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.
Highlights
Newcastle disease (ND) is a highly contagious infection caused by Newcastle disease virus (NDV) which affects more than 250 species of birds
R75/98 F is encoded by an open reading frame of 1,662 bases and exhibits features like other NDV F proteins
The cleavage site is the major difference between the F proteins of lentogenic NDV Clone 30 (112G-R-Q-G-R*L117) and NDV R75/98
Summary
Newcastle disease (ND) is a highly contagious infection caused by Newcastle disease virus (NDV) which affects more than 250 species of birds. Based on the severity of clinical signs in chickens, three pathotypes, i.e. lentogenic, mesogenic or velogenic NDV can be distinguished by their intracerebral pathogenicity index (ICPI). Lentogenic strains (ICPI,0.7) induce only mild respiratory signs in young chickens, whereas mesogenic strains (ICPI 0.7–1.5) cause moderate mortality. Infection with velogenic strains (ICPI.1.5) results in diarrhea, hemorrhages, intestinal lesions, respiratory and neurological signs with mortality up to 100% [6]. In the 1980ies, a disastrous epidemic in pigeons spread over Europe and other countries [7] primarily associated with neurological signs similar to NDV in chickens. Most important was the demonstration of a lack of pathogenicity of these PPMV-1 isolates for chickens, whereas morbidity was 80% and mortality 55% after experimental infection of pigeons [9]. PPMV-1 strains may pose a risk for chickens and turkeys, since virulence of PPMV-1 isolates increases following passages in chickens [10, 11] and a number of ND outbreaks in chickens have been attributed to PPMV-1 [6, 12, 13]
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