Biology subjects

Henderson, S. R.

Publications and source records attributed to Henderson, S. R..

3 recordsLinked to original sources

bioRxiv2024

Vincristine treatment reverses podocyte damage in focal segmental glomerulosclerosis

IntroductionFocal segmental glomerulosclerosis (FSGS) is a significant cause of chronic kidney disease and triggered by podocyte damage which can result in cytoskeletal alterations leading to foot process effacement. Vincristine is a chemoprotective drug which alters cytoskeletal microtubules and has been used clinically to reverse FSGS. However, the mechanisms underlying the beneficial effect of vincristine are not understood. MethodsWe exposed immortalised human podocytes to serum obtained from an FSGS patient before, during, and after vincristine treatment. Using RNA-sequencing we determined the effect on the podocyte transcriptome alongside impacts on cytoskeletal structure and filtration barrier integrity using a glomerulus-on-a-chip model. ResultsWe describe an adult index FSGS patient successfully treated on multiple occasions by vincristine. Podocytes exposed to serum obtained during or after vincristine treatment contained lower levels of genes associated with microtubule function compared with cells stimulated with serum collected before treatment during disease presentation. Presentation serum altered the patterning of two key podocyte cytoskeletal components, tubulin and F-actin and increased albumin permeability, changes prevented by vincristine treatment. Immunoglobulin depletion experiments revealed that the podocyte damage initiated by the presentation serum was not due to circulating autoantibodies. Defects in tubulin patterning were observed when podocytes were exposed to serum from other FSGS patients, suggestive of a common disease mechanism. ConclusionVincristine therapy produces a milieu that protects against pathological changes induced by FSGS serum, associated with preservation of tubulin and F-actin organisation. The functional role of vincristine warrants further investigation, to advance our understanding of this alternative FSGS therapeutic.

cell biology↗

bioRxiv2023

The anticancer chemotherapy drug 5-Fluorouracil has positive interaction with antibiotics and can select for antibiotic resistance in Staphylococcus aureus

Antibiotic resistance is a major global issue in healthcare and understanding the drivers of resistance is key in developing effective strategies to counter it. Many non-antibiotic drugs, such as cancer chemotherapy drugs, can have antimicrobial properties but their effects on bacteria in the context of infection and drug resistance have only recently begun to be explored. Here we investigate the antimicrobial properties of the cancer drug 5-fluorouracil (5-FU) on the common human commensal and pathogen Staphylococcus aureus. 5-FU can be metabolized by S. aureus and ultimately results in the inhibition of ThyA, involved in the folate synthesis and thymine synthesis pathways. Bacterial growth was inhibited by 5-FU, and the drug had additive or synergistic interactions with the antibiotics trimethoprim and sulfamethoxazole. The addition of thymidine overcame the inhibitory effects of 5-FU. Strains of S. aureus evolved in the presence of 5-FU developed mutations in the thymidine kinase gene tdk, likely inhibiting the thymine salvage pathway. In mixtures of clinical trimethoprim-resistant S. aureus strains and sensitive strains, the presence of 5-FU conferred a large fitness advantage to the resistant strains and selected for them over the sensitive strains. Together these data show that 5-FU has antimicrobial effects against S. aureus with these effects targeting the same pathway as existing antibiotics, and that the use of 5-FU in patients may be selecting for antibiotic-resistant bacteria.

microbiology↗

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↗