Zoonotic Potential of Emerging Paramyxoviruses: Knowns and Unknowns

Abstract

The risk of spillover of enzootic paramyxoviruses and the susceptibility of recipient human and domestic animal populations are defined by a broad collection of ecological and molecular factors that interact in ways that are not yet fully understood. Nipah and Hendra viruses were the first highly lethal zoonotic paramyxoviruses discovered in modern times, but other paramyxoviruses from multiple genera are present in bats and other reservoirs that have unknown potential to spillover into humans. We outline our current understanding of paramyxovirus reservoir hosts and the ecological factors that may drive spillover, and we explore the molecular barriers to spillover that emergent paramyxoviruses may encounter. By outlining what is known about enzootic paramyxovirus receptor usage, mechanisms of innate immune evasion, and other host-specific interactions, we highlight the breadth of unexplored avenues that may be important in understanding paramyxovirus emergence.

Keywords: Ecology; Emerging viruses; Henipavirus; Morbillivirus; Paramyxovirus; Pathogenesis; Reservoir; Rubulavirus; Tropism; Zoonotic.

Figure 1. Paramyxovirus genome structures

Depicted here are scaled genomes of representative virus species in 3' to 5' orientation for each of the mammalian-targeting Paramyxovirus genera. JPV is included to represent the putative Jeilongvirus genus. Protein gene products are the larger lettered blocks: replicase proteins are purple (N, P, L), while the remaining virion proteins are red (M, F, G/H/HN). Non-structural accessory proteins are black (V, W, I, SH, TM) or grey (C, Y, ORFX); grey proteins are produced from alternate start codons of a given mRNA. RNA regions are thinner, unlettered horizontal segments: 3’ leader and 5’ trailer regions are black, while the 5’ UTR of each mRNA is colored green, and the 3’ UTR of each mRNA is colored blue. The scale bar indicates 1000 nucleotides. A color version of this figure is available online.

Figure 2. Paramyxovirus attachment proteins demonstrate great diversity within and among genera

Maximum likelihood phylogenetic trees of P, L and attachment (HN/H/G) protein sequences of Paramyxoviridae. Colored circles encompass phylogenetic groupings best characterized as genera. *Jeilongvirus is a proposed genus that has not yet been recognized by the ICTV, and so are encircled in black. Rubula-like viruses have genetic similarities to recognized members of Rubulavirus, but group separately, and so are encircled in a dotted line. Unclassified-but-fully-sequenced Paramyxoviruses are individually labelled in each tree. Scale bar indicates 0.5 amino acid substitutions per site, and trees are scaled such that the scale bar is the same in all trees. Black circles at nodes represent >75% support from 500 bootstrap replicates. All analyses were performed in MEGA 6 using a complete deletion option and a WAG substitution model. A color version of this figure is available online.

Figure 3. Paramyxoviruses demonstrate greater diversity within each genus at virus proteins with significant host interactions

(A) Pairwise distances of Sialic acid (SA)-using paramyxoviruses versus protein (Prot)-receptor using viruses, indicating the number of virus species attachment proteins. Genera included in SA: Rubulavirus, Respirovirus, Ferlavirus, Avulavirus, Aquaparamyxovirus, and Unclassified (including Rubula-like viruses). Genera included in Prot: Morbillivirus, Henipavirus, and Unclassified (including Jeilongvirus and Morbilli-like viruses). Pairwise distance was calculated in MEGA 6.0, and T test was done using SPSS software (IBM). (B) Pairwise distances per gene and per genus across Paramyxoviridae. Genera are labelled within the graph; H = Henipavirus, n=5 (HeV, NiV, CedV, GH-M74a and MojV); M=Morbillivirus, n=7 (FeMV, PDV, CDV, MeV, PPRV, CeMV); Re=Respirovirus, n=6 (SeV, HPIV-1, PPIV-1, CPIV-3, HPIV-3, BPIV-3); Ru=Rubulavirus, n= 9 (MuV, BMV, PIV-5, HPIV-2, SV-41, PorV, MapV, HPIV-4a, HPIV4b); and A=Avulavirus, n=6 (APMV-2, APMV-5, APMV-11, APMV-3, APMV-9, NDV). Grey bars indicate the virus gene being evaluated. Whiskers show minimal and maximal variation within the genus, boxes denote the 25% (low) and 75% (high) percentiles, and horizontal lines indicate medians.