquitoes, and in some cases with biting midges (ceratopogonids), and are distributed primarily in the Americas. Representatives of certain complexes are found partially (Bunyamwera, etc.), predominantly (Simbu, etc.), or exclusively (Bwamba, etc.) in Africa. A small number of viruses, mainly those associated with birds and domestic animals, are also distributed in Europe, Asia, and Australia. Aside from two viruses from the Kongolo antigenic group (genus Bunyavirus), 5 viruses from the Simbu antigenic group (genus Bunyavirus) had been isolated in Australia by early 1982. Like the vast majority of viruses of this group of African origin, the Australian Simbu group viruses are associated with biting midges and cattle. The geographic ranges of most species in the genus are restricted to the equatorial and subequatorial climatic zones (Table 13). In the tropics and subtropics, the number of viruses is twice as low, and in the temperate zone, four times as low.

Table 13. Distribution of various ecological and systematic groups of bunyaviruses across climatic zones

Note. The number of viruses is indicated in parentheses.

The genus Phlebovirus includes approximately 30 representatives, including the causative agents of sandfly fevers and Rift Valley fever, which are of great epidemiological importance in endemic regions. In the ecology of phleboviruses, sandflies play a definite role alongside mosquitoes. The geographic distribution of phleboviruses follows the same general patterns as that of bunyaviruses: an association with the American continent (and for certain species, the African continent), and a preferential confinement to the equatorial and subequatorial climatic belts. The ranges of 2–3 phleboviruses associated with synanthropic biocenoses extend into the tropical-subtropical zones. Phleboviruses are absent from the temperate climatic zone.

The genus Nairovirus encompasses about 25 representatives, including the causative agents of diseases in domestic animals (Nairobi sheep disease) and humans (Crimean-Congo hemorrhagic fever). Nairoviruses are distributed in Africa and Asia. Notable exceptions include several viruses ecologically associated with birds that occupy specific yet similar ecological niches at the intersections of the temperate and subarctic climatic belts across all continents [Lvov D.K., Ilyichev V.D., 1979]. Unlike the members of the two genera described above, virtually all nairoviruses are permanent parasites of ixodid ticks. A slightly higher number of nairoviruses has been identified in the tropics, where these viruses are adapted primarily to argasid ticks. The genus Uukuvirus includes 6–7 representatives whose role in human pathology remains unclear. They are adapted to subtropical and temperate climatic conditions and act as parasites of ixodid ticks, although some have been proven capable of Replication in mosquitoes followed by biological transmission.

The range of vertebrate hosts for bunyaviruses is broad. Among the viruses isolated from vertebrates, over 50% are associated with rodents and lagomorphs, about 25% with birds, and about 25% with ruminants and other domestic animals. Several viruses are associated with marsupials, bats, primates, and other animals.

The Nature of the interaction between bunyaviruses and arthropods is similar to that of Togaviruses. However, unlike some members of the family Togaviridae, all bunyaviruses are obligate parasites of arthropods, predominantly insects such as mosquitoes, sandflies, and biting midges (genera Bunyavirus and Phlebovirus). Most bunyaviruses are transmitted by mosquitoes of the subfamily Culicinae, with transovarial and sexual transmission demonstrated for at least some of these viruses [Calisher C., 1980]. The confinement of most bunyaviruses to the equatorial and subequatorial climatic zones is also similar to togaviruses. All this provides grounds to infer parallel evolutionary pathways for the viruses of these two families. The Evolution of the relatively small number of genera adapted to ixodid ticks (Nairovirus and Uukuvirus) should be viewed as an adaptation of viral populations to the relatively harsh, arid Regions of the tropics and subtropics, as well as the Temperature-unfavorable areas of the temperate climatic zone.

Bunyaviruses possess a segmented genome (3 segments), which accounts for The high frequency of recombination during the replication of two different viruses in a single cell [Bishop D., Shope R., 1979]. Under natural conditions, such a situation can arise through the simultaneous infection of a host by different bunyaviruses. A high frequency of recombination (at least among closely related viruses), followed by the Selection of recombinants endowed with high ecological plasticity, likely underlies the evolution of bunyaviruses.

Thus, bunyaviruses, much like togaviruses, can be regarded as arthropod-borne parasites (primarily of mosquitoes), with the center of origin of their primary geographic range situated in climatic conditions analogous to those of the equatorial and subequatorial belts.

The modern distribution of Representatives of the genera Bunyavirus and Phlebovirus across all continents can be regarded as evidence of their ancient origin. Presumably, ancestral bunyaviruses parasitizing mosquitoes emerged under the corresponding climatic conditions of Gondwana during the Paleogene (30–40 million years ago). Subsequently, isolated antigenic complexes formed as South America separated from Africa (Eocene–Oligocene) and as Australia drifted (with a brief connection between Australia and South America occurring at the Oligocene–Miocene boundary). The Emergence of the ixodid tick-associated nairoviruses and uukuviruses, given their current Afro-Euro-Asian distribution, occurred later, in the late Miocene to Pliocene. It was precisely during this epoch that savanna and steppe faunas underwent their greatest development. Representatives of these genera failed to colonize the American and Australian continents. Exceptions include certain viruses from the Hughes, Uukuniemi, and Sakhalin complexes that are ecologically linked to birds. In these cases, the exchange of viral populations between different continents occurs during avian Migrations.

The geographic range of Crimean-Congo hemorrhagic fever (CCHF) virus, which spans vast territories in Africa, southern Europe, and western Asia, is largely confined to semi-arid and steppe landscapes. Under these conditions, the pathogen adapted to ixodid ticks, predominantly of the genus Hyalomma. The northward expansion of the pathogen's range occurred through adaptation to the ticks Rhipicephalus rossicus and Dermacentor marginatus, which are better suited to survive cold winters compared to the primary virus reservoir, Hyalomma marginatum. In environments that are harsh for mosquito-borne bunyaviruses, the virus survives through prolonged persistence across various stages of tick metamorphosis, involving transstadial and transovarial transmission. In the vertebrate Organism, the lifespan of viral populations is limited to just 7–10 days. The wide distribution of the pathogen across three continents can be attributed to centuries of livestock driving along ancient caravan routes and The transport of infected ticks over vast distances. Existing epidemiologically significant foci of CCHF can disappear when ecological structures change. For example, The Development of irrigated cotton farming has led to the disappearance of epidemiologically significant vectors in Central Asia.

Another example of the evolution of bunyoviral infections is Rift Valley fever. Until the 1970s, the infection was known in eastern and southern Africa, where it caused severe epizootics, particularly among sheep. Since the mid-1970s, epizootics have also appeared in Sudan. In 1977, a severe epizootic among sheep, cattle, Water buffaloes, and camels broke out in Egypt. The Introduction of the pathogen into Egypt from Sudan likely resulted from the importation of infected camels or other domestic livestock. In Egypt, the epizootic was accompanied by a large-scale human epidemic with a high case-fatality rate. Human infection occurred primarily through the handling and consumption of meat from infected animals [Bishop D., Shope R., 1979]. Due to the significant export of domestic animals from Egypt to other Mediterranean countries, There is a serious threat of the further spread of Rift Valley fever.

As already noted, the Origin of the extensive group of bunyaviruses remains unclear, and one can only reiterate what has been said about togaviruses. Apparently, the dispersal of these viruses across the globe and The formation of various types of natural foci occurred in the mid-Cenozoic, and since then bunyaviruses have undergone little evolution, retaining antigenic relatedness among species that have dispersed far apart and remained isolated for many millions of years. None of these viruses have become obligate permanent parasites of humans or domestic animals, and human activity has merely resulted in domestic animals occasionally becoming actively involved in epizootics (Nairobi sheep disease). It is likely that human activity leads to the disruption of the biocenoses necessary for the Circulation of these viruses, while the low pathogenicity of most of them for humans and livestock makes the formation of anthroponotic or synanthropic foci unlikely.

However, human contact with bunyaviruses has not always been benign, as exemplified by The history of CCHF. Although mentions of this disease can be found in 12th-century Tajik chronicles, the epidemic drew serious medical attention only in 1944, when outbreaks of severe hemorrhagic fever occurred among troops and civilians in areas of Crimea liberated from German occupation. The Study of this disease established its natural focal nature. Infection occurs through the bites of ticks belonging to the genera Hyalomma, Rhipicephalus, and Dermacentor. Warm-blooded hosts and potential virus reservoirs include hares and livestock. The disruption of the pre-existing ecological equilibrium As a result of war exposed humans to biotic factors, precipitating epidemic outbreaks of CCHF. It was subsequently established that this disease—or more precisely, its natural foci—occurs in the steppe and semi-desert regions of Central Asia, the North Caucasus, the Caspian region, Transcaucasia, as well as in Bulgaria and Yugoslavia. Nosocomial infections among medical personnel have also been documented. A similar, immunologically related virus was discovered in Congo (Zaire), Uganda, and Nigeria, where it also caused human disease outbreaks. Future research will show whether these two geographically isolated ranges are relict or connected (e.g., via migratory birds), or whether additional natural foci of related viruses exist.

Similar episodes include outbreaks of Human and Animal diseases caused by Rift Valley fever virus, California encephalitis viruses, Oropouche virus, and others. Therefore, future human encounters with natural foci of bunyaviral infections may hold further surprises.

Phlebotomus fevers certainly deserve special mention. These diseases are caused by a group of immunologically related bunyaviruses and occur across all continents within tropical and subtropical zones. Their natural foci are maintained through the circulation of viruses among small rodents (such as those in Central Asia) and sandflies. However, along the Mediterranean, Black, and Caspian coasts, as well as in adjacent inland regions of Africa, Europe, and Asia, human activity has significantly impacted these natural foci. Periodic outbreaks of phlebotomus fever occur in urban areas, where the virus is transmitted from human to human by sandflies, temporarily «breaking away» from its natural reservoirs. This creates a scenario similar to that repeatedly observed in urban foci of Japanese encephalitis.

We will conclude this chapter by mentioning hemorrhagic fevers with renal syndrome, whose causative agents range from Korea to the Balkans and Western Europe. Korean hemorrhagic fever has drawn particular attention due to its severity, and its virus, named Hantaan, was isolated from the striped field mouse Apodemus agrarius [Lee H. et al., 1978]. The wide geographic distribution of this disease group and the presence of several distinct viruses comprising it [Schmaljohn C. et al., 1985] warrant classifying them into a separate genus within this family, which already comprises at least 4 serological groups [Lee R. et al., 1984]. This group of diseases not only spans virtually all of Eurasia, but there is also serological evidence [Gajdusek D., 1982], along with direct virus isolations, in North and South America.