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Comparative Genomics of a Bovine Mycobacterium tuberculosis Isolate and Other Strains Reveals Its Potential Mechanism of Bovine Adaptation.

ABSTRACT: The Mycobacterium tuberculosis complex causes tuberculosis (TB) in humans and other animal species, but Mycobacterium tuberculosis has a distinct host preference to humans. The present study aimed to determine whether a bovine M. tb strain 1458 has evolved some genetic properties in their genome that might be associated with their bovine adaptation. The genome of the M. tb strain 1458 was sequenced and subjected to an extensive comparative genomic analysis. A phylogenetic analysis showed that strain 1458 is most closely related to a Chinese M. tb strain, CCDC5079, of the same Beijing family. Compared with three human M. tb Beijing family strains, the strain 1458 has the fewest unique genes. However, there are most (21) IS6110 insertion sequences in the strain 1458 genome at either intragenic or intergenic sites, resulting in the interruption of 11 genes including three PPE family-encoding genes (PPE16, PPE38, and PPE59). Only the strain 1458 genome has the upstream insertion in esxS and phoP genes. PCR confirmed four upstream insertions and qPCR determined that transcription of esxS, phoP, dnaN, and ctpD genes differed significantly between M. tb strain 1458 and H37Rv or M. bovis. A Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the genes affected by non-synonymous SNPs are enriched in RNA polymerase. Moreover, 127 of the 133 unique SNPs in strain 1458 are either different to those in the M. bovis genome. In conclusion, some critical genes responsible for bacterial virulence and immunogenicity were interrupted in the genome of bovine M. tb strain 1458 by IS insertions and non-synonymous SNPs, which might contribute to its bovine adaptation, and the modification of its virulence and immunogenicity in cattle.

SUBMITTER: Xiong X

PROVIDER: S-EPMC5733104 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Comparative Genomics of a Bovine Mycobacterium tuberculosis Isolate and Other Strains Reveals Its Potential Mechanism of Bovine Adaptation.

Xiong Xuekai X Wang Rui R Deng Dachuan D Chen Yingyu Y Liu Han H Wang Tianqi T Wang Jieru J Zhu Xiaojie X Zhu Xifang X Zhu Yongqiang Y Lu Xinyan X Chen Huanchun H Zheng Huajun H Guo Aizhen A

Frontiers in microbiology 20171212

The Mycobacterium tuberculosis complex causes tuberculosis (TB) in humans and other animal species, but Mycobacterium tuberculosis has a distinct host preference to humans. The present study aimed to determine whether a bovine M. tb strain 1458 has evolved some genetic properties in their genome that might be associated with their bovine adaptation. The genome of the M. tb strain 1458 was sequenced and subjected to an extensive comparative genomic analysis. A phylogen ...[more]

PMID: 29312206

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Project description:BackgroundTuberculosis is a serious infectious disease affecting millions of people. In spite of efforts to reduce the disease, increasing antibiotic resistance has contributed to persist in the top 10 causes of death worldwide. In fact, the increased cases of multi (MDR) and extreme drug resistance (XDR) worldwide remains the main challenge for tuberculosis control. Whole genome sequencing is a powerful tool for predicting drug resistance-related variants, studying lineages, tracking transmission, and defining outbreaks. This study presents the identification and characterization of resistant clinical isolates of Mycobacterium tuberculosis including a phylogenetic and molecular resistance profile study by sequencing the complete genome of 24 strains from different provinces of Ecuador.ResultsGenomic sequencing was used to identify the variants causing resistance. A total of 15/21 isolates were identified as MDR, 4/21 as pre-XDR and 2/21 as XDR, with three isolates discarded due to low quality; the main sub-lineage was LAM (61.9%) and Haarlem (19%) but clades X, T and S were identified. Of the six pre-XDR and XDR strains, it is noteworthy that five come from females; four come from the LAM sub-lineage and two correspond to the X-class sub-lineage. A core genome of 3,750 genes, distributed in 295 subsystems, was determined. Among these, 64 proteins related to virulence and implicated in the pathogenicity of M. tuberculosis and 66 possible pharmacological targets stand out. Most variants result in nonsynonymous amino acid changes and the most frequent genotypes were identified as conferring resistance to rifampicin, isoniazid, ethambutol, para-aminosalicylic acid and streptomycin. However, an increase in the resistance to fluoroquinolones was detected.ConclusionThis work shows for the first time the variability of circulating resistant strains between men and women in Ecuador, highlighting the usefulness of genomic sequencing for the identification of emerging resistance. In this regard, we found an increase in fluoroquinolone resistance. Further sampling effort is needed to determine the total variability and associations with the metadata obtained to generate better health policies.

Project description:Mycobacterium bovis causes bovine tuberculosis and is the main organism responsible for zoonotic tuberculosis in humans. We performed the sequencing, assembly and annotation of a Brazilian strain of M. bovis named SP38, and performed comparative genomics of M. bovis genomes deposited in GenBank. M. bovis SP38 has a traditional tuberculous mycobacterium genome of 4,347,648 bp, with 65.5% GC, and 4,216 genes. The majority of CDSs (2,805, 69.3%) have predictive function, while 1,206 (30.07%) are hypothetical. For comparative analysis, 31 M. bovis, 32 M. bovis BCG, and 23 Mycobacterium tuberculosis genomes available in GenBank were selected. M. bovis RDs (regions of difference) and Clonal Complexes (CC) were identified in silico. Genome dynamics of bacterial groups were analyzed by gene orthology and polymorphic sites identification. M. bovis polymorphic sites were used to construct a phylogenetic tree. Our RD analyses resulted in the exclusion of three genomes, mistakenly annotated as virulent M. bovis. M. bovis SP38 along with strain 35 represent the first report of CC European 2 in Brazil, whereas two other M. bovis strains failed to be classified within current CC. Results of M. bovis orthologous genes analysis suggest a process of genome remodeling through genomic decay and gene duplication. Quantification, pairwise comparisons and distribution analyses of polymorphic sites demonstrate greater genetic variability of M. tuberculosis when compared to M. bovis and M. bovis BCG (p ≤ 0.05), indicating that currently defined M. tuberculosis lineages are more genetically diverse than M. bovis CC and animal-adapted MTC (M. tuberculosis Complex) species. As expected, polymorphic sites annotation shows that M. bovis BCG are subjected to different evolutionary pressures when compared to virulent mycobacteria. Lastly, M. bovis phylogeny indicates that polymorphic sites may be used as markers of M. bovis lineages in association with CC. Our findings highlight the need to better understand host-pathogen co-evolution in genetically homogeneous and/or diverse host populations, considering the fact that M. bovis has a broader host range when compared to M. tuberculosis. Also, the identification of M. bovis genomes not classified within CC indicates that the diversity of M. bovis lineages may be larger than previously thought or that current classification should be reviewed.

Project description:Tuberculosis caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (MTB) strains is a growing problem in many countries. The availability of the complete nucleotide sequences of several MTB genomes allows to use the comparative genomics as a tool to study the relationships of strains and differences in their evolutionary history including acquisition of drug-resistance. In our work, we sequenced three genomes of Russian MTB strains of different phenotypes--drug susceptible, MDR and XDR. Of them, MDR and XDR strains were collected in Tomsk (Siberia, Russia) during the local TB outbreak in 1998-1999 and belonged to rare KQ and KY families in accordance with IS6110 typing, which are considered endemic for Russia. Based on phylogenetic analysis, our isolates belonged to different genetic families, Beijing, Ural and LAM, which made the direct comparison of their genomes impossible. For this reason we performed their comparison in the broader context of all M. tuberculosis genomes available in GenBank. The list of unique individual non-synonymous SNPs for each sequenced isolate was formed by comparison with all SNPs detected within the same phylogenetic group. For further functional analysis, all proteins with unique SNPs were ascribed to 20 different functional classes based on Clusters of Orthologous Groups (COG). We have confirmed drug resistant status of our isolates that harbored almost all known drug-resistance associated mutations. Unique SNPs of an XDR isolate CTRI-4(XDR), belonging to a Beijing family were compared in more detail with SNPs of additional 14 Russian XDR strains of the same family. Only type specific mutations in genes of repair, replication and recombination system (COG category L) were found common within this group. Probably the other unique SNPs discovered in CTRI-4(XDR) may have an important role in adaptation of this microorganism to its surrounding and in escape from antituberculosis drugs treatment.

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Comparative Genomics of a Bovine Mycobacterium tuberculosis Isolate and Other Strains Reveals Its Potential Mechanism of Bovine Adaptation.

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Comparative Genomics of a Bovine <i>Mycobacterium tuberculosis</i> Isolate and Other Strains Reveals Its Potential Mechanism of Bovine Adaptation.

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