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Molecular basis for a lack of correlation between viral fitness and cell killing capacity.

Herrera M, García-Arriaza J, Pariente N, Escarmís C, Domingo E - PLoS Pathog. (2007)

Bottom Line: The relationship between parasite fitness and virulence has been the object of experimental and theoretical studies often with conflicting conclusions.However, subsequent plaque-to-plaque transfers resulted in profound fitness loss, but only a minimal decrease of virulence.As a consequence, depending on the passage regime, viral fitness and virulence can follow different evolutionary trajectories.

View Article: PubMed Central - PubMed

Affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, Madrid, Spain.

ABSTRACT
The relationship between parasite fitness and virulence has been the object of experimental and theoretical studies often with conflicting conclusions. Here, we provide direct experimental evidence that viral fitness and virulence, both measured in the same biological environment provided by host cells in culture, can be two unrelated traits. A biological clone of foot-and-mouth disease virus acquired high fitness and virulence (cell killing capacity) upon large population passages in cell culture. However, subsequent plaque-to-plaque transfers resulted in profound fitness loss, but only a minimal decrease of virulence. While fitness-decreasing mutations have been mapped throughout the genome, virulence determinants-studied here with mutant and chimeric viruses-were multigenic, but concentrated on some genomic regions. Therefore, we propose a model in which viral virulence is more robust to mutation than viral fitness. As a consequence, depending on the passage regime, viral fitness and virulence can follow different evolutionary trajectories. This lack of correlation is relevant to current models of attenuation and virulence in that virus de-adaptation need not entail a decrease of virulence.

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Amino Acid Substitutions Found in the FMDV							 Genome as Compared to FMDV C-S8c1						The FMDV C-S8c1 genome (8,115 residues excluding the internal poly(C) and the 3′ poly(A)) composed of the 5′ and 3′ UTRs (lines) and coding regions (boxes), which include protease L, structural proteins (VP4, VP2, VP3, and VP1), and non-structural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D). Genomic regions are based in [14] and references therein; VPg is the protein (3B) covalently linked to the 5′ end of the RNA, poly(C) is the internal polyribocytidylate tract, and poly(A) is the 3′ terminal polyadenylate tract. The FMDV C-S8c1- and 							-coding regions are represented in white and blue, respectively. Amino acids in 							 that differ from the corresponding ones in C-S8c1 are indicated in red. Replacements found also in the 							 genome are encircled. Numbering of amino acids for each individual protein is as in [11].
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ppat-0030053-g003: Amino Acid Substitutions Found in the FMDV Genome as Compared to FMDV C-S8c1 The FMDV C-S8c1 genome (8,115 residues excluding the internal poly(C) and the 3′ poly(A)) composed of the 5′ and 3′ UTRs (lines) and coding regions (boxes), which include protease L, structural proteins (VP4, VP2, VP3, and VP1), and non-structural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D). Genomic regions are based in [14] and references therein; VPg is the protein (3B) covalently linked to the 5′ end of the RNA, poly(C) is the internal polyribocytidylate tract, and poly(A) is the 3′ terminal polyadenylate tract. The FMDV C-S8c1- and -coding regions are represented in white and blue, respectively. Amino acids in that differ from the corresponding ones in C-S8c1 are indicated in red. Replacements found also in the genome are encircled. Numbering of amino acids for each individual protein is as in [11].

Mentions: The comparison of the consensus nucleotide sequence of the genome with that of C-S8c1 revealed a total of 47 mutations (Table S2), leading to 21 amino acid replacements affecting structural and non-structural proteins (Figure 3). To identify the genomic regions associated with the increased virulence of with respect to C-S8c1, we measured the BHK-21 cell killing capacity of nine chimeric viruses rescued from constructs obtained by introducing fragments of cDNA of the genome into plasmid pMT28, which encodes infectious C-S8c1 RNA [21] (Figure 4). The results (Figure 5; Tables 2 and S1) show that several genomic regions contribute to the virulence of for BHK-21 cells, and that the major contributors map within genomic positions 2046 to 3760 (residues encoding part of VP2, VP3, and part of VP1, Figure 5A) and 3760 to 5839 (residues encoding 2A, 2B, 2C, and 3A, Figure 5B). The results exclude the internal ribosome entry site and the 3C- and 3D-coding regions as significant virulence determinants of for BHK-21 cells (virulence of the relevant chimeric viruses ≤ 2.5, relative to C-S8c1; Tables 2 and S1). Infectious progeny production by each chimeric virus was intermediate between the production of the parental viruses pMT28 and , with no significant differences that could be correlated with virulence (Table 2).


Molecular basis for a lack of correlation between viral fitness and cell killing capacity.

Herrera M, García-Arriaza J, Pariente N, Escarmís C, Domingo E - PLoS Pathog. (2007)

Amino Acid Substitutions Found in the FMDV							 Genome as Compared to FMDV C-S8c1						The FMDV C-S8c1 genome (8,115 residues excluding the internal poly(C) and the 3′ poly(A)) composed of the 5′ and 3′ UTRs (lines) and coding regions (boxes), which include protease L, structural proteins (VP4, VP2, VP3, and VP1), and non-structural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D). Genomic regions are based in [14] and references therein; VPg is the protein (3B) covalently linked to the 5′ end of the RNA, poly(C) is the internal polyribocytidylate tract, and poly(A) is the 3′ terminal polyadenylate tract. The FMDV C-S8c1- and 							-coding regions are represented in white and blue, respectively. Amino acids in 							 that differ from the corresponding ones in C-S8c1 are indicated in red. Replacements found also in the 							 genome are encircled. Numbering of amino acids for each individual protein is as in [11].
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC1851977&req=5

ppat-0030053-g003: Amino Acid Substitutions Found in the FMDV Genome as Compared to FMDV C-S8c1 The FMDV C-S8c1 genome (8,115 residues excluding the internal poly(C) and the 3′ poly(A)) composed of the 5′ and 3′ UTRs (lines) and coding regions (boxes), which include protease L, structural proteins (VP4, VP2, VP3, and VP1), and non-structural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D). Genomic regions are based in [14] and references therein; VPg is the protein (3B) covalently linked to the 5′ end of the RNA, poly(C) is the internal polyribocytidylate tract, and poly(A) is the 3′ terminal polyadenylate tract. The FMDV C-S8c1- and -coding regions are represented in white and blue, respectively. Amino acids in that differ from the corresponding ones in C-S8c1 are indicated in red. Replacements found also in the genome are encircled. Numbering of amino acids for each individual protein is as in [11].
Mentions: The comparison of the consensus nucleotide sequence of the genome with that of C-S8c1 revealed a total of 47 mutations (Table S2), leading to 21 amino acid replacements affecting structural and non-structural proteins (Figure 3). To identify the genomic regions associated with the increased virulence of with respect to C-S8c1, we measured the BHK-21 cell killing capacity of nine chimeric viruses rescued from constructs obtained by introducing fragments of cDNA of the genome into plasmid pMT28, which encodes infectious C-S8c1 RNA [21] (Figure 4). The results (Figure 5; Tables 2 and S1) show that several genomic regions contribute to the virulence of for BHK-21 cells, and that the major contributors map within genomic positions 2046 to 3760 (residues encoding part of VP2, VP3, and part of VP1, Figure 5A) and 3760 to 5839 (residues encoding 2A, 2B, 2C, and 3A, Figure 5B). The results exclude the internal ribosome entry site and the 3C- and 3D-coding regions as significant virulence determinants of for BHK-21 cells (virulence of the relevant chimeric viruses ≤ 2.5, relative to C-S8c1; Tables 2 and S1). Infectious progeny production by each chimeric virus was intermediate between the production of the parental viruses pMT28 and , with no significant differences that could be correlated with virulence (Table 2).

Bottom Line: The relationship between parasite fitness and virulence has been the object of experimental and theoretical studies often with conflicting conclusions.However, subsequent plaque-to-plaque transfers resulted in profound fitness loss, but only a minimal decrease of virulence.As a consequence, depending on the passage regime, viral fitness and virulence can follow different evolutionary trajectories.

View Article: PubMed Central - PubMed

Affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, Madrid, Spain.

ABSTRACT
The relationship between parasite fitness and virulence has been the object of experimental and theoretical studies often with conflicting conclusions. Here, we provide direct experimental evidence that viral fitness and virulence, both measured in the same biological environment provided by host cells in culture, can be two unrelated traits. A biological clone of foot-and-mouth disease virus acquired high fitness and virulence (cell killing capacity) upon large population passages in cell culture. However, subsequent plaque-to-plaque transfers resulted in profound fitness loss, but only a minimal decrease of virulence. While fitness-decreasing mutations have been mapped throughout the genome, virulence determinants-studied here with mutant and chimeric viruses-were multigenic, but concentrated on some genomic regions. Therefore, we propose a model in which viral virulence is more robust to mutation than viral fitness. As a consequence, depending on the passage regime, viral fitness and virulence can follow different evolutionary trajectories. This lack of correlation is relevant to current models of attenuation and virulence in that virus de-adaptation need not entail a decrease of virulence.

Show MeSH
Related in: MedlinePlus