Different Regions of the Newcastle Disease Virus Fusion Protein Modulate Pathogenicity

Abstract

Newcastle disease virus (NDV), also designated as Avian paramyxovirus type 1 (APMV-1), is the causative agent of a notifiable disease of poultry but it exhibits different pathogenicity dependent on the virus strain. The molecular basis for this variability is not fully understood. The efficiency of activation of the fusion protein (F) is determined by presence or absence of a polybasic amino acid sequence at an internal proteolytic cleavage site which is a major determinant of NDV virulence. However, other determinants of pathogenicity must exist since APMV-1 of high (velogenic), intermediate (mesogenic) and low (lentogenic) virulence specify a polybasic F cleavage site. We aimed at elucidation of additional virulence determinants by constructing a recombinant virus that consists of a lentogenic NDV Clone 30 backbone and the F protein gene from a mesogenic pigeon paramyxovirus-1 (PPMV-1) isolate with an intracerebral pathogenicity index (ICPI) of 1.1 specifying the polybasic sequence R-R-K-K-R*F motif at the cleavage site. The resulting virus was characterized by an ICPI of 0.6, indicating a lentogenic pathotype. In contrast, alteration of the cleavage site G-R-Q-G-R*L of the lentogenic Clone 30 to R-R-K-K-R*F resulted in a recombinant virus with an ICPI of 1.36 which was higher than that of parental PPMV-1. Substitution of different regions of the F protein of Clone 30 by those of PPMV-1, while maintaining the polybasic amino acid sequence at the F cleavage site, resulted in recombinant viruses with ICPIs ranging from 0.59 to 1.36 suggesting that virulence is modulated by regions of the F protein other than the polybasic cleavage site.

Exploring the Prospects of Engineered Newcastle Disease Virus in Modern Vaccinology

“…Recently, [23] observed an increase in virus virulence following deletion of N glycans from the heptad repeats of the NDV F protein. Furthermore, [24] showed a dramatic increase in NDV virulence when the cytoplasmic tail from a mesogenic strain was used to replace its counterparts in another lentogenic strain, suggesting the possible role of the F protein's cytoplasmic domain in determining the virulence of NDV. The HN protein is also believed to be a determinant of NDV virulence.…”

Different Origins of Newcastle Disease Virus Hemagglutinin-Neuraminidase Protein Modulate the Replication Efficiency and Pathogenicity of the Virus

“…The HN protein of NDV plays an important role in viral infection because it possesses the receptor recognition activity, while viral infection is initiated by attachment of the virion to the sialic acid-containing receptors on the surface of the target cell. HN protein can also promote fusion activity via its interaction with the F protein and act as an NA by removing sialic acid from progeny virus particles to prevent viral self-aggregation, aiding virus infection ( Mirza et al, 1994 ; Huang et al, 2004 ; Melanson and Iorio, 2004 ; Heiden et al, 2014 ; Liu B. et al, 2015 ; Jin et al, 2016 ). Our results showed that HN proteins of the five selected NDV strains in this study had markedly different HAd, NA and fusogenic promotion activities at the protein level.…”

A Review of Functional Motifs Utilized by Viruses

“…Moreover, the F protein mediates virus entry and fusion with the cell membrane for most avian paramyxoviruses type 9 (APMV-9) strains. Recent reports show that the F protein cleavage site sequence is not a major determinant of pathogenicity and virulence of APMV-7 in chickens [171], and other regions of the F protein could modulate virus virulence [172]. In influenza A virus, the cleavage site of HA is Rx[RK]RÓGLF in highly pathogenic avian influenza virus H5N1, while RxxRÓ, RxRRÓ, and KKKRÓ are also reported [111].…”