Browsing by Author "van Tilburg Bernardes, Erik"
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Item Open Access Small Molecule Biofilm Inhibitors with Antivirulence Properties against Pseudomonas aeruginosa(2017) van Tilburg Bernardes, Erik; Lewenza, Shawn; DeVinney, Rebekah; Dong, Tao; Harrison, JoeThe opportunistic pathogen Pseudomonas aeruginosa grows within biofilms in the Cystic Fibrosis airways, leading to chronic, life-threatening infections. Biofilms are dense communities of bacteria surrounded by a protective polymeric extracellular matrix comprised of exopolysaccharides (EPS), proteins and extracellular DNA. The two major EPS molecules produced by P. aeruginosa are the Pel and Psl. Considering the essential role of EPS in biofilm formation, antimicrobial resistance and immune evasion, we developed a high-throughput gene expression screen for the identification of small molecules that reduce both pel and psl gene expression. Testing of the identified pel/psl repressors demonstrated their antibiofilm activity against static and flow biofilm models. Moreover, these antibiofilm molecules also reduce PAO1 virulence in a nematode infection model, as well as increase P. aeruginosa biofilm susceptibility to antibiotic killing. These small molecules represent a novel anti-infective strategy for the possible adjuvant treatment of chronic P. aeruginosa infections.Item Open Access The role of intestinal fungi on microbiome ecology, host immune development, and susceptibility to airway inflammation(2023-12-04) van Tilburg Bernardes, Erik; Arrieta, Marie-Claire; Proud, David; McCoy, Kathy D.; McDonald, Braedon A.Early-life microbiome alterations can lead to immune dysregulation and increase susceptibility to asthma. Bacterial changes often precede asthma development in humans and have been causally linked to heightened airway inflammation in mice. Prospective infant studies have also identified fungal microbiome (mycobiome) alterations associated with asthma risk. However, it remains unknown if fungi contribute to the pathogenesis of atopy and asthma. My Ph.D. thesis project aimed to determine the causal role of early-life fungal colonization in immune development and susceptibility to allergic airway inflammation. We determined the role of intestinal fungi on microbiome structure, function, and host immune development in gnotobiotic mice colonized with defined communities of 12 bacteria and/or five fungi. Gut fungi exerted significant ecological pressures to the coexisting bacterial microbiome, and vice versa. Early-life fungal colonization also induced robust host systemic immune changes and influenced the immune phenotype of lung’s inflammatory response to ovalbumin allergen. Antibiotic use also impacts the gut microbiome, leading to an increased risk of asthma. However, the impact of antibiotics on the infant mycobiome is unknown. To investigate mycobiome changes associated with antibiotic treatment we conducted an observational, prospective clinical study of 47 infants (under 6 months of age) who received antibiotics. Antibiotic use decreased bacterial and increased fecal fungal DNA and induced the expansion of Malassezia spp. in infants. To evaluate the effect of colonization with Malassezia spp. on immune development and airway inflammation, we assessed early-life immune readouts and susceptibility to a house-dust mite (HDM) model in mice colonized with or without Malassezia restricta. M. restricta colonization increased intestinal immune responses deemed critical in atopy development, and elevated airway inflammation in HDM-challenged mice. Further evaluation in eosinophil-deficient mice revealed that the observed immune response is partially dependent on this cell type. This translational work demonstrates that fungi are integral components of the intestinal microbiome, causally implicated in host immune development and susceptibility to airway inflammation. Fungal overgrowth and expansion of Malassezia spp. are previously overlooked collateral effects of infant antibiotic use, which may offer a potential strategy to prevent or mitigate pediatric asthma and related conditions.