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Peptidyl-Prolyl Isomerase ppiB Is Essential for Proteome Homeostasis and Virulence in Burkholderia pseudomallei
Nicole M Bzdyl1, Nichollas E Scott2, Isobel H Norville3
1Marshall Center for Infectious Diseases Research and Training, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.
Abstract:
Burkholderia pseudomallei is the causative agent of melioidosis, a disease endemic to Southeast Asia and northern Australia. Mortality rates in these areas are high even with antimicrobial treatment, and there are few options for effective therapy. Therefore, there is a need to identify antibacterial targets for the development of novel treatments. Cyclophilins are a family of highly conserved enzymes important in multiple cellular processes. Cyclophilins catalyze the cis-trans isomerization of xaa-proline bonds, a rate-limiting step in protein folding which has been shown to be important for bacterial virulence. B. pseudomallei carries a putative cyclophilin B gene, ppiB, the role of which was investigated. A B. pseudomalleiΔppiB (BpsΔppiB) mutant strain demonstrates impaired biofilm formation and reduced motility. Macrophage invasion and survival assays showed that although the BpsΔppiB strain retained the ability to infect macrophages, it had reduced survival and lacked the ability to spread cell to cell, indicating ppiB is essential for B. pseudomallei virulence. This is reflected in the BALB/c mouse infection model, demonstrating the requirement of ppiB for in vivo disease dissemination and progression. Proteomic analysis demonstrates that the loss of PpiB leads to pleiotropic effects, supporting the role of PpiB in maintaining proteome homeostasis. The loss of PpiB leads to decreased abundance of multiple virulence determinants, including flagellar machinery and alterations in type VI secretion system proteins. In addition, the loss of ppiB leads to increased sensitivity toward multiple antibiotics, including meropenem and doxycycline, highlighting ppiB inhibition as a promising antivirulence target to both treat B. pseudomallei infections and increase antibiotic efficacy.
Insights
Inhibition of cyclophilin B (ppiB) in Burkholderia pseudomallei disrupts virulence, impairs biofilm formation, and increases antibiotic sensitivity, offering a novel therapeutic target for melioidosis.
Area of Science:
- Microbiology
- Infectious Diseases
- Drug Discovery
Background:
- Melioidosis, caused by Burkholderia pseudomallei, has high mortality rates in endemic regions (Southeast Asia, northern Australia).
- Existing antimicrobial treatments are often insufficient, necessitating the identification of novel antibacterial targets.
- Cyclophilins are conserved enzymes involved in crucial cellular processes, including bacterial virulence.
Purpose of the Study:
- To investigate the role of the putative cyclophilin B gene (ppiB) in Burkholderia pseudomallei virulence.
- To evaluate ppiB as a potential target for novel anti-melioidosis therapies.
Main Methods:
- Construction and characterization of a B. pseudomallei ΔppiB mutant strain.
- In vitro assays: biofilm formation, motility, macrophage invasion, and intracellular survival.
- In vivo studies using a BALB/c mouse infection model.
- Proteomic analysis to identify global changes in protein abundance upon PpiB loss.
Main Results:
- The BpsΔppiB mutant exhibited impaired biofilm formation and reduced motility.
- BpsΔppiB showed reduced intracellular survival and lacked cell-to-cell spread in macrophages, indicating ppiB is essential for virulence.
- In vivo, ppiB was required for disease dissemination and progression in mice.
- Loss of PpiB led to decreased abundance of virulence factors (flagellar machinery, type VI secretion system) and increased sensitivity to antibiotics like meropenem and doxycycline.
Conclusions:
- The cyclophilin B gene (ppiB) is essential for Burkholderia pseudomallei virulence, biofilm formation, and intracellular survival.
- PpiB plays a significant role in maintaining proteome homeostasis and regulating the expression of key virulence determinants.
- Inhibiting ppiB represents a promising antivirulence strategy to treat melioidosis and enhance antibiotic efficacy.
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