Approaches to define the viral genetic basis of classical swine fever virus virulence

Leifer, Immanuel; Ruggli, Nicolas; Blome, Sandra

doi:10.1016/j.virol.2013.01.013

Cited by 48 publications

(32 citation statements)

References 82 publications

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“…8). This suggests that the virulence of CSFV is more likely a multi-genic trait determined by a complex interplay of several viral proteins or genes acting in concert as already postulated in previous studies (Leifer et al, 2013;Tamura et al, 2012). To the best of our knowledge, this is the first study to show that the N-terminal domain of CSFV NS4B can confer enhanced pathogenicity to a low virulent virus, which was related to an enhanced viral replication.…”

Section: Discussionsupporting

confidence: 69%

Intracellular membrane association of the N-terminal domain of classical swine fever virus NS4B determines viral genome replication and virulence

Tamura

Ruggli²,

Nagashima

et al. 2015

Journal of General Virology

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Classical swine fever virus (CSFV) causes a highly contagious disease in pigs that can range from a severe haemorrhagic fever to a nearly unapparent disease, depending on the virulence of the virus strain. Little is known about the viral molecular determinants of CSFV virulence. The nonstructural protein NS4B is essential for viral replication. However, the roles of CSFV NS4B in viral genome replication and pathogenesis have not yet been elucidated. NS4B of the GPE 2 vaccine strain and of the highly virulent Eystrup strain differ by a total of seven amino acid residues, two of which are located in the predicted trans-membrane domains of NS4B and were described previously to relate to virulence, and five residues clustering in the N-terminal part. In the present study, we examined the potential role of these five amino acids in modulating genome replication and determining pathogenicity in pigs. A chimeric low virulent GPE 2 -derived virus carrying the complete Eystrup NS4B showed enhanced pathogenicity in pigs. The in vitro replication efficiency of the NS4B chimeric GPE 2 replicon was significantly higher than that of the replicon carrying only the two Eystrup-specific amino acids in NS4B. In silico and in vitro data suggest that the N-terminal part of NS4B forms an amphipathic a-helix structure. The N-terminal NS4B with these five amino acid residues is associated with the intracellular membranes. Taken together, this is the first gain-of-function study showing that the N-terminal domain of NS4B can determine CSFV genome replication in cell culture and viral pathogenicity in pigs.

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Section: Discussionsupporting

confidence: 69%

Intracellular membrane association of the N-terminal domain of classical swine fever virus NS4B determines viral genome replication and virulence

Tamura

Ruggli²,

Nagashima

et al. 2015

Journal of General Virology

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“…Therefore, the gaining in fitness by the CSFV/Santiago de Cuba (CSF1057)/2011 strain, could clearly be the consequence of the enhanced virulence of this strain. A second factor to consider is that proteins other than E2 have been also linked to enhance the virulence of CSFV, such as Npro (Tamura et al, ) and NS4B (Leifer, Ruggli, & Blome, ; Tamura et al, ). Thus, while the positive selection pressure on E2 protein of CSFV seems to induce a decrease in virulence, it is possible that the compensation action of other markers of virulence into the quasispecies cloud could be enough to yield a highly virulent phenotype.…”

Section: Discussionmentioning

confidence: 99%

Positive selection pressure on E2 protein of classical swine fever virus drives variations in virulence, pathogenesis and antigenicity: Implication for epidemiological surveillance in endemic areas

Coronado

Rios

Frı́as

et al. 2019

Transbound Emerg Dis

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Classical swine fever (CSF), caused by CSF virus (CSFV), is considered one of the most important infectious diseases with devasting consequences for the pig industry. Recent reports describe the emergence of new CSFV strains resulting from the action of positive selection pressure, due mainly to the bottleneck effect generated by ineffective vaccination. Even though a decrease in the genetic diversity of the positively selected CSFV strains has been observed by several research groups, there is little information about the effect of this selective force on the virulence degree, antigenicity and pathogenicity of this type of strains. Hence, the aim of the current study was to determine the effect of the positive selection pressure on these three parameters of CSFV strains, emerged as result of the bottleneck effects induced by improper vaccination in a CSF‐endemic area. Moreover, the effect of the positively selected strains on the epidemiological surveillance system was assessed. By the combination of in vitro, in vivo and immunoinformatic approaches, we revealed that the action of the positive selection pressure induces a decrease in virulence and alteration in pathogenicity and antigenicity. However, we also noted that the evolutionary process of CSFV, especially in segregated microenvironments, could contribute to the gain‐fitness event, restoring the highly virulent pattern of the circulating strains. Besides, we denoted that the presence of low virulent strains selected by bottleneck effect after inefficient vaccination can lead to a relevant challenge for the epidemiological surveillance of CSF, contributing to under‐reports of the disease, favouring the perpetuation of the virus in the field. In this study, B‐cell and CTL epitopes on the E2 3D‐structure model were also identified. Thus, the current study provides novel and significant insights into variation in virulence, pathogenesis and antigenicity experienced by CSFV strains after the positive selection pressure effect.

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“…For the establishment of novel safe and efficacious modified live marker vaccines several alternative concepts for attenuation and DIVA properties have been developed in the recent decade. While a number of genetic changes in various coding and non‐coding regions of the genomes of CSFV and related pestiviruses resulted in reduction of viral replication and decreased virulence in the natural host, final conclusions with regard to molecular determinants of virus attenuation require additional studies (Leifer, Ruggli, & Blome, ; Makoschey et al., ; Risatti et al., , ; Van Gennip, Vlot, Hulst, De Smit, & Moormann, ). One promising way for generation of attenuated CSFV was the establishment of cytopathogenic (cp) CSFV strains by introducing genetic elements from cp BVDV strains into the genome of CSFV (Gallei, Rumenapf, Thiel, & Becher, ; Gallei et al., ).…”

Section: Main Means Of Prevention Detection and Controlmentioning

confidence: 99%

Epidemiology, diagnosis and control of classical swine fever: Recent developments and future challenges

Postel¹,

Austermann-Busch²,

Petrov³

et al. 2017

Transbound Emerg Dis

110

116

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Classical swine fever (CSF) represents a major health and trade problem for the pig industry. In endemic countries or those with a wild boar reservoir, CSF remains a priority for Veterinary Services. Surveillance as well as stamping out and/or vaccination are the principle tools of prevention and control, depending on the context. In the past decades, marker vaccines and accompanying diagnostic tests allowing the discrimination of infected from vaccinated animals have been developed. In the European Union, an E2 subunit and a chimeric live vaccine have been licensed and are available for the use in future disease outbreak scenarios. The implementation of commonly accepted and globally harmonized concepts could pave the way to replace the ethically questionable stamping out policy by a vaccination-to-live strategy and thereby avoid culling of a large number of healthy animals and save food resources. Although a number of vaccines and diagnostic tests are available worldwide, technological advancement in both domains is desirable. This work provides a summary of an analysis undertaken by the DISCONTOOLS group of experts on CSF. Details of the analysis can be downloaded from the web site at http://www.discontools.eu/.

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Approaches to define the viral genetic basis of classical swine fever virus virulence

Cited by 48 publications

References 82 publications

Intracellular membrane association of the N-terminal domain of classical swine fever virus NS4B determines viral genome replication and virulence

Intracellular membrane association of the N-terminal domain of classical swine fever virus NS4B determines viral genome replication and virulence

Positive selection pressure on E2 protein of classical swine fever virus drives variations in virulence, pathogenesis and antigenicity: Implication for epidemiological surveillance in endemic areas

Epidemiology, diagnosis and control of classical swine fever: Recent developments and future challenges

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