Identification of positively selected genes in human pathogenic treponemes: Syphilis-, yaws-, and bejel-causing strains differ in sets of genes showing adaptive evolution

Maderankova, Denisa; Mikalová, Lenka; Strouhal, Michal; Vadják, Šimon; Kuklová, Ivana; Pospíšilová, Petra; Krbková, Lenka; Koščová, Pavlína; Provazník, Ivo; Šmajs, David

doi:10.1371/journal.pntd.0007463

Cited by 14 publications

(12 citation statements)

References 73 publications

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“…Most of these genes encode proteins that reside at the host–pathogen interface ( table 1 and supplementary tables 9 and 10 , Supplementary Material online ). This result is congruent with the results obtained in previous studies ( Arora et al 2016 ; Kumar, Caimano, et al 2018 ; Maděránková et al 2019 ) in that the variation present in these genes maintained by the selective forces that act on them contributes significantly to the evolution of T. pallidum. Although lack of a culture system for T. pallidum has prevented experimental confirmation of most inferred protein functions for this species, these genes have been suggested as potentially involved in virulence, with an important role in the defense of the pathogen against the host and the evasion of the immune system ( Kumar, Caimano, et al 2018 ).…”

Section: Discussionsupporting

confidence: 92%

Evolutionary Processes in the Emergence and Recent Spread of the Syphilis Agent,Treponema pallidum

Pla-Díaz

Sánchez-Busó

Giacani

et al. 2021

Molecular Biology and Evolution

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The incidence of syphilis has risen worldwide in the last decade in spite of being an easily treated infection. The causative agent of this sexually transmitted disease is the bacterium Treponema pallidum subspecies pallidum (TPA), very closely related to subsp. pertenue (TPE) and endemicum (TEN), responsible for the human treponematoses yaws and bejel, respectively. Although much focus has been placed on the question of the spatial and temporary origins of TPA, the processes driving the evolution and epidemiological spread of TPA since its divergence from TPE and TEN are not well understood. Here, we investigate the effects of recombination and selection as forces of genetic diversity and differentiation acting during the evolution of T. pallidum subspecies. Using a custom-tailored procedure, named phylogenetic incongruence method, with 75 complete genome sequences, we found strong evidence for recombination among the T. pallidum subspecies, involving 12 genes and 21 events. In most cases, only one recombination event per gene was detected and all but one event corresponded to intersubspecies transfers, from TPE/TEN to TPA. We found a clear signal of natural selection acting on the recombinant genes, which is more intense in their recombinant regions. The phylogenetic location of the recombination events detected and the functional role of the genes with signals of positive selection suggest that these evolutionary processes had a key role in the evolution and recent expansion of the syphilis bacteria and significant implications for the selection of vaccine candidates and the design of a broadly protective syphilis vaccine.

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Section: Discussionsupporting

confidence: 92%

Evolutionary Processes in the Emergence and Recent Spread of the Syphilis Agent,Treponema pallidum

Pla-Díaz

Sánchez-Busó

Giacani

et al. 2021

Molecular Biology and Evolution

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“…Finally, to infer the potential selection on the observed sequence variation, mutational rate ratio ω ( dN/dS ) at the cyp51A locus was tested using MEGA version 6 ( 82 ). The ratio of nonsynonymous to synonymous mutational rates was calculated to infer the types of selection impacting specific sites, with ω between 0 and 1, equal to 1, and >1 representing negative purifying selection, neutral evolution, and positive selection, respectively ( 83 ).…”

Section: Methodsmentioning

confidence: 99%

Extensive Genetic Diversity and Widespread Azole Resistance in Greenhouse Populations of Aspergillus fumigatus in Yunnan, China

Zhou

Korfanty

et al. 2021

mSphere

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Aspergillus fumigatus is the main cause of invasive aspergillosis (IA) with a high annual global incidence and mortality rate. Recent studies have indicated an increasing prevalence of azole-resistant A. fumigatus (ARAF) strains, with agricultural use of azole fungicides as a potential contributor. China has an extensive agricultural production system and uses a wide array of fungicides for crop production, including in modern growth facilities such as greenhouses. Soils in greenhouses are among the most intensively cultivated. However, little is known about the occurrence and distribution of ARAF in greenhouse soils. Here, we investigated genetic variation and triazole drug susceptibility in A. fumigatus from greenhouses around metropolitan Kunming in Yunnan, southwest China. Abundant allelic and genotypic variations were found among 233 A. fumigatus strains isolated from nine greenhouses in this region. Significantly, ∼80% of the strains were resistant to at least one medical triazole drug, with >30% showing cross-resistance to both itraconazole and voriconazole. Several previously reported mutations associated with triazole resistance in the triazole target gene cyp51A were also found in our strains, with a strong positive correlation between the frequency of mutations at the cyp51A promoter and that of voriconazole resistance. Phylogenetic analyses of cyp51A gene sequences showed evidence for multiple independent origins of azole-resistant genotypes of A. fumigatus in these greenhouses. Evidence for multiple origins of azole resistance and the widespread distributions of genetically very diverse triazole-resistant strains of A. fumigatus in greenhouses calls for significant attention from public health agencies. IMPORTANCE The origin and prevalence of azole-resistant Aspergillus fumigatus have been attracting increasing attention from biologists, clinicians, and public health agencies. Current evidence suggests agricultural fungicide use as a major cause. In southwest China, greenhouses are used to produce large amounts of fruits, flowers, and vegetables for consumers throughout China as well as those in other countries, primarily in southeast Asia. Here, we found a very high frequency (∼80%) of triazole-resistant A. fumigatus in our sample, the highest reported so far, with a significant proportion of these strains resistant to both tested agricultural fungicides and medical triazole drugs. In addition, we found novel allelic and genotypic diversities and evidence for multiple independent origins of azole-resistant genotypes of A. fumigatus in greenhouse populations in this region. Our study calls for a systematic evaluation of the effects of azole fungicide usage in greenhouses on human health.

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“…Intriguingly, 9 of the 14 genes with coding differences between the two strains have been demonstrated or predicted to encode for outer membrane or periplasmic proteins [33][34][35][36][37][38][39][40][41]. These include TP0040, TP0134, TP0136, TP0151, TP0325, TP0326, TP0515, TP0548 and The color of each of node depicts the strain from which the full-length TprK sequence originated.…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

Comparative genomics and full-length Tprk profiling of Treponema pallidum subsp. pallidum reinfection

et al. 2020

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Developing a vaccine against Treponema pallidum subspecies pallidum, the causative agent of syphilis, remains a public health priority. Syphilis vaccine design efforts have been complicated by lack of an in vitro T. pallidum culture system, prolific antigenic variation in outer membrane protein TprK, and lack of functional annotation for nearly half of the genes. Understanding the genetic basis of T. pallidum reinfection can provide insights into variation among strains that escape cross-protective immunity. Here, we present comparative genomic sequencing and deep, fulllength tprK profiling of two T. pallidum isolates from blood from the same patient that were collected six years apart. Notably, this patient was diagnosed with syphilis four times, with two of these episodes meeting the definition of neurosyphilis, during this interval. Outside of the highly variable tprK gene, we identified 14 coding changes in 13 genes. Nine of these genes putatively localized to the periplasmic or outer membrane spaces, consistent with a potential role in serological immunoevasion. Using a newly developed full-length tprK deep sequencing protocol, we profiled the diversity of this gene that far outpaces the rest of the genome. Intriguingly, we found that the reinfecting isolate demonstrated less diversity across each tprK variable region compared to the isolate from the first infection. Notably, the two isolates did not share any full-length TprK sequences. Our results are consistent with an immunodominant-evasion model in which the diversity of TprK explains the ability of T. pallidum to successfully reinfect individuals, even when they have been infected with the organism multiple times.

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Identification of positively selected genes in human pathogenic treponemes: Syphilis-, yaws-, and bejel-causing strains differ in sets of genes showing adaptive evolution

Cited by 14 publications

References 73 publications

Evolutionary Processes in the Emergence and Recent Spread of the Syphilis Agent,Treponema pallidum

Evolutionary Processes in the Emergence and Recent Spread of the Syphilis Agent,Treponema pallidum

Extensive Genetic Diversity and Widespread Azole Resistance in Greenhouse Populations of Aspergillus fumigatus in Yunnan, China

Comparative genomics and full-length Tprk profiling of Treponema pallidum subsp. pallidum reinfection

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