The family Rhabdoviridae is included with the families Bornaviridae, Filoviridae, Pneumoviridae, and Paramyxoviridae in the order Mononegavirales (see Chapter 17: Paramyxoviridae, and Pneumoviridae Fig. 17.1). Rhabdoviruses are enveloped, single-stranded, negative-sense RNA viruses. The family Rhabdoviridae currently includes eleven genera, with additional genera proposed. The increasing taxonomic subdivision of rhabdoviruses is a reflection of their inherent genome plasticity, likely as a result of the discontinuous replication strategy they utilize that leads to remarkable variation in both genome size and organization among these viruses. Pathogenic rhabdoviruses of warm-blooded animals are included in the genera Lyssavirus, Vesiculovirus, and Ephemerovirus, and those of fish in the genera Novirhabdovirus, Perhabdovirus, and Sprivivirus (Table 18.1). The genus Tibrovirus includes viruses that have been isolated from healthy cattle and Culicoides biting midges in Australia, and the genus Tupavirus includes viruses of birds (American coot, Fulica americana), tree shrews (Tupaia belangeri) and, provisionally, a virus that recently was identified in healthy wild and domestic pigs in Japan. A proposed new genus Ledantevirus includes a monophyletic group of viruses with strong ecological association with bats, some of which have also been isolated from humans, rodents and livestock. Two additional genera (Cytorhabdovirus and Nucleorhabdovirus) include viruses that exclusively infect plants, and the genus Sigmavirus includes viruses that infect insects. Individual species of rhabdovirus are distinguished genetically and serologically.

Rhabdovirus virions are approximately 45–100 nm in diameter and 100–430 nm long, and consist of a helically coiled cylindrical nucleocapsid surrounded by an envelope with large (5–10 nm in length) glycoprotein spikes (Table 18.2). The precise cylindrical form of the nucleocapsid is what gives the viruses their distinctive bullet or conical shape (Fig. 18.1). The genome is a single molecule of linear, negative-sense, single-stranded RNA, 11–15 kb in size. For example, the rabies virus (Pasteur strain) genome consists of 11,932 nucleotides that encode five genes in the order 3′-N-P-M-G-L-5′: N is the nucleoprotein gene that encodes the major component of the viral nucleocapsid; P is a phosphoprotein that serves as a cofactor for the viral polymerase; M is an inner virion protein that facilitates virion budding by binding to the nucleocapsid and to the cytoplasmic domain of the glycoprotein; G is the glycoprotein that forms trimers that make up the virion surface spikes; L is the RNA-dependent RNA polymerase that functions in transcription and RNA replication. The glycoprotein (G) contains neutralizing epitopes, which are targets of antibody-mediated immunity (eg, antibodies induced by vaccination); it and the nucleoprotein include epitopes involved in cell-mediated immunity. Virions also contain lipids, their composition reflecting the composition of host-cell membranes, and carbohydrates as side chains on the glycoprotein.

Replication of rhabdoviruses is described and illustrated in Chapter 2, Virus Replication (Fig. 2.8). Virus entry into host cells occurs by receptor-mediated endocytosis via coated pits, and subsequent pH-dependent fusion of the viral envelope with the endosomal membrane releases the viral nucleocapsid into the cytoplasm, where replication exclusively occurs. The viral glycoprotein G is solely responsible for receptor recognition and cell entry. Specific cell receptors have not clearly been identified for individual rhabdoviruses; several apparently nonessential (or redundant) receptors have been identified for rabies virus, including: neurotrophin receptor p75NTR, a member of the tumor necrosis factor receptor family; the muscular form of the nicotinic acetylcholine receptor; neuronal cell adhesion molecule, a member of the immunoglobulin superfamily; and perhaps other components of the cell membrane such as gangliosides. Phosphatidyl choline is a proposed receptor for vesicular stomatitis virus, and fibronectin for viral hemorrhagic septicemia virus.

Replication first involves messenger RNA (mRNA) transcription from the genomic RNA via the virion polymerase (Fig. 18.2). When sufficient quantities of the nucleocapsid (N) and phosphoprotein (P) have been expressed, there is a switch from transcription of mRNA to positive-sense antigenomes, which then serve as the template for synthesis of negative-stranded, genomic RNA. Using virion RNA as a template, the viral transcriptase transcribes five subgenomic mRNA species. There is only a single promoter site, located at the 3′ end of the viral genome; the polymerase attaches to the genomic RNA template at this site and, as it moves along the viral RNA, it encounters stop–start signals at the boundaries of each of the viral genes. Only a fraction of the polymerase molecules move past each junction and continue the transcription process. This mechanism of discontinuous transcription of genomic RNA-called attenuated transcription, or stop–start transcription or stuttering transcription-results in more mRNA being made from genes that are located at the 3′ end of the genome and a gradient of progressively less mRNA from downstream genes N>P>M>G>L. This allows large amounts of the structural proteins such as the nucleocapsid protein to be produced relative to the amount of the L (RNA polymerase) protein.

Attachment of nucleocapsid protein to newly formed genomic RNA molecules leads to the self-assembly of helically wound nucleocapsids. Through the action of the matrix protein (M) protein, nucleocapsids are in turn bound to cell membranes at sites where the envelope spike glycoprotein is inserted. The M protein is also translocated to the nucleus of infected cells, and may inhibit host-cell transcription. Virions are formed by the budding of nucleocapsids through cell membranes. Budding of rabies virus occurs principally from intracytoplasmic membranes of infected neurons, whereas the same process occurs almost exclusively on plasma membranes of salivary gland epithelial cells. Vesicular stomatitis virus causes rapid cytopathology in cell culture, whereas the replication of unadapted rabies and bovine ephemeral fever viruses is slower and usually noncytopathic, because these viruses do not shut down host-cell protein and nucleic acid synthesis. Rabies virus produces prominent cytoplasmic inclusion bodies (Negri bodies) in infected cells (Fig. 18.3).

Defective interfering virus particles are commonly formed during rhabdovirus replication (see Chapter 2: Virus Replication). These are complex deletion mutants with substantially truncated genomic RNA, which interfere with normal virus replication processes. Defective interfering particles are proportionately shorter than infectious virions.

Rabies virus can infect all mammals and infection virtually always results in the death of susceptible (ie, unvaccinated) individuals, unless they are aggressively treated before signs appear. The disease occurs or has occurred throughout extensive portions of the world (Fig. 18.4), although certain regions have never reported domestic rabies (eg, Japan, New Zealand) and others are now considered to be free of terrestrial rabies after wildlife rabies eradication campaigns (eg, Switzerland, France). Complicating the concept of countries having terrestrial rabies-free status are situations in which rabies-related lyssaviruses that are transmitted by bats are enzootic and human and animal deaths from these agents occur (eg, European bat lyssavirus 2 in the United Kingdom and Australian bat lyssavirus in Australia). Rabies is estimated to cause more than 60,000 human deaths worldwide annually, with 40–50% of rabies deaths in children younger than 15 years of age. An estimated 10 million people receive postexposure treatments each year after being exposed to rabies-suspect animals. A large majority of human rabies cases still result from bites of rabid dogs, particularly in Africa and Asia. In contrast, wildlife rabies is now the major threat in North America.

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