Biology subjects

Barer, M. R.

Publications and source records attributed to Barer, M. R..

3 recordsLinked to original sources

bioRxiv2022

CD98 is critical for a conserved inflammatory response to diverse injury stimuli relevant to IPF exacerbations and COVID pneumonitis

Progressive fibrosing interstitial lung diseases (PFILDs) cause substantial morbidity and mortality. Antifibrotic agents slow progression, but most of the clinical need remains unmet. The archetypal PFILD is idiopathic pulmonary fibrosis (IPF). Chronic progression is driven by transforming growth factor (TGF-){beta}1 signalling. It is punctuated by inflammatory flares known as acute exacerbations (AE-IPF), which are associated with accelerated decline and high mortality. We hypothesized that acute injury responses underlying exacerbations and the mechanisms of chronic fibrosis overlap at the molecular level, via a cell surface assembly nucleated by galectin-3 that we term the gal-3-fibrosome. We focused upon a putative pro-inflammatory galectin-3 ligand, the CD98:integrin complex. Our data indicate CD98 and {beta}1-integrin co-localise with galectin-3 within epithelial cells in IPF lung tissue, and within 40 nm in human lung tissue treated with TGF-{beta}1 compared to controls. CD98 is required for interleukin (IL-)6 and IL-8 responses to biochemical and biophysical conditions mimicking stimuli of AE-IPF in vivo, ex vivo and in cells, and for an interstitial neutrophilic response in a mouse model. We demonstrate this pathway progresses via intracellular influx of Ca2+ mediated by TRPV4, and NF-{kappa}B activation, operating in positive feedback. Lastly we show the CD98- and galectin-3-dependence of IL-6 and IL-8 responses to the SARS-CoV-2 spike protein receptor binding domain and the conservation of this response pattern between lung epithelial cells and monocyte-derived macrophages. Taken together our findings identify CD98 as a key mediator of both pro-fibrotic and acute inflammatory responses in the lung with relevance to AE- and chronic progression of IPF, and the priming of fibrotic lungs for acute inflammatory responses. They similarly implicate CD98 and galectin-3 as mediators of COVID pneumonitis and worse outcomes in ILD patients with COVID.

cell biology↗

bioRxiv2020

A virulence associated siderophore importer causes antimicrobial efflux in Klebsiella pneumoniae

The accessory genome of many pathogenic bacteria includes ABC transporters that scavenge metal by siderophore uptake and ABC transporters that contribute to antimicrobial resistance by multidrug efflux. There are mechanistic and recently recognised structural similarities between siderophore importer proteins and efflux pumps. Here we investigated the influence of siderophore importer YbtPQ on antimicrobial resistance of Klebsiella pneumoniae. YbtPQ is encoded in the yersiniabactin cluster in a prevalent mobile genetic element ICEKp, and is also common in pathogenicity islands of Escherichia coli and Yersinia species, where yersiniabactin enhances virulence. Deletion of ICEKp increased the sensitivity of K. pneumoniae to all antimicrobials tested. The mechanism was dependent on the yersiniabactin importer YbtPQ and involved antimicrobial efflux, since it was affected by the inhibitor reserpine. The element ICEKp is naturally highly mobile, indeed the accessory genome of K. pneumoniae is recognised as a reservoir of genes for the emergence of hospital outbreak strains and for transfer to other Gram-negative pathogens. Introduction of ICEKp, or a plasmid encoding YbtPQ, to E. coli decreased its sensitivity to a broad range of antimicrobials. Thus, a confirmed siderophore importer, on a rapidly evolving and highly mobile element capable of interspecies transfer, may have a secondary function exporting antimicrobials.

microbiology↗

bioRxiv2018

Twenty-four hour face mask sampling in pulmonary tuberculosis reveals three distinct patterns of bacterial aerosol production dissociated from conventional markers of transmission risk.

Rationale: Although tuberculosis (TB) is transmitted by Mycobacterium tuberculosis (Mtb) in aerosols, little is known of the dynamic characteristics of spontaneous output of bacilli in this form. We have developed and implemented a mask aerosol sampling system (MASS) for longitudinal capture and study of spontaneous aerosol.\n\nObjective: To determine patterns of Mtb output in aerosols, captured using the MASS over 24 hours and their association with existing criteria used to assess transmission risk in patients with pulmonary TB.\n\nMethods: Twenty-four hospitalised patients with newly diagnosed pulmonary TB recruited in Pretoria, South Africa, wore FFP1 masks for one hour out of every three for 24 hours. Aerosol was captured in a gelatine filter processed for Mtb quantitation by PCR. Serial sputum was collected and objective cough frequency monitoring performed over the same period.\n\nMeasurements and Main Results: Mtb was detected in 86.5% of 192 mask samples and 20.7% of 38 assessable sputum samples obtained from the cohort. Mtb was detected by MASS in all but two patients. Three dynamic patterns of expression were identifiable in Mtb aerosol producers: i. variable high; ii. consistent; and iii. variable low. No diurnal variation was apparent and there was no correlation between mask Mtb and either sputum Mtb levels or cough frequency. Sputum smear status, culture time to positivity and chest radiographic characteristics also failed to associate with MASS bacillary output.\n\nConclusions: Conventional markers of tuberculosis case infectivity do not predict bacillary aerosols detected by the MASS. The MASS provides a novel, non-invasive tool for tuberculosis diagnosis and control.

microbiology↗