Biology subjects

Geoghegan, J. A.

Publications and source records attributed to Geoghegan, J. A..

3 recordsLinked to original sources

bioRxiv2025

Plasmin-Mediated Processing of Clumping Factor A Impacts Bacterial Aggregation and Abscess Formation during Staphylococcus aureus Infection

The interface between pathogenic bacteria and the host plays a critical role during the progression of infection. Bacterial surface components, such as the Staphylococcus aureus cell wall-anchored protein clumping factor A (ClfA), interact with host factors. ClfA promotes bacterial aggregation in plasma by binding to fibrinogen. Here, we show that the host serine endopeptidase plasmin cleaves ClfA, disrupting its interaction with fibrinogen and promoting bloodstream survival and virulence in S. aureus. We found that plasmin cleaves ClfA between residues Arg214 and Ala215. Cleavage occurs in human serum regardless of whether plasmin becomes activated by host tissue-plasminogen activator or by the activity of the S. aureus enzyme staphylokinase. Expressing a plasmin-resistant form of ClfA, and a truncated form that mimics the plasmin-cleaved product on the bacterial cell surface, revealed that following cleavage, ClfA cannot mediate aggregation of S. aureus in fibrinogen. Truncated ClfA on the cell surface cannot bind to fibrinogen and promotes the establishment of renal abscesses in vivo. Collectively, our findings suggest that activation of plasmin during infection leads to site-specific processing of ClfA, and this not only abrogates fibrinogen binding but also facilitates enhanced S. aureus persistence in the host. Thus, we demonstrate that proteolytic processing by plasmin is a mechanism for modulating the host-pathogen interaction during infection. Author SummaryStaphylococcus aureus is a major human bacterial pathogen that binds to host factors during infection using its surface adhesins. Here we describe a novel mechanism by which host proteolytic activity modulates bacterial interaction with the plasma protein fibrinogen to influence the course of infection. The surface adhesin clumping factor A (ClfA), binds to fibrinogen, causing bacterial aggregation in the bloodstream. In this study, we show that the host enzyme plasmin cleaves ClfA at a specific site, disrupting its ability to bind fibrinogen. Cleavage eliminates ClfA-mediated aggregation in plasma fibrinogen and enhances S. aureus virulence in vivo, increasing the formation of kidney abscesses. Our work therefore demonstrates that specific protease-mediated processing of bacterial adhesins by host factors can influence the progression of infection.

microbiology↗

bioRxiv2023

The mutational landscape of Staphylococcus aureus during colonisation

Staphylococcus aureus is an important human pathogen but is primarily a commensal of the human nose and skin. Survival during colonisation is likely one of the major drivers of S. aureus evolution. Here we use a genome-wide mutation enrichment approach to analyse a genomic dataset of 3,060 S. aureus isolates from 791 individuals to show that despite limited within-host genetic diversity, an excess of protein-altering mutations can be found in genes encoding key metabolic pathways, in regulators of quorum-sensing and in known antibiotic targets. Nitrogen metabolism and riboflavin synthesis are the metabolic processes with strongest evidence of adaptation. Further evidence of adaptation to nitrogen availability was revealed by enrichment of mutations in the assimilatory nitrite reductase and urease, including mutations that enhance growth with urea as the sole nitrogen source. Inclusion of an additional 4,090 genomes from 802 individuals revealed eight additional genes including sasA/sraP, pstA, and rsbU with signals adaptive variation that warrant further characterisation. Our study provides the most comprehensive picture to date of the heterogeneity of adaptive changes that occur in the genomes of S. aureus during colonisation, revealing the likely importance of nitrogen metabolism, loss of quorum sensing and antibiotic resistance for successful human colonisation.

genomics↗

bioRxiv2023

The A domain of clonal complex 1-type fibronectin binding protein B promotes adherence and biofilm formation in Staphylococcus aureus

Adhesive interactions between Staphylococcus aureus and the host rely on cell wall-anchored proteins such as fibronectin binding protein B (FnBPB). Recently we showed that the FnBPB protein expressed by clonal complex (CC) 1 isolates of S. aureus mediates bacterial adhesion to corneodesmosin. The proposed ligand binding region of CC1-type FnBPB shares just 60% amino acid identity with the archetypal FnBPB protein from CC8. Here we investigated ligand binding and biofilm formation by CC1-type FnBPB. We found that the A domain of FnBPB binds to fibrinogen and corneodesmosin and identified residues within the hydrophobic ligand trench in the A domain that are essential for the binding of CC1-type FnBPB to ligands and during biofilm formation. We further investigated the interplay between different ligands and the influence of ligand binding on biofilm formation. Overall, our study provides new insights into the requirements for CC1-type FnBPB-mediated adhesion to host proteins and FnBPB-mediated biofilm formation in S. aureus.

microbiology↗