Relationship between within-Host Fitness and Virulence in the Vesicular Stomatitis Virus: Correlation with Partial Decoupling

Abstract

e Given the parasitic nature of viruses, it is sometimes assumed that rates of viral replication and dissemination within hosts (within-host fitness) correlate with virulence. However, there is currently little empirical evidence supporting this principle. To test this, we quantified the fitness and virulence of 21 single-or double-nucleotide mutants of the vesicular stomatitis virus in baby hamster kidney cells (BHK-21). We found that, overall, these two traits correlated positively, but significant outliers were identified. Particularly, a single mutation in the conserved C terminus of the N nucleocapsid (U1323A) had a strongly deleterious fitness effect but did not alter or even slightly increased virulence. We also found a double mutant of the M matrix protein and G glycoprotein (U2617G/A3802G mutant) with high fitness yet low virulence. We further characterized these mutants in primary cultures from mouse brain cells and in vivo and found that their relative fitness values were similar to those observed in BHK-21 cells. The mutations had weak effects on the virus-induced death rate of total brain cells, although they specifically reduced neuron death rates. Furthermore, increased apoptosis levels were detected in neurons infected with the U2617G/A3802G mutant, consistent with its known inability to block interferon secretion. In vivo, this mutant had reduced virulence and, despite its low brain titer, it retained a relatively high fitness value owing to its ability to suppress competitor viruses. Overall, our results are in broad agreement with the notion that viral fitness and virulence should be positively correlated but show that certain mutations can break this association and that the fitness-virulence relationship can depend on complex virus-host and virus-virus interactions.

Association of haplotypes for SNPs in the LTR regions of bovine leukemia virus with hematological indices of cattle

“…The fact that the former haplotype is more common is indicative of an evolutionary advantage of more virulent strains over less virulent. Similar results were obtained in many experiments with RNA viruses of mice, rats, and rabbits (Furió et al, 2012;Elsworth et al, 2014;Korboukh et al, 2014;Fitzsimmons et al, 2018). Moreover, in some cases there was an increase in the evolutionary flexibility of viruses.…”

Quantitative Trait Locus Based Virulence Determinant Mapping of the HSV-1 Genome in Murine Ocular Infection: Genes Involved in Viral Regulatory and Innate Immune Networks Contribute to Virulence

“…It should be noted that the R 2 values for the linear regression analyses of mean peak titer versus phenotypic disease were low, with several low pathogenic strains replicating to high titers (Figs 1 and 2 ), suggesting that additional factors beyond replication efficiency contribute to virulence. Finding a correlation between virulence and replication in HSV-1 is not unexpected, as similar phenomena have been observed in poliovirus 1 [ 46 ], vesicular stomatitis virus [ 47 ], and Marek’s disease virus, another alphaherpesvirus [ 48 ]. Based on this finding, determining the viral replication potential of HSV-1 strains in MEF cells or another restrictive cell line may be a rapid method of estimating HSV-1 virulence.…”

Analysis of Nipah Virus Codon Usage and Adaptation to Hosts

“…A quantification of viral fitness and virulence has been done for vesicular stomatitis virus (VSV) using 21 single- or double-nucleotide mutants in the BHK-21 cell line. Broadly speaking, a positive correlation has been found between these two phenomena, however, significant outliers (high fitness yet relatively low virulence and reduced fitness with no effects on virulence) have also been reported (Furió et al, 2012). This experiment of Furió et al (2012) is able to explain our results, showing low calculated fitness, yet high virulence in a ferret model and vice versa in bats.…”