Genome-wide association study of signature genetic alterations among pseudomonas aeruginosa cystic fibrosis isolates

Hwang, Won Ju; Yong, Ji Hyun; Min, Kyung Bae; Lee, Kang-Mu; Pascoe, Ben; Sheppard, Samuel K.; Yoon, Sang Sun

doi:10.1371/journal.ppat.1009681

Cited by 10 publications

(5 citation statements)

References 81 publications

(121 reference statements)

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“…For laboratory-based researchers, validation is only considered valid when effects can be reproduced using complementary experimental approaches (see, e.g. [50]). Experimental validation by reverse genetics of the many markers associated with phenotypes of interest for microbial risk assessment is probably not feasible, at least in the short term.…”

Section: From Identification Of Markers To Their Use In Quantitative ...mentioning

confidence: 99%

Taking account of genomics in quantitative microbial risk assessment: what methods? what issues?

Guillier

Palma²,

Fritsch³

2022

Current Opinion in Food Science

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Section: From Identification Of Markers To Their Use In Quantitative ...mentioning

confidence: 99%

Taking account of genomics in quantitative microbial risk assessment: what methods? what issues?

Guillier

Palma²,

Fritsch³

2022

Current Opinion in Food Science

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“…GWAS approaches have shown promising disease prediction results (31,43,44), as well as AMR profiles (45). As in other bacterial species (46)(47)(48), a better understanding of genome and transcriptome variation in hypervirulent infection types shows promise for our ability to predict disease severity in Staphylococci (49).…”

Section: Despitementioning

confidence: 99%

Multiple hypervirulent methicillin-sensitiveStaphylococcus aureuslineages contribute towards poor patient outcomes in orthopedic device-related infections

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Pascoe

Mourkas

et al. 2022

Preprint

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Staphylococci are the most common cause of orthopedic device-related infections (ODRIs), withStaphylococcus aureusresponsible for a third or more of cases. This prospective clinical and laboratory study investigated the association of genomic and phenotypic variation with treatment outcomes in ODRI isolates. Eighty-six invasiveS. aureusisolates were collected from patients with ODRI, and clinical outcome was assessed after a follow-up examination of 24 months. Each patient was then considered to have been “cured” or “not cured” based on predefined clinical criteria. Whole genome sequencing and molecular characterization identified isolates belonging to globally circulating community- and hospital-acquired pandemic lineages. Most isolates were phenotypically susceptible to methicillin and lacked the SCCmeccassette (MSSA), but contained several (hyper) virulence genes, including toxins and biofilm genes. While recognizing the role of the host immune response, we identify characteristics of isolate genomes that, with larger datasets, could help contribute to infection severity or clinical outcome predictions. While this and several other studies reinforce the role antibiotic resistance (e.g., MRSA infection) has on treatment failure, it is important not to overlook MSSA that can cause equally destructive infections and lead to poor patient outcomes.ImportanceStaphylococcus aureusis a prominent cause of orthopedic device-associated infections, yet little is known about how the infecting pathogen, and specifically the repertoire of genome-encoded virulence factors can impact treatment outcome. Past studies have focused on distinguishing commensal from invasiveS. aureusisolates but in this study, we aim to investigate traits in infecting isolates that influence patient outcomes. InvasiveS. aureusisolates were collected from orthopedic-device related infection patients and categorized according to the success of subsequent treatment (“cured” /”not cured”), as determined following hospital discharge two years after initial presentation. Several MSSA hypervirulent clones were associated with a “not cured” clinical outcome. Improved understanding of the bacterial traits associated with treatment failure in ODRI will inform the risk assessment, prognosis, and therapy of these infections.

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“…Constitutively mucoid P. aeruginosa strains from the majority of CF patients have mucA mutations (24)(25)(26)(27)(28)(29)(30). Many of these cause a C-terminal truncation of MucA, and one of the most common is the mucA22 allele (24)(25)(26)(27)31).…”

Section: Introductionmentioning

confidence: 99%

In vivoandin vitroanalysis of the role of the Prc protease in inducing mucoidy inPseudomonas aeruginosa

Sommerfield,

Wang,

Mamana

et al. 2024

Preprint

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InPseudomonas aeruginosa,alginate biosynthesis gene expression is inhibited by the transmembrane anti-sigma factor MucA, which sequesters the AlgU sigma factor. Cell envelope stress initiates cleavage of the MucA periplasmic domain by site-1 protease AlgW, followed by further MucA degradation to release AlgU. However, after colonizing the lungs of people with cystic fibrosis,P. aeruginosaconverts to a mucoid form that produces alginate constitutively. Mucoid isolates often havemucAmutations, with the most common beingmucA22, which truncates the periplasmic domain. MucA22 is degraded constitutively, and genetic studies suggested that the Prc protease is responsible. Some studies also suggested that Prc contributes to induction in strains with wild type MucA, whereas others suggested the opposite. However, missing from all previous studies is a demonstration that Prc cleaves any protein directly, which leaves open the possibility that the effect of aprcnull mutation is indirect. To address the ambiguities and shortfalls, we reevaluated the roles of AlgW and Prc as MucA and MucA22 site-1 proteases.In vivoanalyses using three different assays, and two different inducing conditions, all suggested that AlgW is the only site-1 protease for wild type MucA in any condition. In contrast, genetics suggested that AlgW or Prc act as MucA22 site-1 proteases in inducing conditions, whereas Prc is the only MucA22 site-1 protease in non-inducing conditions. For the first time, we also show that Prc is unable to degrade the periplasmic domain of wild type MucA, but does degrade the mutated periplasmic domain of MucA22 directly.IMPORTANCEAfter colonizing the lungs of individuals with cystic fibrosis,P. aeruginosaundergoes mutagenic conversion to a mucoid form, worsening the prognosis. Most mucoid isolates have a truncated negative regulatory protein MucA, which leads to constitutive production of the extracellular polysaccharide alginate. The protease Prc has been implicated, but not shown, to degrade the most common MucA variant, MucA22, to trigger alginate production. This work provides the first demonstration that the molecular mechanism of Prc involvement is direct degradation of the MucA22 periplasmic domain, and perhaps other truncated MucA variants as well. MucA truncation and degradation by Prc might be the predominant mechanism of mucoid conversion in cystic fibrosis infections, suggesting that Prc activity could be a useful therapeutic target.

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Genome-wide association study of signature genetic alterations among pseudomonas aeruginosa cystic fibrosis isolates

Cited by 10 publications

References 81 publications

Taking account of genomics in quantitative microbial risk assessment: what methods? what issues?

Taking account of genomics in quantitative microbial risk assessment: what methods? what issues?

Multiple hypervirulent methicillin-sensitiveStaphylococcus aureuslineages contribute towards poor patient outcomes in orthopedic device-related infections

In vivoandin vitroanalysis of the role of the Prc protease in inducing mucoidy inPseudomonas aeruginosa

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