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Contact-dependent growth inhibition induces high levels of antibiotic-tolerant persister cells in clonal bacterial populations
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.ORCID iD: 0000-0003-2480-563
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2018 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 37, no 9, article id UNSP e98026Article in journal (Refereed) Published
Abstract [en]

Bacterial populations can use bet-hedging strategies to cope with rapidly changing environments. One example is non-growing cells in clonal bacterial populations that are able to persist antibiotic treatment. Previous studies suggest that persisters arise in bacterial populations either stochastically through variation in levels of global signalling molecules between individual cells, or in response to various stresses. Here, we show that toxins used in contact-dependent growth inhibition (CDI) create persisters upon direct contact with cells lacking sufficient levels of CdiI immunity protein, which would otherwise bind to and neutralize toxin activity. CDI-mediated persisters form through a feedforward cycle where the toxic activity of the CdiA toxin increases cellular (p)ppGpp levels, which results in Lon-mediated degradation of the immunity protein and more free toxin. Thus, CDI systems mediate a population density-dependent bet-hedging strategy, where the fraction of non-growing cells is increased only when there are many cells of the same genotype. This may be one of the mechanisms of how CDI systems increase the fitness of their hosts.

Place, publisher, year, edition, pages
WILEY , 2018. Vol. 37, no 9, article id UNSP e98026
Keywords [en]
bet-hedging, contact-dependent growth inhibition, persisters, toxin
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-356400DOI: 10.15252/embj.201798026ISI: 000431279400003PubMedID: 29572241OAI: oai:DiVA.org:uu-356400DiVA, id: diva2:1235426
Funder
Swedish Foundation for Strategic Research Swedish Research CouncilEU, European Research Council
Note

Anirban Ghosh and Özden Baltekin contributed equally to this work.

Available from: 2018-07-25 Created: 2018-07-25 Last updated: 2019-12-19Bibliographically approved
In thesis
1. Too close for comfort: The role of Contact-Dependent growth Inhibition (CDI) in interbacterial competition and cooperation
Open this publication in new window or tab >>Too close for comfort: The role of Contact-Dependent growth Inhibition (CDI) in interbacterial competition and cooperation
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Contact-Dependent growth inhibition (CDI) was discovered in 2005 in the E. coli isolate EC93. Since then our knowledge of CDI systems and their impact on bacterial communities have increased exponentially. Yet many biological aspects of CDI systems are still unknown and their impact on complex microbial communities have only just begun to be studied. CDI systems require the function of three proteins; CdiBAI. The outer-membrane transport protein, CdiB, allows for the transportation of the toxin delivery protein CdiA to the cell surface of an inhibitor cell. Through a contact- and receptor-dependent interaction with a target cell the toxic C-terminal domain of CdiA is cleaved off and delivered into the target cell were it mediates a growth arrest. Different CdiA-CT domains encodes for diverse toxic activities, such as nucleases and membrane ionophore toxins. Each unique CdiA-CT toxin has a cognate immunity protein (CdiI) that binds and neutralize against its toxic activity, thus preventing a possible self-inhibition.

In this thesis I have studied the effect of CDI system(s) on both single cell and population level, within both intra- and interspecies bacterial communities. The findings presented here shows that multiple class I cdiBAI loci within a cell can function in a synergetic manner and act as versatile interbacterial warfare systems able to inhibit the growth of rival bacteria, even when CdiA expression is low. We also show that class II CdiA receptor-binding domains can mediate broad-range cross-species toxin delivery and growth inhibition, even when a non-optimal target cell receptor is expressed at a low level. Additionally, we show that the cdiA gene supports the expression of two separate proteins. The full-length CdiA protein, able to mediate an extracellular toxin delivery, but also the discrete CdiA-CT toxin domain. This stand-alone CdiA-CT expression was stress-dependent and together with its cognate CdiI immunity protein functioned as a selfish-genetic element. Moreover, we show that CDI systems can increase bacterial stress tolerance via an extracellular toxin delivery between kin-cells. This stress tolerance phenotype only occurred under conditions when we also observed a selective degradation of the CdiI immunity protein. Therefore, we suggest that a selective CdiI degradation allows for a sub-population of cells to self-intoxicate, thereby becoming transiently dormant, which confers an increase in stress tolerance. The findings presented in this thesis collectively suggest that CDI systems could function as a pseudo-quorum sensing system able to mediate behavioral changes and stress tolerance within a sub-population of cells in a bacterial community.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 80
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1891
Keywords
bacterial interactions, cell-cell binding, contact-dependent growth inhibition, CDI, CdiB, CdiA, CdiI, outer-membrane receptor, BamA, OmpC, OmpF, extracellular toxin delivery, Toxin-Antitoxin, TA-system, persister cells, stress tolerance, stress response, rpoS, rssB, quorum sensing, multicellular behavior
National Category
Microbiology
Research subject
Biology with specialization in Microbiology
Identifiers
urn:nbn:se:uu:diva-400201 (URN)978-91-513-0841-8 (ISBN)
Public defence
2020-02-21, Room A1:111a, BMC, Husargatan 3, Uppsala, 13:00 (English)
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Available from: 2020-01-31 Created: 2019-12-19 Last updated: 2020-01-31

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Ghosh, AnirbanBaltekin, ÖzdenWäneskog, MarcusLarsson, DisaElf, JohanKoskiniemi, Sanna

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