Paramyxoviruses: Pathogenesis, Vaccines, Antivirals, and Prototypes for Pandemic Preparedness

Abstract

The Paramyxoviridae family includes established human pathogens such as measles virus, mumps virus, and the human parainfluenza viruses; highly lethal zoonotic pathogens such as Nipah virus; and a number of recently identified agents, such as Sosuga virus, which remain poorly understood. The high human-to-human transmission rate of paramyxoviruses such as measles virus, high case fatality rate associated with other family members such as Nipah virus, and the existence of poorly characterized zoonotic pathogens raise concern that known and unknown paramyxoviruses have significant pandemic potential. In this review, the general life cycle, taxonomic relationships, and viral pathogenesis are described for paramyxoviruses that cause both systemic and respiratory system-restricted infections. Next, key gaps in critical areas are presented, following detailed conversations with subject matter experts and based on the current literature. Finally, we present an assessment of potential prototype pathogen candidates that could be used as models to study this important virus family, including assessment of the strengths and weaknesses of each potential prototype.

Keywords: pandemic preparedness; paramyxovirus; prototype pathogens; zoonosis.

Figure 1.

Generalized paramyxovirus life cycle. (1) Attachment of the viral particle, mediated by the attachment protein. (2) Fusion between the viral and a cellular membrane to release the ribonucleoprotein complex containing the negative sensed genome into the cytosol. Transcription (3a) of viral messenger RNA (mRNA) is promoted by the viral polymerase complex within viral-induced inclusion bodies, followed by translation (3b) in the cytosol, and replication of viral genomes within intracytoplasmic inclusion bodies (3c). (4) Viral proteins and encapsidated genome are transported to sites of assembly and budding occurs from the plasma membrane.

Figure 2.

Maximum likelihood phylogenetic tree of L and attachment (HN/H/G) proteins of recognized Paramyxoviridae families. Colored circles correspond to characterized genera by the International Committee on Taxonomy of Viruses. Avulavirinae subfamily members (genera Metaavulavirus, Orthoavulavirus, and Paraavulavirus) are not shown for clarity of presentation. Scale bar indicates 0.5 amino acid substitutions per site. Genera prioritized for discussion by the Paramyxovirus Expert Review Group were the rubulaviruses, respiroviruses, morbilliviruses and Henipaviruses. Trees were constructed using Mega 6 using a complete deletion option and WAG substitution model. Trees constructed by Andres Moreira-Soto and Jan Felix Drexler, Charité, Berlin, Germany.

Figure 3.

Pandemic pathogen prioritization matrix. Five decision drivers considered to increase the likelihood of selection of a prototypic virus from the selected genera (↑) and 2 decision drivers considered to decrease the likelihood of selection of a prototypic virus from the selected genera (↓) were prioritized by the Paramyxovirus Expert Group. These were assigned a number from 1 (dark green) to 5 (red) by the group with of goal of objective ranking. This evaluative tool proved to be useful in helping the group to prioritize prototypes iteratively. This led to a ranking of henipaviruses < morbilliviruses < respiroviruses < pararubulaviruses/orthorubulaviruses as indicated by the arrows.