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

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 outb...

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Autores principales: Debowski, Aleksandra W., Bzdyl, Nicole M., Thomas, David R., Scott, Nichollas E., Jenkins, Christopher H., Iwasaki, Jua, Kibble, Emily A., Khoo, Chen Ai, Scheuplein, Nicolas J., Seibel, Pamela M., Lohr, Theresa, Metters, Georgie, Bond, Charles S., Norville, Isobel H., Stubbs, Keith A., Harmer, Nicholas J., Holzgrabe, Ulrike, Newton, Hayley J., Sarkar-Tyson, Mitali
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348545/
https://www.ncbi.nlm.nih.gov/pubmed/37399210
http://dx.doi.org/10.1371/journal.ppat.1011491
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author Debowski, Aleksandra W.
Bzdyl, Nicole M.
Thomas, David R.
Scott, Nichollas E.
Jenkins, Christopher H.
Iwasaki, Jua
Kibble, Emily A.
Khoo, Chen Ai
Scheuplein, Nicolas J.
Seibel, Pamela M.
Lohr, Theresa
Metters, Georgie
Bond, Charles S.
Norville, Isobel H.
Stubbs, Keith A.
Harmer, Nicholas J.
Holzgrabe, Ulrike
Newton, Hayley J.
Sarkar-Tyson, Mitali
author_facet Debowski, Aleksandra W.
Bzdyl, Nicole M.
Thomas, David R.
Scott, Nichollas E.
Jenkins, Christopher H.
Iwasaki, Jua
Kibble, Emily A.
Khoo, Chen Ai
Scheuplein, Nicolas J.
Seibel, Pamela M.
Lohr, Theresa
Metters, Georgie
Bond, Charles S.
Norville, Isobel H.
Stubbs, Keith A.
Harmer, Nicholas J.
Holzgrabe, Ulrike
Newton, Hayley J.
Sarkar-Tyson, Mitali
author_sort Debowski, Aleksandra W.
collection PubMed
description 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 H(2)O(2) 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.
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spelling pubmed-103485452023-07-15 Macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for Coxiella burnetii growth and pathogenesis Debowski, Aleksandra W. Bzdyl, Nicole M. Thomas, David R. Scott, Nichollas E. Jenkins, Christopher H. Iwasaki, Jua Kibble, Emily A. Khoo, Chen Ai Scheuplein, Nicolas J. Seibel, Pamela M. Lohr, Theresa Metters, Georgie Bond, Charles S. Norville, Isobel H. Stubbs, Keith A. Harmer, Nicholas J. Holzgrabe, Ulrike Newton, Hayley J. Sarkar-Tyson, Mitali PLoS Pathog Research Article 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 H(2)O(2) 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. Public Library of Science 2023-07-03 /pmc/articles/PMC10348545/ /pubmed/37399210 http://dx.doi.org/10.1371/journal.ppat.1011491 Text en © 2023 Debowski et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Debowski, Aleksandra W.
Bzdyl, Nicole M.
Thomas, David R.
Scott, Nichollas E.
Jenkins, Christopher H.
Iwasaki, Jua
Kibble, Emily A.
Khoo, Chen Ai
Scheuplein, Nicolas J.
Seibel, Pamela M.
Lohr, Theresa
Metters, Georgie
Bond, Charles S.
Norville, Isobel H.
Stubbs, Keith A.
Harmer, Nicholas J.
Holzgrabe, Ulrike
Newton, Hayley J.
Sarkar-Tyson, Mitali
Macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for Coxiella burnetii growth and pathogenesis
title Macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for Coxiella burnetii growth and pathogenesis
title_full Macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for Coxiella burnetii growth and pathogenesis
title_fullStr Macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for Coxiella burnetii growth and pathogenesis
title_full_unstemmed Macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for Coxiella burnetii growth and pathogenesis
title_short Macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for Coxiella burnetii growth and pathogenesis
title_sort macrophage infectivity potentiator protein, a peptidyl prolyl cis-trans isomerase, essential for coxiella burnetii growth and pathogenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348545/
https://www.ncbi.nlm.nih.gov/pubmed/37399210
http://dx.doi.org/10.1371/journal.ppat.1011491
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