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Title: A comparative genomics approach identifies contact-dependent growth inhibition as a virulence determinant

Abstract

Emerging evidence suggests the Pseudomonas aeruginosa accessory genome is enriched with uncharacterized virulence genes. Identification and characterization of such genes may reveal novel pathogenic mechanisms used by particularly virulent isolates. In this work, we utilized a mouse bacteremia model to quantify the virulence of 100 individual P. aeruginosa bloodstream isolates and performed whole-genome sequencing to identify accessory genomic elements correlated with increased bacterial virulence. From this work, we identified a specific contact-dependent growth inhibition (CDI) system enriched among highly virulent P. aeruginosa isolates. CDI systems contain a large exoprotein (CdiA) with a C-terminal toxin (CT) domain that can vary between different isolates within a species. Prior work has revealed that delivery of a CdiA-CT domain upon direct cell-to-cell contact can inhibit replication of a susceptible target bacterium. Aside from mediating interbacterial competition, we observed our virulence-associated CdiA-CT domain to promote toxicity against mammalian cells in culture and lethality during mouse bacteremia. Structural and functional studies revealed this CdiA-CT domain to have in vitro tRNase activity, and mutations that abrogated this tRNAse activity in vitro also attenuated virulence. Furthermore, CdiA contributed to virulence in mice even in the absence of contact-dependent signaling. Overall, our findings indicate that this P. aeruginosa CDImore » system functions as both an interbacterial inhibition system and a bacterial virulence factor against a mammalian host. These findings provide an impetus for continued studies into the complex role of CDI systems in P. aeruginosa pathogenesis.« less

Authors:
ORCiD logo [1];  [1];  [1];  [1];  [1];  [1];  [1]
  1. Northwestern Univ. Feinberg School of Medicine, Chicago, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC); Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor; National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); American Heart Association (AHA); American Cancer Society
OSTI Identifier:
1618481
Grant/Contract Number:  
AC02-06CH11357; 085P1000817; HHSN272201200026C; HHSN272201700060C; F32 AI108247; R01 AI118257; R01 AI053674; U19 AI135964; K24 AI04831; R21 AI129167; 15POST25830019; MRSG-13-220-01
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 117; Journal Issue: 12; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Pseudomonas aeruginosa; whole-genome sequencing; comparative genomics; virulence; contact-dependent growth inhibition

Citation Formats

Allen, Jonathan P., Ozer, Egon A., Minasov, George, Shuvalova, Ludmilla, Kiryukhina, Olga, Satchell, Karla J. F., and Hauser, Alan R. A comparative genomics approach identifies contact-dependent growth inhibition as a virulence determinant. United States: N. p., 2020. Web. https://doi.org/10.1073/pnas.1919198117.
Allen, Jonathan P., Ozer, Egon A., Minasov, George, Shuvalova, Ludmilla, Kiryukhina, Olga, Satchell, Karla J. F., & Hauser, Alan R. A comparative genomics approach identifies contact-dependent growth inhibition as a virulence determinant. United States. https://doi.org/10.1073/pnas.1919198117
Allen, Jonathan P., Ozer, Egon A., Minasov, George, Shuvalova, Ludmilla, Kiryukhina, Olga, Satchell, Karla J. F., and Hauser, Alan R. Tue . "A comparative genomics approach identifies contact-dependent growth inhibition as a virulence determinant". United States. https://doi.org/10.1073/pnas.1919198117. https://www.osti.gov/servlets/purl/1618481.
@article{osti_1618481,
title = {A comparative genomics approach identifies contact-dependent growth inhibition as a virulence determinant},
author = {Allen, Jonathan P. and Ozer, Egon A. and Minasov, George and Shuvalova, Ludmilla and Kiryukhina, Olga and Satchell, Karla J. F. and Hauser, Alan R.},
abstractNote = {Emerging evidence suggests the Pseudomonas aeruginosa accessory genome is enriched with uncharacterized virulence genes. Identification and characterization of such genes may reveal novel pathogenic mechanisms used by particularly virulent isolates. In this work, we utilized a mouse bacteremia model to quantify the virulence of 100 individual P. aeruginosa bloodstream isolates and performed whole-genome sequencing to identify accessory genomic elements correlated with increased bacterial virulence. From this work, we identified a specific contact-dependent growth inhibition (CDI) system enriched among highly virulent P. aeruginosa isolates. CDI systems contain a large exoprotein (CdiA) with a C-terminal toxin (CT) domain that can vary between different isolates within a species. Prior work has revealed that delivery of a CdiA-CT domain upon direct cell-to-cell contact can inhibit replication of a susceptible target bacterium. Aside from mediating interbacterial competition, we observed our virulence-associated CdiA-CT domain to promote toxicity against mammalian cells in culture and lethality during mouse bacteremia. Structural and functional studies revealed this CdiA-CT domain to have in vitro tRNase activity, and mutations that abrogated this tRNAse activity in vitro also attenuated virulence. Furthermore, CdiA contributed to virulence in mice even in the absence of contact-dependent signaling. Overall, our findings indicate that this P. aeruginosa CDI system functions as both an interbacterial inhibition system and a bacterial virulence factor against a mammalian host. These findings provide an impetus for continued studies into the complex role of CDI systems in P. aeruginosa pathogenesis.},
doi = {10.1073/pnas.1919198117},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 12,
volume = 117,
place = {United States},
year = {2020},
month = {3}
}

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