Major properties of paramyxoviruses are listed in Table 1.

Table1. Important Properties of Paramyxoviruses

Structure and Composition

The morphology of Paramyxoviridae is pleomorphic, with particles 150 nm or more in diameter, occasionally ranging up to 700 nm. A typical particle is shown in Figure 1. The envelope of paramyxoviruses seems to be fragile, making virus particles labile to storage conditions and prone to distortion in electron micrographs.

Fig1. Ultrastructure of parainfluenza virus type 1. The virion is partially disrupted, showing the nucleocapsid. Surface projections are visible along the edge of the particle. (Courtesy of FA Murphy and EL Palmer.)

The viral genome is linear, negative-sense, single-stranded, nonsegmented RNA, about 15 kb in size (Figure 2). Because the genome is not segmented, this negates any opportunity for frequent genetic reassortment, resulting in antigenic stability.

Fig2. Genetic maps of representative members of the genera of the family Paramyxoviridae. Gene sizes (boxes) are drawn approximately to scale. (Copyright GD Parks and RA Lamb, 2006.)

Most paramyxoviruses contain six structural proteins. Three proteins are complexed with the viral RNA—the nucleocapsid (N) protein that forms the helical nucleocapsid (13 or 18 nm in diameter) and represents the major internal protein and two other large proteins (designated P and L), which are involved in the viral polymerase activity that functions in transcription and RNA replication.

Three proteins participate in the formation of the viral envelope. Matrix (M) protein underlies the viral envelope; it has an affinity for both the N and the viral surface glycoproteins and is important in virion assembly. The nucleocapsid is surrounded by a lipid envelope that is studded with 8- to 12-nm spikes of two different transmembrane glycoproteins. The activities of these surface glycoproteins help differentiate the various genera of the Paramyxoviridae family (Table 2). The larger glycoprotein (HN or G) may or may not possess hemagglutination and neuraminidase activities and is responsible for attachment to the host cell. It is assembled as a tetramer in the mature virion. The other glycoprotein (F) mediates membrane fusion and hemolysin activities. The pneumoviruses and metapneumoviruses contain two additional small envelope proteins (M2-1 and SH).

Table2. Characteristics of Genera in the Subfamilies of the Family Paramyxoviridae

A diagram of a paramyxovirus particle is shown in Figure 3.

Fig3. Schematic diagram of a paramyxovirus showing major components (not drawn to scale). The viral matrix protein (M) underlies the lipid bilayer. Inserted through the viral membrane are the hemagglutinin–neuraminidase (HN) attachment glycoprotein and the fusion (F) glycoprotein. Only some paramyxoviruses contain the SH protein. Inside the virus is the negative-strand virion RNA, which is encased in the nucleocapsid protein (N). Associated with the nucleocapsid are the L and P proteins, and together this complex has RNA-dependent RNA transcriptase activity. The V protein is only found in rubulavirus virions. (Copyright GD Parks and RA Lamb, 2006.)

Classification

The Paramyxoviridae family is divided into two subfamilies and seven genera, six of which contain human pathogens (see Table 2). Most of the members are monotypic (ie, they consist of a single serotype); all are antigenically stable.

The genus Respirovirus contains two serotypes of human parainfluenza viruses, and the genus Rubulavirus contains two other parainfluenza viruses as well as mumps virus. Some animal viruses are related to the human strains. Sendai virus of mice, which was the first parainfluenza virus isolated and is now recognized as a common infection in mouse colonies, is a subtype of human type 1 virus. Simian parainfluenza virus 5 (PIV5), a common contaminant of primary monkey cells, is the same as canine parainfluenza virus type 2; shipping fever virus of cattle and sheep is a subtype of type 3. Newcastle disease virus, the prototype avian parainfluenza virus of genus Avulavirus, is also related to the human viruses.

Members within a genus share common antigenic determinants. Although the viruses can be distinguished antigenically using well-defined reagents, hyperimmunization stimulates cross-reactive antibodies that react with all four parainfluenza viruses, mumps virus, and Newcastle disease virus. Such heterotypic antibody responses, which include antibodies directed against both internal and surface proteins of the virus, are commonly observed in older people. This phenomenon makes it difficult to determine by serodiagnosis the most likely infecting type. All members of the genera Respirovirus and Rubulavirus possess hemagglutinating and neuraminidase activities, both carried by the HN glycoprotein, as well as membrane fusion and hemolysin properties, both functions of the F protein.

The Morbillivirus genus contains measles virus (rubeola) of humans as well as canine distemper virus, rinderpest virus of cattle, and aquatic morbilliviruses that infect marine mammals. These viruses are antigenically related to each other but not to members of the other genera. Whereas the F protein is highly conserved among the morbilliviruses, the HN/G proteins display more variability. Measles virus has a hemagglutinin but lacks neuraminidase activity. Measles virus induces formation of intranuclear inclusions, but other paramyxoviruses do not.

The Henipavirus genus contains zoonotic paramyxoviruses that are able to infect and cause disease in humans. Hendra and Nipah viruses, both indigenous to fruit bats, are members of the genus. These viruses lack neuraminidase activity.

Respiratory syncytial viruses of humans and cattle and pneumonia virus of mice constitute the genus Pneumovirus. There are two antigenically distinct strains of RSV of humans, subgroups A and B. The larger surface glycoprotein of pneumoviruses lacks hemagglutinating and neuraminidase activities characteristic of respiroviruses and rubulaviruses, so it is designated the G protein. The F protein of RSV exhibits membrane fusion activity but no hemolysin activity. Human metapneumoviruses are respiratory pathogens of humans classified in the genus Metapneumovirus.

Paramyxovirus Replication

The typical paramyxovirus replication cycle is illustrated in Figure4.

Fig4. Paramyxovirus life cycle. The infecting virus particle fuses with the plasma membrane and releases the viral nucleocapsid into the cytoplasm. Solid lines represent transcription and genome replication. Dotted lines indicate transport of newly synthesized viral proteins to plasma membrane. Progeny virions are released from the cell by a budding process. The entire paramyxovirus replication cycle takes place in the cell cytoplasm. ER, endoplasmic reticulum. (Copyright GD Parks and RA Lamb, 2006.)

A. Virus Attachment, Penetration, and Uncoating

Paramyxoviruses attach to host cells via the hemagglutinin glycoprotein (HN, H, or G protein). In the case of measles virus, the receptor is the membrane CD46 or CD150 molecule. Next, the virion envelope fuses with the cell membrane by the action of the fusion glycoprotein F1 cleavage product. The F1 protein undergoes complex refolding during the process of viral and cellular membrane fusion. If the F0 precursor is not cleaved, it has no fusion activity; virion penetration does not occur; and the virus particle is unable to initiate infection. Fusion by F1 occurs at the neutral pH of the extra cellular environment, allowing release of the viral nucleocapsid directly into the cell. Thus, paramyxoviruses are able to bypass internalization through endosomes.

B. Transcription, Translation, and RNA Replication

Paramyxoviruses contain a nonsegmented, negative-strand RNA genome. Messenger RNA transcripts are made in the cell cytoplasm by the viral RNA polymerase. There is no need for exogenous primers and therefore no dependence on cell nuclear functions. The mRNAs are much smaller than genomic size; each represents a single gene. Transcriptional regulatory sequences at gene boundaries signal transcriptional start and termination. The position of a gene relative to the 3′ end of the genome correlates with transcription efficiency. Whereas the most abundant class of transcripts produced by an infected cell is from the N gene, located nearest the 3′ end of the genome, the least abundant is from the L gene, located at the 5′ end (see Figure 2).

Viral proteins are synthesized in the cytoplasm, and the quantity of each gene product corresponds to the level of mRNA transcripts from that gene. Viral glycoproteins are synthesized and glycosylated in the secretory pathway.

The viral polymerase protein complex (P and L proteins) is also responsible for viral genome replication. For successful synthesis of a positive-strand antigenome intermediate template, the polymerase complex must disregard the termination signals interspersed at gene boundaries. Full-length progeny genomes are then copied from the antigenome template.

The nonsegmented genome of paramyxoviruses negates the possibility of gene segment reshuffling (ie, genetic reassortment) so important to the natural history of influenza viruses. The HN/H/G and F surface proteins of paramyxoviruses exhibit minimal antigenic variation over long periods of time. It is surprising that they do not undergo antigenic drift as a result of mutations introduced during replication, because RNA polymerases tend to be error-prone. One possible explanation is that nearly all the amino acids in the primary structures of paramyxovirus glycoproteins may be involved in structural or functional roles, leaving little opportunity for substitutions that would not markedly diminish the viability of the virus.

C. Maturation

 The virus matures by budding from the cell surface. Progeny nucleocapsids form in the cytoplasm and migrate to the cell surface. They are attracted to sites on the plasma membrane that are studded with viral HN/H/G and F0 glycoprotein spikes. The M protein is essential for particle formation, serving to link the viral envelope to the nucleocapsid.

During budding, most host proteins are excluded from the membrane.

The neuraminidase activity of the HN protein of para influenza viruses and mumps virus presumably functions to prevent self-aggregation of virus particles. Other paramyxoviruses do not possess neuraminidase activity (see Table 2).

If appropriate host cell proteases are present, F0 proteins in the plasma membrane will be activated by cleavage. Activated fusion protein will then cause fusion of adjacent cell membranes, resulting in formation of large syncytia (Figure 5). Syncytium formation is a common response to paramyxovirus infection. Acidophilic cytoplasmic inclusions are regularly formed (see Figure 5). Inclusions are believed to reflect sites of viral synthesis and have been found to contain recognizable nucleocapsids and viral proteins. Measles virus also produces intranuclear inclusions (see Figure 5).

Fig5. Syncytial formation induced by paramyxoviruses. A: Respiratory syncytial virus in MA104 cells (unstained, 100×). Syncytia (arrows) result from fusion of plasma membranes; nuclei are accumulated in the center. B: Respiratory syncytial virus in HEp-2 cells (hematoxylin and eosin [H&E] stain, 400×). Syncytium contains many nuclei and acidophilic cytoplasmic inclusions (arrow). C: Measles virus in human kidney cells (H&E stain, 30×). Huge syncytium contains hundreds of nuclei. D: Measles virus in human kidney cells (H&E stain, 400×). Multinucleated giant cell contains acidophilic nuclear inclusions (vertical arrow) and cytoplasmic

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Antigenic Drift and Antigenic Shift

Structure and Function of Neuraminidase

Complications of COVID-19

Clinical Features of SARS-CoV-2 and COVID-19

Modes of Transmission SARS-CoV-2 and COVID-19

Papillomaviruses

Arenaviruses

Adenoviruses

Viral Serology: Immune Status Testing

Structure and Function of Hemagglutinin

Structure and Composition of influenza viruses