Novel Regulation of Alpha-Toxin and the Phenol-Soluble Modulins by Peptidyl-Prolyl cis/trans Isomerase Enzymes in Staphylococcus aureus

• Published in: Toxins Vol. 11; no. 6; p. 343
• Main Authors: Keogh, Rebecca A, Zapf, Rachel L, Trzeciak, Emily, Null, Gillian G, Wiemels, Richard E, Carroll, Ronan K
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16.06.2019; MDPI
• Subjects: Abscesses; alpha-toxin; Animal models; Animals; Bacteria; Bacterial Proteins - metabolism; Bacterial Toxins - metabolism; Cell culture; Enzymes; Epithelial cells; Epithelial Cells - microbiology; Epithelium; Erythrocytes - drug effects; Female; Gene deletion; Hemolysis - drug effects; Humans; Immunoprecipitation; Infections; Isomerization; Lungs; Macrophages; Macrophages - microbiology; Mice, Inbred BALB C; Mutants; Peptides; Peptidylprolyl isomerase; Peptidylprolyl Isomerase - metabolism; Phenols; PPIase; PpiB; Proline; Protein folding; Proteins; PrsA; PSMs; Rabbits; S. aureus; Sepsis; Staphylococcal Infections - metabolism; Staphylococcal Infections - microbiology; Staphylococcus aureus; Staphylococcus aureus - metabolism; Staphylococcus aureus - pathogenicity; Staphylococcus infections; Target recognition; THP-1 Cells; Toxins; Virulence; Virulence Factors - metabolism; α-Toxin; S. aureus; PrsA; PPIase; toxins; alpha-toxin; PSMs; PpiB
• ISSN: 2072-6651; 2072-6651
• DOI: 10.3390/toxins11060343

Peptidyl-prolyl isomerases (PPIases) are enzymes that catalyze the -to- isomerization around proline bonds, allowing proteins to fold into their correct confirmation. Previously, we identified two PPIase enzymes in (PpiB and PrsA) that are involved in the regulation of virulence determinants and have shown that PpiB contributes to virulence in a murine abscess model of infection. Here, we further examine the role of these PPIases in virulence and, in particular, their regulation of hemolytic toxins. Using murine abscess and systemic models of infection, we show that a mutant in a USA300 background is attenuated for virulence but that a mutant is not. Deletion of the gene leads to decreased bacterial survival in macrophages and nasal epithelial cells, while there is no significant difference when is deleted. Analysis of culture supernatants reveals that a mutant strain has reduced levels of the phenol-soluble modulins and that both and mutants have reduced alpha-toxin activity. Finally, we perform immunoprecipitation to identify cellular targets of PpiB and PrsA. Results suggest a novel role for PpiB in protein secretion. Collectively, our results demonstrate that PpiB and PrsA influence toxins via distinct mechanisms, and that PpiB but not PrsA contributes to disease.