Macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for Coxiella burnetii growth and pathogenesis

Aleksandra W. Debowski; Nicole M. Bzdyl; David R. Thomas; Nichollas E. Scott; Christopher H. Jenkins; Jua Iwasaki; Emily A. Kibble; Chen Ai Khoo; Nicolas J. Scheuplein; Pamela M. Seibel; Theresa Lohr; Georgie Metters; Charles S. Bond; Isobel H. Norville; Keith A. Stubbs; Nicholas J. Harmer; Ulrike Holzgrabe; Hayley J. Newton; Mitali Sarkar-Tyson

doi:10.1371/journal.ppat.1011491

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Macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for Coxiella burnetii growth and pathogenesis

Journal article

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Peer reviewed

Macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for Coxiella burnetii growth and pathogenesis

Aleksandra W. Debowski, Nicole M. Bzdyl, David R. Thomas, Nichollas E. Scott, Christopher H. Jenkins, Jua Iwasaki, Emily A. Kibble, Chen Ai Khoo, Nicolas J. Scheuplein, Pamela M. Seibel, …

PLoS pathogens, Vol.19(7), e1011491

2023

DOI: https://doi.org/10.1371/journal.ppat.1011491

PMID: 37399210

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Abstract

Biology and Life Sciences

Medicine and Health Sciences

Research and analysis methods

Coxiella burnetii is a Gram-negative intracellular pathogen that causes the debilitating disease Q fever, which affects both animals and humans. The only available human vaccine, Q-Vax, is effective but has a high risk of severe adverse reactions, limiting its use as a countermeasure to contain outbreaks. Therefore, it is essential to identify new drug targets to treat this infection. Macrophage infectivity potentiator (Mip) proteins catalyse the folding of proline-containing proteins through their peptidyl prolyl cis-trans isomerase (PPIase) activity and have been shown to play an important role in the virulence of several pathogenic bacteria. To date the role of the Mip protein in C. burnetii pathogenesis has not been investigated. This study demonstrates that CbMip is likely to be an essential protein in C. burnetii. The pipecolic acid derived compounds, SF235 and AN296, which have shown utility in targeting other Mip proteins from pathogenic bacteria, demonstrate inhibitory activities against CbMip. These compounds were found to significantly inhibit intracellular replication of C. burnetii in both HeLa and THP-1 cells. Furthermore, SF235 and AN296 were also found to exhibit antibiotic properties against both the virulent (Phase I) and avirulent (Phase II) forms of C. burnetii Nine Mile Strain in axenic culture. Comparative proteomics, in the presence of AN296, revealed alterations in stress responses with H2O2 sensitivity assays validating that Mip inhibition increases the sensitivity of C. burnetii to oxidative stress. In addition, SF235 and AN296 were effective in vivo and significantly improved the survival of Galleria mellonella infected with C. burnetii. These results suggest that unlike in other bacteria, Mip in C. burnetii is required for replication and that the development of more potent inhibitors against CbMip is warranted and offer potential as novel therapeutics against this pathogen.

Details

Title: Macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for Coxiella burnetii growth and pathogenesis
Authors/Creators: Aleksandra W. Debowski - The University of Western Australia
Nicole M. Bzdyl - The University of Western Australia
David R. Thomas - Australian Regenerative Medicine Institute
Nichollas E. Scott - Peter Doherty Institute
Christopher H. Jenkins - Defence Science and Technology Laboratory
Jua Iwasaki - The Kids Research Institute Australia
Emily A. Kibble - The University of Western Australia
Chen Ai Khoo - Peter Doherty Institute
Nicolas J. Scheuplein - University of Würzburg
Pamela M. Seibel - The University of Western Australia
Theresa Lohr - University of Würzburg
Georgie Metters - University of Exeter
Charles S. Bond - The University of Western Australia
Isobel H. Norville - University of Exeter
Keith A. Stubbs - The University of Western Australia
Nicholas J. Harmer - University of Exeter
Ulrike Holzgrabe - University of Würzburg
Hayley J. Newton - Australian Regenerative Medicine Institute
Mitali Sarkar-Tyson - The University of Western Australia
Publication Details: PLoS pathogens, Vol.19(7), e1011491
Publisher: Public Library of Science
Identifiers: 991005593758007891
Murdoch Affiliation: College of Environmental and Life Sciences
Language: English
Resource Type: Journal article

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.258 Zoonotic Diseases; 1.258.2263 Coxiella Burnetii
Web Of Science research areas: Microbiology; Parasitology; Virology
ESI research areas: Microbiology