No abstract

Serine hydrolases play diverse roles in regulating host-pathogen interactions in a number of organisms, yet few have been characterized in the human pathogen Staphylococcus aureus. Here, we describe a chemical proteomic screen that identified 10 previously uncharacterized S. aureus serine hydrolases that mostly lack human homologues. We termed these enzymes Fluorophosphonate-binding hydrolases (FphA-J). One hydrolase, FphB, can process short fatty acid esters, exhibits increased activity in response to host cell factors, is located predominantly on the bacterial cell surface in a subset of cells, and is concentrated in the division septum. Genetic disruption of the fphB gene confirms that the enzyme is dispensable for bacterial growth in culture but crucial for establishing infection in distinct sites in vivo. A selective small molecule inhibitor of FphB effectively reduces infectivity in vivo, suggesting that it may be a viable therapeutic target for the treatment or management of Staphylococcus infections.

Staphylococcus aureus is both a transient skin colonizer and a formidable human pathogen, ranking among the leading causes of skin and soft tissue infections as well as severe pneumonia. The secreted bacterial α-toxin is essential for S. aureus virulence in these epithelial diseases. To discover host cellular factors required for α-toxin cytotoxicity, we conducted a genetic screen using mutagenized haploid human cells. Our screen identified a cytoplasmic member of the adherens junctions, plekstrin-homology domain containing protein 7 (PLEKHA7), as the second most significantly enriched gene after the known α-toxin receptor, a disintegrin and metalloprotease 10 (ADAM10). Here we report a new, unexpected role for PLEKHA7 and several components of cellular adherens junctions in controlling susceptibility to S. aureus α-toxin. We find that despite being injured by α-toxin pore formation, PLEKHA7 knockout cells recover after intoxication. By infecting PLEKHA7 −/− mice with methicillin-resistant S. aureus USA300 LAC strain, we demonstrate that this junctional protein controls disease severity in both skin infection and lethal S. aureus pneumonia. Our results suggest that adherens junctions actively control cellular responses to a potent pore-forming bacterial toxin and identify PLEKHA7 as a potential nonessential host target to reduce S. aureus virulence during epithelial infections.Staphylococcus aureus | α-toxin | adherens junctions | MRSA | PLEKHA7

Background: Peritoneal dialysis (PD) has been described for use in animals with acute kidney injury refractory to fluid therapy. However, no study has examined the use of PD in a large group of cats.Hypothesis: PD is an important adjunctive therapy to treat acute kidney injury in cats. Animals: The medical records of 22 cats with acute kidney injury that had received PD were examined. Animals were excluded if acute uremia was a result of postrenal causes such as uroabdomen or urethral obstruction.Methods: Medical records were reviewed for the following: indication for PD, outcome, number of cycles performed, survival time, and predialysis and postdialysis results for blood urea nitrogen (BUN), creatinine, potassium, chloride, sodium, phosphorus, total protein, and albumin concentrations, and urine output.Results: Indications for PD include acute-on-chronic kidney injury, acute kidney injury caused by toxins, bilateral ureteroliths, bilateral ureteral ligation as a complication of ovariohysterectomy, and unknown causes. The median survival time for all cats on PD was 4 days, although the median survival time for the cats that were discharged was 774 days. The most common complications were dialysate retention and sequestration of dialysate SC. There was a significant (Po .05) decrease between predialysis and postdialysis results for BUN, creatinine, potassium, phosphorus, total protein, and albumin concentrations. There was a significant (Po .05) difference in survival times between sexes.Conclusions and Clinical Importance: PD is an effective option for treatment of cats with acute kidney injury refractory to fluid therapy.