Pathogenicity and virulence of henipaviruses

Abstract

Paramyxoviruses are a family of single-stranded negative-sense RNA viruses, many of which are responsible for a range of respiratory and neurological diseases in humans and animals. Among the most notable are the henipaviruses, which include the deadly Nipah (NiV) and Hendra (HeV) viruses, the causative agents of outbreaks of severe disease and high case fatality rates in humans and animals. NiV and HeV are maintained in fruit bat reservoirs primarily in the family Pteropus and spillover into humans directly or by an intermediate amplifying host such as swine or horses. Recently, non-chiropteran associated Langya (LayV), Gamak (GAKV), and Mojiang (MojV) viruses have been discovered with confirmed or suspected ability to cause disease in humans or animals. These viruses are less genetically related to HeV and NiV yet share many features with their better-known counterparts. Recent advances in surveillance of wild animal reservoir viruses have revealed a high number of henipaviral genome sequences distributed across most continents, and mammalian orders previously unknown to harbour henipaviruses. In this review, we summarize the current knowledge on the range of pathogenesis observed for the henipaviruses as well as their replication cycle, epidemiology, genomics, and host responses. We focus on the most pathogenic viruses, including NiV, HeV, LayV, and GAKV, as well as the experimentally non-pathogenic CedV. We also highlight the emerging threats posed by these and potentially other closely related viruses.

Keywords: Henipavirus; Paramyxovirus; Pathogenesis; Virulence; Virus.

Figure 1.

Neighbor end joining tree of L protein CDS for selected paramyxoviruses. L CDS neighbor end joining homology tree made with Tamara Nei consensus sequence of 23 sequences. L CDS from MeV (NC_001498.1), GhV (HQ660129), CedPV-CG1a (NC_025351), CedPV-Geelong (KP271122), NiV-B (AY988601), NiV-M (NC_002728), HeV (AF017149), HeV (MZ318101), AngV (ON613535), DARV (MZ574408), MojV, (NC_025352), LayV (OM101125), GAKV (MZ574409), DenV (OK623355), and MeliV (OK623354).

Figure 2.

Genomic organization of henipaviruses and related species: of the selected genomes (a) the HeV genome has the conserved gene order N-P-M-F-G-L where each ORF is encoded on a separate mRNA which differs from (b) which is the MeliV genome characteristic of LayV, MojV, GAKV, DARV, and related viruses where the F gene encodes an additional ORF X in the 5’ UTR producing the S protein. AngV (c) has the smallest genome and each mRNA is likely monocistronic. MeV (d) which is representative of the morbillivirus genus as an outgroup is markedly smaller compared to (a) and (b). The transcriptional unit length (all nucleotides from last intergenic residue to the first residue of the next intergenic region) from each major branch of the henipavirus phylogeny compared to each other for (e) the N gene of genomes with intergenic region present in the leader, (f) for P gene in all genomes, (g) M in all genomes, (h) F transcriptional unit (including ORF X/S protein CDS for early diverging genomes), (i) G gene, (j) for the L gene in all genomes with intergenic sequence in the trailer, and (k) total reported genome length. The length of early diverging henipavirus genomes (including LayV and MojV) is longer compared to later diverging genomes (including HeV, NiV, and CedV) and the transcriptional unit encoding the F protein and/or S protein is significantly longer (f).

Figure 3.

Map of where henipavirus related genomes have been sequenced or detected. Countries are subdivided into colours by proposed genotype, unchategorized genotypes are grey, early diverging genotypes are in Orange, late diverging genotypes are in blue. (created with mapchart.net).

Figure 4.

Comparisons of P genes from selected genotypes (a) MeV, (b) AngV, (c) LayV, MojV, GAKV, (d) NiV, HeV, GhV.

Figure 5.

Predicted structures of S proteins. highest scoring Alphafold predictions with regions in blue: N-terminal and predicted intracellular region, Grey: predicted transmembrane region, Orange: predicted ectodomain of S protein CDS from (a) LayV SDQD_H1801 [OM101125], (b) Jingmen Crocidura shantungensis henipavirus 2 isolate SYS_SheQu [OM030315], (c) DewiV strain BE/Ninove/Cr/1/2019 [OK623354], (d) Melian virus strain GN/Meliandou/Cg/1/2018 [OK623353], (e) GAKV Cs17-65 [MZ574409], (f) Wufeng Crocidura attenuata henipavirus 1 isolate WFS_SheQu [OM030317], (g) MojV isolate Tongguan1 [NC_025352], (h) DARV Cl17-46 [MZ574408], (i) GAKV Cs17-65 [MZ574409], (j) MAG: chodsigoa hypsibia henipavirus isolate PMV/SC/C7-49.4/2022 [OQ236120], (k) Wenzhou apodemus agrarius henipavirus 1 [MZ328275], (l) Wufeng Chodsigoa smithii henipavirus 1 isolate WFS_ChangWei [OM030316], (m) schematic of LayV S protein [OM101125] with furin cleavage site in orange.

Figure 6.

Progression of infection with NiV or HeV. (a) Flow chart of a typical infection, (b) routes of virus entry and dissemination, (c) organ targets including the lungs, CNS, heart, kidneys, spleen, and brain. Made with BioRender.