Streptococcus pneumoniae TIGR4 Phase-Locked Opacity Variants Differ in Virulence Phenotypes

Oliver, Melissa B.; Roy, Ankita; Kumar, Ranjit; Lefkowitz, Elliot J.; Swords, W. Edward

doi:10.1128/msphere.00386-17

Cited by 42 publications

(74 citation statements)

References 43 publications

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“…Increased capsule thickness of the ⌬adcAII strains correlated closely with specific hsd alleles. The S. pneumoniae SpnD39III (ST5556II) type I restriction-modification locus undergoes genetic variation due to recombination within the locus between pairs of inverted repeats, generating six allelic variants which are linked to opaque (increased capsule expression) and transparent (reduced capsule expression) colony morphology (14)(15)(16). This suggests that the detected changes in expression of genes within the SpnD39III (ST5556II) locus could reflect differences in the proportions of the allelic variants between the WT and ⌬adcAII strains, and these differences could underpin the hyperencapsulated phenotype of the latter.…”

Section: Consistent Association Of the Adcaii Mutation With Increasedmentioning

confidence: 99%

“…The SpnD39III (ST5556II) system consists of multiple genes that can be shuffled by recombination on inverted repeats to create enzymes capable of methylation at six different recognition sites. Capsule expression and thickness (opaque versus transparent) have been correlated with different SpnD39III alleles (14)(15)(16), and this system may be involved in regulating at least some aspects of S. pneumoniae phase variation. As yet, both the environmental conditions influencing allele distribution and how the effects of methylation patterns on gene expression lead to changes in capsule thickness have not been resolved.…”

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confidence: 99%

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Deletion of the Zinc Transporter Lipoprotein AdcAII Causes Hyperencapsulation of Streptococcus pneumoniae Associated with Distinct Alleles of the Type I Restriction-Modification System

Durmort

Ercoli

Ramos‐Sevillano

et al. 2020

mBio

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The capsule is the dominant Streptococcus pneumoniae virulence factor, yet how variation in capsule thickness is regulated is poorly understood. Here, we describe an unexpected relationship between mutation of adcAII, which encodes a zinc uptake lipoprotein, and capsule thickness. Partial deletion of adcAII in three of five capsular serotypes frequently resulted in a mucoid phenotype that biochemical analysis and electron microscopy of the D39 adcAII mutants confirmed was caused by markedly increased capsule thickness. Compared to D39, the hyperencapsulated ΔadcAII mutant strain was more resistant to complement-mediated neutrophil killing and was hypervirulent in mouse models of invasive infection. Transcriptome analysis of D39 and the ΔadcAII mutant identified major differences in transcription of the Sp_0505-0508 locus, which encodes an SpnD39III (ST5556II) type I restriction-modification system and allelic variation of which correlates with capsule thickness. A PCR assay demonstrated close linkage of the SpnD39IIIC and F alleles with the hyperencapsulated ΔadcAII strains. However, transformation of ΔadcAII with fixed SpnD39III alleles associated with normal capsule thickness did not revert the hyperencapsulated phenotype. Half of hyperencapsulated ΔadcAII strains contained the same single nucleotide polymorphism in the capsule locus gene cps2E, which is required for the initiation of capsule synthesis. These results provide further evidence for the importance of the SpnD39III (ST5556II) type I restriction-modification system for modulating capsule thickness and identified an unexpected linkage between capsule thickness and mutation of ΔadcAII. Further investigation will be needed to characterize how mutation of adcAII affects SpnD39III (ST5556II) allele dominance and results in the hyperencapsulated phenotype. IMPORTANCE The Streptococcus pneumoniae capsule affects multiple interactions with the host including contributing to colonization and immune evasion. During infection, the capsule thickness varies, but the mechanisms regulating this are poorly understood. We have identified an unsuspected relationship between mutation of adcAII, a gene that encodes a zinc uptake lipoprotein, and capsule thickness. Mutation of adcAII resulted in a striking hyperencapsulated phenotype, increased resistance to complement-mediated neutrophil killing, and increased S. pneumoniae virulence in mouse models of infection. Transcriptome and PCR analysis linked the hyperencapsulated phenotype of the ΔadcAII strain to specific alleles of the SpnD39III (ST5556II) type I restriction-modification system, a system which has previously been shown to affect capsule thickness. Our data provide further evidence for the importance of the SpnD39III (ST5556II) type I restriction-modification system for modulating capsule thickness and identify an unexpected link between capsule thickness and ΔadcAII, further investigation of which could further characterize mechanisms of capsule regulation.

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Section: Consistent Association Of the Adcaii Mutation With Increasedmentioning

confidence: 99%

mentioning

confidence: 99%

Deletion of the Zinc Transporter Lipoprotein AdcAII Causes Hyperencapsulation of Streptococcus pneumoniae Associated with Distinct Alleles of the Type I Restriction-Modification System

Durmort

Ercoli

Ramos‐Sevillano

et al. 2020

mBio

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“…[20][21][22][23][24] A phasevarion controlled by a Type I R-M system in the major human pathogen Streptococcus pneumoniae has been characterized by a number of groups. 25,26 A phase-variable Type I R-M system has also been well characterized in Mycoplasma pulmonis, 27,28 but the effect on gene expression has not been studied. Rather than the ON-OFF switching seen with Type III R-M mod genes containing SSRs, the systems described in S. pneumoniae and M. pulmonis shuffle between variable hsdS specificity genes resulting in the expression of multiple different HsdS specificity proteins.…”

Section: Introductionmentioning

confidence: 99%

DNA sequence repeats identify numerous Type I restriction‐modification systems that are potential epigenetic regulators controlling phase‐variable regulons; phasevarions

et al. 2019

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Over recent years several examples of randomly switching methyltransferases, associated with Type III restriction-modification (R-M) systems, have been described in pathogenic bacteria. In every case examined, changes in simple DNA sequence repeats result in variable methyltransferase expression and result in global changes in gene expression, and differentiation of the bacterial cell into distinct phenotypes.These epigenetic regulatory systems are called phasevarions, phase-variable regulons, and are widespread in bacteria, with 17.4% of Type III R-M system containing simple DNA sequence repeats. A distinct, recombination-driven random switching system has also been described in Streptococci in Type I R-M systems that also regulate gene expression. Here, we interrogate the most extensive and well-curated database of R-M systems, REBASE, by searching for all possible simple DNA sequence repeats in the hsdRMS genes that encode Type I R-M systems. We report that 7.9% of hsdS, 2% of hsdM, and of 4.3% of hsdR genes contain simple sequence repeats that are capable of mediating phase variation. Phase variation of both hsdM and hsdS genes will lead to differential methyltransferase expression or specificity, and thereby the potential to control phasevarions. These data suggest that in addition to well characterized phasevarions controlled by Type III mod genes, and the previously described Streptococcal Type I R-M systems that switch via recombination, approximately 10% of all Type I R-M systems surveyed herein have independently evolved the ability to randomly switch expression via simple DNA sequence repeats. K E Y W O R D Sbacterial pathogenesis, epigenetics, phase variation, phasevarion, R-M systems | 1039 ATACK eT Al.

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“…For example, sub‐components of the hsdS gene of the well‐characterised complex PV RM of Streptococcus pneumoniae , SpnIII, can exist in one of six possible orientations. Each of these unique TRD combinations is associated with a different DNA methylation pattern and some of them can impact on invasive disease potential in mice and the invasion‐associated opaque colony phenotype (Li et al, , ; Manso et al, ; Oliver, Roy, Kumar, Lefkowitz & Swords, ). The simplicity of these findings is challenged by variable experimental observations, suggesting that genetic background may influence links between methylation and colony opacity, and by the extensive hsdS allelic variation resulting in differing dominant methylation patterns among pneumococcal strains (De Ste Croix et al, ).…”

Section: Specific Hypermutable Mechanisms Found In Bacterial Pathogensmentioning

confidence: 99%

Selective and non‐selective bottlenecks as drivers of the evolution of hypermutable bacterial loci

Croix

Holmes

Wanford

et al. 2020

Molecular Microbiology

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Bottlenecks reduce the size of the gene pool within populations of all life forms with implications for their subsequent survival. Here, we examine the effects of bottlenecks on bacterial commensal‐pathogens during transmission between, and dissemination within, hosts. By reducing genetic diversity, bottlenecks may alter individual or population‐wide adaptive potential. A diverse range of hypermutable mechanisms have evolved in infectious agents that allow for rapid generation of genetic diversity in specific genomic loci as opposed to the variability arising from increased genome‐wide mutation rates. These localised hypermutable mechanisms include multi‐gene phase variation (PV) of outer membrane components, multi‐allele PV of restriction systems and recombination‐driven antigenic variation. We review selected experimental and theoretical (mathematical) models pertaining to the hypothesis that localised hypermutation (LH) compensates for fitness losses caused by bottlenecks and discuss whether bottlenecks have driven the evolution of hypermutable loci.

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Streptococcus pneumoniae TIGR4 Phase-Locked Opacity Variants Differ in Virulence Phenotypes

Cited by 42 publications

References 43 publications

Deletion of the Zinc Transporter Lipoprotein AdcAII Causes Hyperencapsulation of Streptococcus pneumoniae Associated with Distinct Alleles of the Type I Restriction-Modification System

Deletion of the Zinc Transporter Lipoprotein AdcAII Causes Hyperencapsulation of Streptococcus pneumoniae Associated with Distinct Alleles of the Type I Restriction-Modification System

DNA sequence repeats identify numerous Type I restriction‐modification systems that are potential epigenetic regulators controlling phase‐variable regulons; phasevarions

Selective and non‐selective bottlenecks as drivers of the evolution of hypermutable bacterial loci

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