Biology subjects

Kau, A. L.

Publications and source records attributed to Kau, A. L..

3 recordsLinked to original sources

bioRxiv2024

Monoclonal antibodies targeting the FimH adhesin protect against uropathogenic E. coli UTI

As antimicrobial resistance increases, urinary tract infections (UTIs) are expected to pose an increased burden in morbidity and expense on the healthcare system, increasing the need for alternative antibiotic-sparing treatments. Most UTIs are caused by uropathogenic Escherichia coli (UPEC), while Klebsiella pneumoniae causes a significant portion of non-UPEC UTIs. Both bacteria express type 1 pili tipped with the mannose-binding FimH adhesin critical for UTI pathogenesis. We generated and biochemically characterized 33 murine monoclonal antibodies (mAbs) to FimH. Two mAbs protected mice from E. coli UTI. Mechanistically, we show that this protection is Fc-independent and mediated by the ability of these mAbs to sterically block FimH function. Our data reveals that FimH mAbs hold promise as an antibiotic-sparing treatment strategy.

microbiology↗

bioRxiv2023

Autophagy functions in lung macrophages and dendritic cells to suppress TH17 responses and neutrophil accumulation during allergic airway inflammation

Asthma affects 260 million people worldwide, with severe asthma cases that are associated with TH17/TH1 responses and neutrophil dominated inflammation being the most difficult to treat due to corticosteroid insensitivity. Single nucleotide polymorphisms in the ATG5 gene, which encodes for a protein required for the cellular recycling process of autophagy, are associated with higher risk for developing severe asthma. However, the role for ATG5 during allergic inflammation remains mostly unknown. We have identified an autophagy-dependent role for ATG5 in lung macrophages and dendritic cells (DCs) for suppressing TH17 responses and neutrophil accumulation in house dust mite (HDM)-challenged mice, a TH17/TH1 dominated model for allergic airway inflammation due to contamination of the HDM with lipopolysaccharide. In contrast, autophagy was required to promote eosinophil accumulation in the TH2-dominated ovalbumin model of allergic airway inflammation, supporting a model where autophagy functions in lung macrophages and DCs to suppress TH17 responses and promote TH2 responses in an allergen-dependent manner. In addition, we discover that autophagy is also required in macrophages exposed to HDM to suppress the secretion of cytokines and chemokines that would otherwise recruit neutrophils to the lungs, independent of T cell responses. Together, our data identify multiple roles for autophagy in suppressing the neutrophil accumulation in lungs that is associated with severe asthma.

immunology↗

bioRxiv2022

The asthma gut microbiota influences lung inflammation in gnotobiotic mice

The composition of the gut microbiota in early childhood is linked to asthma risk but the role of the gut microbiota in older patients with established asthma is less clear. Here, we used a cohort of 38 school-aged children (19 with asthma) and 57 adults (17 with asthma) to develop a model that aids in the design of mechanistic experiments in gnotobiotic mice. These experiments show that enterotoxigenic Bacteroides fragilis (ETBF) is associated with increased gut permeability, oxidative stress, and markers of Th17-mediated inflammation in the lungs of mice following ovalbumin sensitization and challenge (OSC). Further, ETBF is enriched in a human population with asthma compared to healthy controls. Our results provide evidence that ETBF has the potential to alter the phenotype of airway inflammation in a subset of patients with asthma outside of early childhood which suggests that therapies targeting the gut microbiota may be helpful tools for asthma control.

microbiology↗