Bunyaviruses

In terms of the number of members, the bunyavirus family (Bunyaviridae) is one of the largest known, with well over 300 serologically distinct viruses. The family itself consists of five separate genera, as listed in Table 15.2. Most members of this diverse family are arboviruses, being transmitted by mosquitoes, ticks, sandflies, or thrips. The hantaviruses, however, are vectored by rodents.

Virus structure and replication

Bunyaviruses all have tripartite, negative-sense RNA genomes. As outlined in Fig. 15.8, the enveloped virions are about 90-110 nm in diameter. The membrane contains two viral glycoproteins: G1 and G2. Within the particle are three size classes of circular nucleocapsids,

Table 15.2 The bunyaviruses.

Genus

Vector

Examples

Bunyavirus

Mosquito

La Crosse encephal

itis virus, Bunyamwera virus

Nairovirus

Tick

Dugbe virus, Nairobi sheep disease virus

Phlebovirus

Sandfly

Rift Valley fever virus, Uukuniemi

virus

Hantavirus

Rodent

Hantaan virus, Sin Nombre virus

Tospovirus

Thrip

Tomato spotted wi

lt virus

Table 15.3 Genome

sizes of gene products of the Bunyaviridae

Gene or protein

Bunyavirus

Nairovirus

Phlebovirus

Hantavirus

Tospovirus

L RNA

6.4-6.7 kb

12 kb

6.4-6.7 kb

6.4-6.7 kb

8.9 kb

L protein

240-260 kd

460 kd

240-260 kd

240-260 kd

331 kd

M RNA

4.S kb

4.9 kb

3.2-3.9 kb

3.6 kb

4.8-4.9 kba

G1

108-120 kd

68-76 kd

SS-70 kd

68-76 kd

78 kd

G2

29-41 kd

30-45 kd

S0-60 kd

52-58 kd

S2-S8 kd

NSM

10-16 kd

None

78 kd, 14 kd

None

34 kd

S RNA

0.98 kb

1.8 kb

1.7-1.9 kb

1.8 kb

2.9 kb

N

19-2S kd

48-54 kd

24-30 kd

48-54 kd

28.8 kd

NSs

10-13 kd

None

29-37 kd

None

S2.4 kd

a Genes are ambisense.

a Genes are ambisense.

each consisting of one of the genomic RNAs in a helically symmetric complex with the nucleo-capsid (N) protein and the viral polymerase (L). Genome sizes and gene products for each of the genera are shown in Table 15.3.

Since these are negative-sense viruses, the first event after infection is transcription. For La Crosse virus, a typical bunyavirus, viral mRNAs are produced from each genome segment, as also shown in Fig. 15.8. Viral messages have 5' capped termini and 3' ends with no polyA. The cap structures are derived from cytoplasmic host mRNA by endonucleolytic cleavage. This cap-snatching reaction, although similar to that described for influenza virus, takes place outside the nucleus.

The viral mRNAs are subgenomic, as with influenza. Replication of the bunyavirus genomic (and antigenomic) RNA occurs in the cytoplasm. These RNAs have 3' and 5' inverted complementary sequences of about 10—14 nucleotides that may play a role in the replication event. The nucleocapsids themselves have a circular form that may reflect base pairing of these sequences.

The three genome segments demonstrate a variety of expression strategies; some of these are also shown in Fig. 15.8. The gene products expressed are shown in Table 15.3. The largest segment expresses a single protein, the viral polymerase (L). The middle-sized segment encodes two or three proteins, depending on the specific virus in question. Expressed proteins are the two glycoproteins G1 and G2, along with — where present — a nonstructural protein NSm. These proteins are translated as a precursor polyprotein that is posttranslationally cleaved.

The smallest RNA genome segment encodes one or two viral proteins. For the nairoviruses and hantaviruses, this segment expresses mRNA for the N protein. In Bunyavirus genus, the subgenomic RNA from this segment can be translated into the N protein or, using a separate,

Bunyavirus

Bunyavirus

Glycoproteins G2

Lipid bilayer

Glycoproteins G2

Lipid bilayer

Transcription Transcription Transcription

Translation

Translation

( NS ) Translation from alternate reading frames

Protein

Polymerase

Proteolytic cleavage

G1 NSm G2

Fig. 15.8 The bunyavirus virion. The three ribonucleoprotein (RNP) segments, each associated with both L and N protein, are contained within a well-defined envelope made up of two glycoproteins. The virion diameter ranges from 80 to 120 nm. The size of the RNPs as determined by their sedimentation rates (see Chapter 11) and the size of the RNA genomes and the proteins encoded by the various members of the Bunyaviridae are shown in Table 15.3. The general scheme of gene expression and genome replication of La Crosse virus is also shown. Expression and replication take place in the cytoplasm, but have many similarities to the process outlined for influenza virus. The positive-sense strand mRNA expressed from the S genomic segment contains two partially overlapping translational reading frames that are out of phase with each other. Alternative recognition of one or the other translation initiation codons by the cellular ribosomes leads to the expression of two proteins with a completely different amino acid sequence.

alternate reading frame, into another nonstructural protein, NS. Apparently the "decision" as to which reading frame is utilized in this small mRNA is entirely random. Sometimes the ribosome starts at one AUG and sometimes at the other.

The small genomic segments of the phleboviruses and the tospoviruses are ambisense genomes; i.e., they contain both positive- and negative-sense genes. The term "ambisense" refers to the fact that the open reading frames defining the two proteins are oriented in opposite directions in the genome RNA, and their expression requires a strategy that is vaguely reminiscent of that utilized in the expression of Sindbis virus subgenomic RNA. This is shown in Fig. 15.9. The small (S) virion-genomic RNP is transcribed into a positive-sense mRNA that is translated as the N protein encoded within the negative-sense portion of the ambisense virion genomic segment. The genomic ambisense RNA also serves as the template for the transcription of a separate ambisense antigenomic RNA that acts as a template for the transcription of capped mRNA encoding the NSS (nonstructural S) protein. This RNA is the same sense as the virion RNA; thus, even though Phlebo- and Tospoviruses are negative-strand RNA viruses, a portion of their genome is mRNA (i.e., positive) sense.

Fig. 15.9 The ambisense strategy of gene expression exhibited by some bunyaviruses and by arenaviruses. The expression of the small genomic segment of a tospovirus as phlebovirus is shown. With these viruses, full gene expression requires the generation of a subgenomic mRNA of same sense as the genomic RNA. Thus, even though the genomic RNA is nominally negative sense, it has regions of positive-sense information in it! This strategy is referred to as ambisense since both senses are present in the genome.

Pathogenesis

Members of the bunyavirus family infecting vertebrates cause four kinds of disease in humans and other animals: encephalitis, hemorrhagic fever, hemorrhagic fever with renal involvement, and hemorrhagic fever with pulmonary involvement. La Crosse encephalitis virus is transmitted by mosquitoes and is one of the main causes of viral encephalitis during spring and summer in the upper Midwest. Rift Valley fever virus, transmitted by the sandfly, causes recurring zoonoses and epidemics of hemorrhagic fever in sub-Saharan Africa. Hantaan virus, transmitted by rats, is the prototype of the Hantavirus genus and causes Korean hemorrhagic fever, a disease complicated by renal failure.

Sin Nombre virus, another member of the Hantavirus genus, was identified as the causative agent of outbreaks of a relatively fatal hemorrhagic fever with pulmonary involvement, termed hantavirus adult respiratory distress syndrome (HARDS) in the early 1990s. This and related viruses, transmitted by aerosols from fecal pellets of small rodents such as the deer mouse, are found distributed throughout the United States, although localized epidemics of HARDS have occurred in areas such as the Southwest. Epidemiological investigations of these outbreaks suggest that increases in the rodent vector population (aided by sporadic mild wet winters that increase forage for the rodents) result in increasing likelihood of transmission to humans.

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