Abstract
BackgroundLoss of virulence is a phenotypic adaptation commonly seen in prokaryotic and eukaryotic pathogens. This mechanism is not well studied, especially in organisms with multiple host and life cycle stages such as Babesia, a tick-transmitted hemoparasite of humans and animals. B. bovis, which infects cattle, has naturally occurring virulent strains that can be reliably attenuated in vivo. Previous studies suggest the virulence loss mechanism may involve post-genomic modification. We investigated the transcriptome profiles of two geographically distinct B. bovis virulent and attenuated strain pairs to better understand virulence loss and to gain insight into pathogen adaptation strategies.ResultsExpression microarray and RNA-sequencing approaches were employed to compare transcriptome profiles of two B. bovis strain pairs, with each pair consisting of a virulent parental and its attenuated derivative strain. Differentially regulated transcripts were identified within each strain pair. These included genes encoding for VESA1, SmORFs, undefined membrane and hypothetical proteins. The majority of individual specific gene transcripts differentially regulated within a strain were not shared between the two strains. There was a disproportionately greater number of ves genes upregulated in the virulent parental strains. When compared with their attenuated derivatives, divergently oriented ves genes were included among the upregulated ves genes in the virulent strains, while none of the upregulated ves genes in the attenuated derivatives were oriented head to head. One gene family whose specific members were consistently and significantly upregulated in expression in both attenuated strains was spherical body protein (SBP) 2 encoding gene where SBP2 truncated copies 7, 9 and 11 transcripts were all upregulated.ConclusionsWe conclude that ves heterodimer pair upregulation and overall higher frequency of ves gene expressions in the virulent strains is consistent with the involvement of this gene family in virulence. This is logical given the role of VESA1 proteins in cytoadherence of infected cells to endothelial cells. However, upregulation of some ves genes in the attenuated derivatives suggests that the consequence of upregulation is gene-specific. Furthermore, upregulation of the spherical body protein 2 gene family may play a role in the attenuated phenotype. Exactly how these two gene families may contribute to the loss or gain of virulence is discussed.
Highlights
Loss of virulence is a phenotypic adaptation commonly seen in prokaryotic and eukaryotic pathogens
T2Bo and L17 transcriptome approaches In order to determine if virulence loss is controlled at the transcriptional level, we compared the global transcriptomes of two strain pairs of B. bovis
The utilization of the T2Bo genome-based microarray for L17 transcriptome investigation would reflect gene expressions shared between T2Bo and L17 and exclude L17-specific transcripts as gene family member variations are known to exist between different B. bovis strains [15]
Summary
Loss of virulence is a phenotypic adaptation commonly seen in prokaryotic and eukaryotic pathogens. This mechanism is not well studied, especially in organisms with multiple host and life cycle stages such as Babesia, a tick-transmitted hemoparasite of humans and animals. Depending on the environmental milieu there may be strong selection for specific pathogenic phenotypes such as virulence or attenuation acquisition. These phenotypic shifts may be achieved through sexual reproduction where novel recombinations often lead to genome diversity [1]. For many multi-stage pathogens, this cannot occur during haploid life stages and they depend on genomic mutations or adaptations through non-mutational mechanisms such as phenotypic variation. With increased emphasis on the development and delivery of vaccines for hemoparasites such as Babesia, Theileria, and Plasmodium spp. [7,8,9,10], the ability to predictably and stably attenuate pathogens would be a significant step toward disease control strategies
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