Modulation of epithelial immunity by mucosal fluid

Mun, Jeomhee; Tam, Connie; Evans, David J.; Fleiszig, Suzanne M. J.

doi:10.1038/srep00008

Cited by 33 publications

(35 citation statements)

References 37 publications

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“…However, traversal of a multilayered epithelium that has formed on the surface of an actual cornea (or other tissue) in the context of other factors present in vivo could be a different task for the bacteria than traversing a monolayer grown in vitro. Indeed, in previous studies we reported that exposure of cultured epithelial cells to mucosal (tear) fluid protected against bacterial virulence, a phenomenon that endured after the mucosal fluid was removed (43). This, and changes to gene expression in the mucosal fluid treated epithelial cells, revealed that the mechanism for protection involved lasting changes to the state of the epithelial cell once exposed to mucosal fluid and that it involved specific microRNAs (43,44).…”

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confidence: 99%

The Importance of the Pseudomonas aeruginosa Type III Secretion System in Epithelium Traversal Depends upon Conditions of Host Susceptibility

et al. 2015

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Pseudomonas aeruginosa is invasive or cytotoxic to host cells, depending on the type III secretion system (T3SS) effectors encoded. While the T3SS is known to be involved in disease in vivo, how it participates remains to be clarified. Here, mouse models of superficial epithelial injury (tissue paper blotting with EGTA treatment) and immunocompromise (MyD88 deficiency) were used to study the contribution of the T3SS transcriptional activator ExsA to epithelial traversal. Corneas of excised eyeballs were inoculated with green fluorescent protein (GFP)-expressing PAO1 or isogenic exsA mutants for 6 h ex vivo before bacterial traversal and epithelial thickness were quantified by using imaging. In the blotting-EGTA model, exsA mutants were defective in capacity for traversal. Accordingly, an ϳ16-fold variability in exsA expression among PAO1 isolates from three sources correlated with epithelial loss. In contrast, MyD88؊/؊ epithelia remained susceptible to P. aeruginosa traversal despite exsA mutation. Epithelial lysates from MyD88 ؊/؊ mice had reduced antimicrobial activity compared to those from wild-type mice with and without prior antigen challenge, particularly 30-to 100-kDa fractions, for which mass spectrometry revealed multiple differences, including (i) lower baseline levels of histones, tubulin, and lumican and (ii) reduced glutathione S-transferase, annexin, and dermatopontin, after antigen challenge. Thus, the importance of ExsA in epithelial traversal by invasive P. aeruginosa depends on the compromise enabling susceptibility, suggesting that strategies for preventing infection will need to extend beyond targeting the T3SS. The data also highlight the importance of mimicking conditions allowing susceptibility in animal models and the need to monitor variability among bacterial isolates from different sources, even for the same strain. P seudomonas aeruginosa remains a leading cause of respiratory infections, septicemia, and urinary tract and burn wound infections (1-4). It is also the most common cause of corneal infection associated with contact lens wear (5, 6). Our research has shown that clinical and laboratory isolates of P. aeruginosa can be divided into invasive or cytotoxic strains based upon how they interact with host cells (7). Invasive strains can survive and replicate inside epithelial cells dependent on the type III secretion system (T3SS) effector ExoS (8-10), while cytotoxic strains instead encode ExoU, which can induce rapid death of intoxicated host cells (11,12). While details of how invasive and cytotoxic strains impact host cells vary, both types can cause human disease, and they can each be virulent in animal models of infection (13-15).Several in vivo models exist for studying P. aeruginosa pathogenicity. They include Caenorhabditis elegans (16-18) and Drosophila melanogaster (19), in addition to mouse models of pneumonia with sepsis (20-22), burn wound infection with sepsis (23-25), and gastrointestinal colonization and sepsis (26,27) and corneal scarification models (28)(29)(30)...

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confidence: 99%

The Importance of the Pseudomonas aeruginosa Type III Secretion System in Epithelium Traversal Depends upon Conditions of Host Susceptibility

et al. 2015

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“…This suggests that the rapid bacterial clearance from the ocular surface is not simply due to tear fluid antimicrobial activity. Rather, our data show that tear fluid acts upon the corneal cells to trigger their defenses against bacterial virulence strategies 9 . Indeed, human tear fluid protects mouse eyes against P. aeruginosa colonization.…”

Section: Eradicating Infection (From the Research Of Fleiszig And Colmentioning

confidence: 65%

“…The protective activity of tear fluid is associated with changes in gene expression in corneal epithelial cells, and subsequently increased antimicrobial activity within them 9 . Figure 3 shows all the genes impacted upon exposure of corneal epithelial cells to tear fluid.…”

Section: Eradicating Infection (From the Research Of Fleiszig And Colmentioning

confidence: 99%

Cornea and Ocular Surface Disease

Robertson

Alexander²,

Bonanno

et al. 2014

Optometry and Vision Science

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Clinician-scientists bridge the gap between basic research and patient care. At the 2012 Annual Meeting, a symposium highlighting the application of cutting edge optometric research within the anterior segment was held to present and discuss some of the recent basic scientific advances that will both shape and guide the development of future clinical care practices. This paper summarizes this work, bringing together four experts, all clinician-scientists in the field of cornea and ocular surface. Collectively, this work provides new insights to clinicians and researchers alike, as well as brings forth a greater appreciation of the impact of on-going optometric bench research in advancing clinical care.

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“…However, our data have shown that the capacity of tear fluid to protect cells against P. aeruginosa is independent of direct antimicrobial activity 14 . In fact, we found that many P. aeruginosa strains, including clinical isolates from microbial keratitis, grow readily in undiluted human tear fluid, yet tear fluid can still protect corneal epithelial cells against them 14, 18 .…”

Section: Tear Fluidmentioning

confidence: 98%

“…We showed this experimentally by pre-treating human corneal epithelial cells with human tear fluid, and then washing the tear fluid away before adding a bacterial inoculum. The results showed that human tear pre-treatment rendered human corneal epithelial cells more resistant to invasion by invasive P. aeruginosa strains and cell death caused by cytotoxic strains 18 . Tear fluid-induced resistance was associated with an up-regulation of stress response transcription factors, NF-κB (Nuclear Factor-kappaB) and AP-1 (Activating Protein-1), and the up- and down-regulated expression of many epithelial genes.…”

Section: Tear Fluidmentioning

confidence: 99%

Why Does the Healthy Cornea Resist Pseudomonas aeruginosa Infection?

Evans

Fleiszig

2013

American Journal of Ophthalmology

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Purpose To provide our perspective on why the cornea is resistant to infection based on our research results with Pseudomonas aeruginosa. Perspective We focus on our current understanding of the interplay between bacteria, tear fluid and the corneal epithelium that determine health as the usual outcome, and propose a theoretical model for how contact lens wear might change those interactions to enable susceptibility to P. aeruginosa infection. Methods Use of “null-infection” in vivo models, cultured human corneal epithelial cells, contact lens-wearing animal models, and bacterial genetics help to elucidate mechanisms by which P. aeruginosa survive at the ocular surface, adheres, and traverses multilayered corneal epithelia. These models also help elucidate the molecular mechanisms of corneal epithelial innate defense. Results and Discussion Tear fluid and the corneal epithelium combine to make a formidable defense against P. aeruginosa infection of the cornea. Part of that defense involves the expression of antimicrobials such as β-defensins, the cathelicidin LL-37, cytokeratin-derived antimicrobial peptides, and RNase7. Immunomodulators such as SP-D and ST2 also contribute. Innate defenses of the cornea depend in part on MyD88, a key adaptor protein of TLR and IL-1R signaling, but the basal lamina represents the final barrier to bacterial penetration. Overcoming these defenses involves P. aeruginosa adaptation, expression of the type three secretion system, proteases, and P. aeruginosa biofilm formation on contact lenses. Conclusion After more than two decades of research focused on understanding how contact lens wear predisposes to P. aeruginosa infection, our working hypothesis places blame for microbial keratitis on bacterial adaptation to ocular surface defenses, combined with changes to the biochemistry of the corneal surface caused by trapping bacteria and tear fluid against the cornea under the lens.

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Modulation of epithelial immunity by mucosal fluid

Cited by 33 publications

References 37 publications

The Importance of the Pseudomonas aeruginosa Type III Secretion System in Epithelium Traversal Depends upon Conditions of Host Susceptibility

The Importance of the Pseudomonas aeruginosa Type III Secretion System in Epithelium Traversal Depends upon Conditions of Host Susceptibility

Cornea and Ocular Surface Disease

Why Does the Healthy Cornea Resist Pseudomonas aeruginosa Infection?

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