- Open Access
Emerging Viruses: The Bunyaviridae
© Picower Institute Press 1997
- Published: 1 September 1997
The family Bunyaviridae is a large but perhaps relatively unfamiliar group of viruses (even among virologists) which contains more than 300 members [reviewed in (1)]. One of the unifying characteristics of these viruses is possession of a tripartite, single-stranded RNA genome. The three genome segments encode four structural proteins, which make up the virus particle, and perhaps one or two nonstructural proteins (accessory proteins required for replication), usually in a negative-sense manner, i.e., anti-message sense. This coding strategy requires that the infecting virus particle contain its own RNA-dependent RNA-polymerase to transcribe the genome into mRNAs, which in turn are translated to make new viral proteins. Virus multiplication occurs in the cytoplasm of infected cells and virus particles mature inside the cell by budding primarily at membranes of the Golgi apparatus. Viruses in this family can infect a diverse range of hosts, from mosquitoes to marsupials, and thrips to tomatoes. Several of the Bunyaviridae cause serious diseases in humans, and they are recognized as posing an increasing threat to human health and are good examples of the so-called emerging infections (2).
The family Bunyaviridae is divided into five genera on the basis of serological and biochemical characteristics. Four of these genera—Bunyavi rus, Hantavirus, Nairovirus, and Phlebovirus—contain vertebrate-infecting viruses while members of the Tospovirus genus infect plants. Members of these genera are thus referred to as bunyavi ruses, hantaviruses, nairoviruses, etc. Although all viruses in the family share the less than stringent criteria outlined above, considerable diversity exists at the biological level in terms of hosts and vectors infected and at the molecular level in terms of genome coding and replication strategies (see below). Most of the viruses are transmitted by arthropod vectors (and hence are known as arboviruses, from (arthropod borne): in general, bunyaviruses are transmitted by mosquitoes or midges, nairoviruses by ticks, and phleboviruses by sandflies or ticks. Tospoviruses are spread to plants by thrips. Hantaviruses do not have arthropod vectors but are maintained in nature as persistent infections of rodents (hence the term robovirus, from rodent-borne, has been coined) and are transmitted to humans via aerosolized infectious rodent secretions.
The S segments of hanta- and nairoviruses just encode the N protein (about 50 kD) in a negative-sense manner. Bunya-, phlebo-, and tospovirus S segments encode two proteins, N (25-30 kD) and a second nonstructural protein, also of unknown function, called NSs. Both the bunyavirus proteins are encoded in the same mRNA and are translated as the result of alternative initiation at different AUG codons (9,10). In contrast, the phlebo- and tospovirus S segments are ambisense, with the N protein encoded in genome complementary RNA while the NSs protein is translated from a subgenomic genome-sense RNA (11,12).
Bunyaviridae transcription resembles that of influenza virus (although occurring in the cytoplasm) in that mRNA synthesis is primed by cap-containing oligonucleotides generated by a viral-endonuclease (probably contained in the L protein) which cleaves host-cell mRNAs, the resulting primers being incorporated into the viral mRNA (3). Hence in Bunyaviridae-inteaed cells, three (four for ambisense segments) types of RNA representing each segment are found: full-length negative-sense genomic RNA (vRNA), full-length positive-sense RNA (viral complementary RNA, vcRNA), and positive-sense mRNA which has 5′ nontemplated primer sequences (12–18 bases) and is truncated at the 3′ end (Fig. 2). For the ambisense segments, transcription of both of the subgenomic mRNA species is primed by host-derived oligonucleotides (13). Reverse genetic approaches have been described in which a synthetic viral-like RNA containing a reporter gene can be transcribed and replicated by recombinant transiently expressed viral proteins, which will enable detailed investigation of RNA synthesis by bunyaviruses and phleboviruses to be undertaken (14,15). More recently a system to recover infectious bunyavirus entirely from cloned cDNAs has been developed (16) and this accomplishment opens the way for elucidation of the functions of all the viral proteins, as well as investigation of biological aspects such as tissue tropism, virulence, etc. In the longer term, it may be possible to design modified viruses as potential vaccine strains.
Significant pathogens in the family Bunyaviridae, listing diseases, vectors, and distribution
Cattle: abortion & congenital defects
Africa, Asia, Australia
Sheep, cattle: congenital defects
Human: severe hemorrhagic fever with renal syndrome, HFRS (F = 5–15%)
Eastern Europe, Asia
Human: moderate HFRS (F = 1%)
Human: mild HFRS, nephropathia epidemica (F = 0.1%)
Sin Nombre-like viruses
Human: hantavirus pulmonary syndrome (F = 50%)
N. and S. America
Crimean-Congo hemorrhagic fever
Human: hemorrhagic fever (F = 20–80%)
Eastern Europe, Africa, Asia
Nairobi sheep disease
Sheep, goats: fever, hemorrhagic gasteroeneritis, abortion
Rift Valley fever
Human: encephalitis, hemorrhagic fever, retinitis (F = 1–10%) p ]Domestic ruminants: necrotic hepatitis, hemorrhage, abortion
Sandfly fever Naples
Europe, Africa, Asia
Sandfly fever Sicilian
Tomato spotted wilt virus
>650 plant species: various symptoms
Encephalitis is caused by La Crosse virus infection, and since the discovery of the virus in the early 1960s, the annual reported incidence of La Crosse bunyavirus infection has remained fairly constant at around 100 cases per year (range 42-174), primarily in children and young adults in the midwestern United States. The infection is rarely fatal (<1%), although the acute illness is severe, with about half the patients having seizures and about 10% developing epilepsy or chronic seizures.
Crimean-Congo hemorrhagic fever (CCHF) is a particularly severe tick-borne disease whose symptoms are horrifyingly similar to those of other hemorrhagic fevers such as Lassa fever or Ebola fever. The case fatality in tick-acquired disease is around 20%, but it is significantly higher in nosocomial infections acquired from viremic blood, perhaps because the inoculum dose is higher. CCHF occurs in Africa, Asia, and eastern Europe.
In terms of human disease, the most important members of the Bunyaviridae are the hantaviruses, which cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). There are about 200,000 hospitalized cases of HFRS reported each year, with about half of these in China. There are three forms of HFRS—severe, moderate, and mild (Table 1)—caused by different hantaviruses, with fatality rates ranging from less than 0.1% for the Puumala-like viruses to 15% for Han-taan-like viruses. HFRS cases predominantly occur in Asia, the Balkans, and Scandinavia. In 1993 novel hantaviruses were identified in the Americas as responsible for cases of a severe respiratory disease, HPS, or “Four Corners disease,” with about 50% mortality. The severity of the disease prompted much investigation into the ecology and epidemiology of hantaviruses in the Americas, and now more than 250 cases of HPS have been reported and many other new hantaviruses have been described (18).
The large number of viruses in the family Bunyaviridae is taken as evidence of their vast evolutionary potential (19), and together with their capacity for dramatic antigenic shift through genome segment reassortment (1), warrants their continual surveillance and further study. Relatively few vaccines for members of the Bunyaviridae have been developed. A live attenuated vaccine against Rift Valley fever virus is available whereas most other vaccines are inactivated viral preparations. Clearly there is much scope for the development of novel vaccines through molecular biological techniques for the hazardous members of the group.
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