Association of Biofilm Formation, Psl Exopolysaccharide Expression, and Clinical Outcomes in<i>Pseudomonas aeruginosa</i>Keratitis

Zegans, Michael E.; DiGiandomenico, Antonio; Ray, Kathryn J.; Naimie, Amanda A.; Keller, Ashley; Stover, C. Kendall; Lalitha, Prajna; Srinivasan, Muthiah; Acharya, Nisha R.; Lietman, Thomas M.

doi:10.1001/jamaophthalmol.2015.5956

Cited by 29 publications

(19 citation statements)

References 44 publications

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“…Although the majority of keratitis isolates produce Psl, 18 we cannot exclude contributions from other polysaccharides or matrix components in P. aeruginosa biofilms. For example, it is known that PA14 lacks Psl, is virulent in ocular keratitis models.…”

Section: Discussionmentioning

confidence: 99%

“…In biofilms, bacteria increase the synthesis of extracellular polysaccharides (EPS) to generate biomatrix in which the individual bacterial cells are embedded. Three different types of polysaccharides—Psl, Pel, and alginate—have been described as essential to biofilm formation . Importantly, the different polysaccharides demonstrate distinct production kinetics, suggesting differential impact on the biofilm growth .…”

Section: Introductionmentioning

confidence: 99%

“…Three different types of polysaccharides-Psl, Pel, and alginate-have been described as essential to biofilm formation. [13][14][15][16][17][18][19][20] Importantly, the different polysaccharides demonstrate distinct production kinetics, suggesting differential impact on the biofilm growth. 21 Whether P. aeruginosa forms biofilms during acute infections such as ocular keratitis remains controversial.…”

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confidence: 99%

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Frontline Science: Employing enzymatic treatment options for management of ocular biofilm-based infections

Kugadas

Geddes‐McAlister

Guy

et al. 2019

Journal of Leukocyte Biology

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Pseudomonas aeruginosa ‐induced corneal keratitis is a sight‐threatening disease. The rise of antibiotic resistance among P. aeruginosa keratitis isolates makes treatment of this disease challenging, emphasizing the need for alternative therapeutic modalities. By comparing the responses to P. aeruginosa infection between an outbred mouse strain (Swiss Webster, SW) and a susceptible mouse strain (C57BL6/N), we found that the inherent neutrophil‐killing abilities of these strains correlated with their susceptibility to infection. Namely, SW‐derived neutrophils were significantly more efficient at killing P. aeruginosa in vitro than C57BL6/N‐derived neutrophils. To interrogate whether the distinct neutrophil killing capacities were dependent on endogenous or exogenous factors, neutrophil progenitor cell lines were generated. The in vitro differentiated neutrophils from either SW or C57BL6/N progenitors retained the differential killing abilities, illustrating that endogenous factors conferred resistance. Consistently, quantitative LC‐MS/MS analysis revealed strain‐specific and infection‐induced alterations of neutrophil proteomes. Among the distinctly elevated proteins in the SW‐derived proteomes were α‐mannosidases, potentially associated with protection. Inhibition of α‐mannosidases reduced neutrophil bactericidal functions in vitro. Conversely, topical application of α‐mannosidases reduced bacterial biofilms and burden of infected corneas. Cumulatively, these data suggest novel therapeutic approaches to control bacterial biofilm assembly and improve bacterial clearance via enzymatic treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Frontline Science: Employing enzymatic treatment options for management of ocular biofilm-based infections

Kugadas

Geddes‐McAlister

Guy

et al. 2019

Journal of Leukocyte Biology

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“…NCT00324168) was conducted to evaluate topical corticosteroids as an adjunctive treatment to fluoroquinolone (moxifloxacin) in bacterial keratitis patients (19, 20). Among the 101 P. aeruginosa strains isolated from ulcers, 22 had phenotypes associated with severely decreased or absent LasR activity.…”

Section: Introductionmentioning

confidence: 99%

Environmentally Endemic Pseudomonas aeruginosa Strains with Mutations in lasR Are Associated with Increased Disease Severity in Corneal Ulcers

Hammond

Hebert

Naimie

et al. 2016

mSphere

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The LasR transcription factor is an important regulator of quorum sensing in P. aeruginosa and positively controls multiple virulence-associated pathways. The emergence of strains with lasR loss-of-function alleles in chronic disease is well described and is thought to represent a specific adaptation to the host environment. However, the prevalence and virulence of these strains in acute infections remain unclear. This report describes observations revealing that lasR mutants were common among isolates from a large, multicenter clinical study of keratitis and were associated with worse clinical outcomes than LasR-intact strains despite reduced production of LasR-regulated factors. Additionally, these lasR mutants were closely related strains or clones, as determined by molecular analysis. Because bacterial keratitis is community acquired, these data indicate infection by endemic, LasR-deficient strains in the environment. These results suggest that the conventional paradigm regarding the role for LasR-mediated regulation of virulence is more complex than previously appreciated.

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“…It also remains to be evaluated whether Pel is a good drug target. Since the majority of keratitis-and CF-associated P. aeruginosa strains express Psl, it appears that this polysaccharide is a good target for drug development [36]. The prophylactic and therapeutic outcomes of the anti-Psl antibodies have been extensively studied [37].…”

Section: A Structure Designed To Protectmentioning

confidence: 99%

Tasked with a Challenging Objective: Why Do Neutrophils Fail to Battle Pseudomonas aeruginosa Biofilms

2019

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Multidrug-resistant (MDR) bacterial infections are a leading cause of mortality, affecting approximately 250,000 people in Canada and over 2 million people in the United States, annually. The lack of efficacy of antibiotic-based treatments is often caused by inability of the drug to penetrate bacterial biofilms in sufficient concentrations, posing a major therapeutic challenge. Here, we review the most recent information about the architecture of Pseudomonas aeruginosa biofilms in vivo and describe how advances in imaging and mass spectroscopy analysis bring about novel therapeutic options and challenge existing dogmas.

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Association of Biofilm Formation, Psl Exopolysaccharide Expression, and Clinical Outcomes inPseudomonas aeruginosaKeratitis

Cited by 29 publications

References 44 publications

Frontline Science: Employing enzymatic treatment options for management of ocular biofilm-based infections

Frontline Science: Employing enzymatic treatment options for management of ocular biofilm-based infections

Environmentally Endemic Pseudomonas aeruginosa Strains with Mutations in lasR Are Associated with Increased Disease Severity in Corneal Ulcers

Tasked with a Challenging Objective: Why Do Neutrophils Fail to Battle Pseudomonas aeruginosa Biofilms

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