--- _id: '6784' abstract: - lang: eng text: Mathematical models have been used successfully at diverse scales of biological organization, ranging from ecology and population dynamics to stochastic reaction events occurring between individual molecules in single cells. Generally, many biological processes unfold across multiple scales, with mutations being the best studied example of how stochasticity at the molecular scale can influence outcomes at the population scale. In many other contexts, however, an analogous link between micro- and macro-scale remains elusive, primarily due to the challenges involved in setting up and analyzing multi-scale models. Here, we employ such a model to investigate how stochasticity propagates from individual biochemical reaction events in the bacterial innate immune system to the ecology of bacteria and bacterial viruses. We show analytically how the dynamics of bacterial populations are shaped by the activities of immunity-conferring enzymes in single cells and how the ecological consequences imply optimal bacterial defense strategies against viruses. Our results suggest that bacterial populations in the presence of viruses can either optimize their initial growth rate or their population size, with the first strategy favoring simple immunity featuring a single restriction modification system and the second strategy favoring complex bacterial innate immunity featuring several simultaneously active restriction modification systems. article_number: e1007168 article_processing_charge: No article_type: original author: - first_name: Jakob full_name: Ruess, Jakob id: 4A245D00-F248-11E8-B48F-1D18A9856A87 last_name: Ruess orcid: 0000-0003-1615-3282 - first_name: Maros full_name: Pleska, Maros id: 4569785E-F248-11E8-B48F-1D18A9856A87 last_name: Pleska orcid: 0000-0001-7460-7479 - first_name: Calin C full_name: Guet, Calin C id: 47F8433E-F248-11E8-B48F-1D18A9856A87 last_name: Guet orcid: 0000-0001-6220-2052 - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 citation: ama: Ruess J, Pleska M, Guet CC, Tkačik G. Molecular noise of innate immunity shapes bacteria-phage ecologies. PLoS Computational Biology. 2019;15(7). doi:10.1371/journal.pcbi.1007168 apa: Ruess, J., Pleska, M., Guet, C. C., & Tkačik, G. (2019). Molecular noise of innate immunity shapes bacteria-phage ecologies. PLoS Computational Biology. Public Library of Science. https://doi.org/10.1371/journal.pcbi.1007168 chicago: Ruess, Jakob, Maros Pleska, Calin C Guet, and Gašper Tkačik. “Molecular Noise of Innate Immunity Shapes Bacteria-Phage Ecologies.” PLoS Computational Biology. Public Library of Science, 2019. https://doi.org/10.1371/journal.pcbi.1007168. ieee: J. Ruess, M. Pleska, C. C. Guet, and G. Tkačik, “Molecular noise of innate immunity shapes bacteria-phage ecologies,” PLoS Computational Biology, vol. 15, no. 7. Public Library of Science, 2019. ista: Ruess J, Pleska M, Guet CC, Tkačik G. 2019. Molecular noise of innate immunity shapes bacteria-phage ecologies. PLoS Computational Biology. 15(7), e1007168. mla: Ruess, Jakob, et al. “Molecular Noise of Innate Immunity Shapes Bacteria-Phage Ecologies.” PLoS Computational Biology, vol. 15, no. 7, e1007168, Public Library of Science, 2019, doi:10.1371/journal.pcbi.1007168. short: J. Ruess, M. Pleska, C.C. Guet, G. Tkačik, PLoS Computational Biology 15 (2019). date_created: 2019-08-11T21:59:19Z date_published: 2019-07-02T00:00:00Z date_updated: 2023-08-29T07:10:06Z day: '02' ddc: - '570' department: - _id: CaGu - _id: GaTk doi: 10.1371/journal.pcbi.1007168 external_id: isi: - '000481577700032' file: - access_level: open_access checksum: 7ded4721b41c2a0fc66a1c634540416a content_type: application/pdf creator: dernst date_created: 2019-08-12T12:27:26Z date_updated: 2020-07-14T12:47:40Z file_id: '6803' file_name: 2019_PlosComputBiology_Ruess.pdf file_size: 2200003 relation: main_file file_date_updated: 2020-07-14T12:47:40Z has_accepted_license: '1' intvolume: ' 15' isi: 1 issue: '7' language: - iso: eng month: '07' oa: 1 oa_version: Published Version project: - _id: 251D65D8-B435-11E9-9278-68D0E5697425 grant_number: '24210' name: Effects of Stochasticity on the Function of Restriction-Modi cation Systems at the Single-Cell Level - _id: 251BCBEC-B435-11E9-9278-68D0E5697425 grant_number: RGY0079/2011 name: Multi-Level Conflicts in Evolutionary Dynamics of Restriction-Modification Systems publication: PLoS Computational Biology publication_identifier: eissn: - 1553-7358 publication_status: published publisher: Public Library of Science quality_controlled: '1' related_material: record: - id: '9786' relation: research_data status: public scopus_import: '1' status: public title: Molecular noise of innate immunity shapes bacteria-phage ecologies tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 15 year: '2019' ... --- _id: '9786' article_processing_charge: No author: - first_name: Jakob full_name: Ruess, Jakob id: 4A245D00-F248-11E8-B48F-1D18A9856A87 last_name: Ruess orcid: 0000-0003-1615-3282 - first_name: Maros full_name: Pleska, Maros id: 4569785E-F248-11E8-B48F-1D18A9856A87 last_name: Pleska orcid: 0000-0001-7460-7479 - first_name: Calin C full_name: Guet, Calin C id: 47F8433E-F248-11E8-B48F-1D18A9856A87 last_name: Guet orcid: 0000-0001-6220-2052 - first_name: Gašper full_name: Tkačik, Gašper id: 3D494DCA-F248-11E8-B48F-1D18A9856A87 last_name: Tkačik orcid: 0000-0002-6699-1455 citation: ama: Ruess J, Pleska M, Guet CC, Tkačik G. Supporting text and results. 2019. doi:10.1371/journal.pcbi.1007168.s001 apa: Ruess, J., Pleska, M., Guet, C. C., & Tkačik, G. (2019). Supporting text and results. Public Library of Science. https://doi.org/10.1371/journal.pcbi.1007168.s001 chicago: Ruess, Jakob, Maros Pleska, Calin C Guet, and Gašper Tkačik. “Supporting Text and Results.” Public Library of Science, 2019. https://doi.org/10.1371/journal.pcbi.1007168.s001. ieee: J. Ruess, M. Pleska, C. C. Guet, and G. Tkačik, “Supporting text and results.” Public Library of Science, 2019. ista: Ruess J, Pleska M, Guet CC, Tkačik G. 2019. Supporting text and results, Public Library of Science, 10.1371/journal.pcbi.1007168.s001. mla: Ruess, Jakob, et al. Supporting Text and Results. Public Library of Science, 2019, doi:10.1371/journal.pcbi.1007168.s001. short: J. Ruess, M. Pleska, C.C. Guet, G. Tkačik, (2019). date_created: 2021-08-06T08:23:43Z date_published: 2019-07-02T00:00:00Z date_updated: 2023-08-29T07:10:05Z day: '02' department: - _id: CaGu - _id: GaTk doi: 10.1371/journal.pcbi.1007168.s001 month: '07' oa_version: Published Version publisher: Public Library of Science related_material: record: - id: '6784' relation: used_in_publication status: public status: public title: Supporting text and results type: research_data_reference user_id: 6785fbc1-c503-11eb-8a32-93094b40e1cf year: '2019' ... --- _id: '82' abstract: - lang: eng text: In experimental cultures, when bacteria are mixed with lytic (virulent) bacteriophage, bacterial cells resistant to the phage commonly emerge and become the dominant population of bacteria. Following the ascent of resistant mutants, the densities of bacteria in these simple communities become limited by resources rather than the phage. Despite the evolution of resistant hosts, upon which the phage cannot replicate, the lytic phage population is most commonly maintained in an apparently stable state with the resistant bacteria. Several mechanisms have been put forward to account for this result. Here we report the results of population dynamic/evolution experiments with a virulent mutant of phage Lambda, λVIR, and Escherichia coli in serial transfer cultures. We show that, following the ascent of λVIR-resistant bacteria, λVIRis maintained in the majority of cases in maltose-limited minimal media and in all cases in nutrient-rich broth. Using mathematical models and experiments, we show that the dominant mechanism responsible for maintenance of λVIRin these resource-limited populations dominated by resistant E. coli is a high rate of either phenotypic or genetic transition from resistance to susceptibility—a hitherto undemonstrated mechanism we term "leaky resistance." We discuss the implications of leaky resistance to our understanding of the conditions for the maintenance of phage in populations of bacteria—their “existence conditions.”. article_number: '2005971' article_processing_charge: Yes author: - first_name: Waqas full_name: Chaudhry, Waqas last_name: Chaudhry - first_name: Maros full_name: Pleska, Maros id: 4569785E-F248-11E8-B48F-1D18A9856A87 last_name: Pleska orcid: 0000-0001-7460-7479 - first_name: Nilang full_name: Shah, Nilang last_name: Shah - first_name: Howard full_name: Weiss, Howard last_name: Weiss - first_name: Ingrid full_name: Mccall, Ingrid last_name: Mccall - first_name: Justin full_name: Meyer, Justin last_name: Meyer - first_name: Animesh full_name: Gupta, Animesh last_name: Gupta - first_name: Calin C full_name: Guet, Calin C id: 47F8433E-F248-11E8-B48F-1D18A9856A87 last_name: Guet orcid: 0000-0001-6220-2052 - first_name: Bruce full_name: Levin, Bruce last_name: Levin citation: ama: Chaudhry W, Pleska M, Shah N, et al. Leaky resistance and the conditions for the existence of lytic bacteriophage. PLoS Biology. 2018;16(8). doi:10.1371/journal.pbio.2005971 apa: Chaudhry, W., Pleska, M., Shah, N., Weiss, H., Mccall, I., Meyer, J., … Levin, B. (2018). Leaky resistance and the conditions for the existence of lytic bacteriophage. PLoS Biology. Public Library of Science. https://doi.org/10.1371/journal.pbio.2005971 chicago: Chaudhry, Waqas, Maros Pleska, Nilang Shah, Howard Weiss, Ingrid Mccall, Justin Meyer, Animesh Gupta, Calin C Guet, and Bruce Levin. “Leaky Resistance and the Conditions for the Existence of Lytic Bacteriophage.” PLoS Biology. Public Library of Science, 2018. https://doi.org/10.1371/journal.pbio.2005971. ieee: W. Chaudhry et al., “Leaky resistance and the conditions for the existence of lytic bacteriophage,” PLoS Biology, vol. 16, no. 8. Public Library of Science, 2018. ista: Chaudhry W, Pleska M, Shah N, Weiss H, Mccall I, Meyer J, Gupta A, Guet CC, Levin B. 2018. Leaky resistance and the conditions for the existence of lytic bacteriophage. PLoS Biology. 16(8), 2005971. mla: Chaudhry, Waqas, et al. “Leaky Resistance and the Conditions for the Existence of Lytic Bacteriophage.” PLoS Biology, vol. 16, no. 8, 2005971, Public Library of Science, 2018, doi:10.1371/journal.pbio.2005971. short: W. Chaudhry, M. Pleska, N. Shah, H. Weiss, I. Mccall, J. Meyer, A. Gupta, C.C. Guet, B. Levin, PLoS Biology 16 (2018). date_created: 2018-12-11T11:44:32Z date_published: 2018-08-16T00:00:00Z date_updated: 2023-09-13T08:45:41Z day: '16' ddc: - '570' department: - _id: CaGu doi: 10.1371/journal.pbio.2005971 external_id: isi: - '000443383300024' file: - access_level: open_access checksum: 527076f78265cd4ea192cd1569851587 content_type: application/pdf creator: dernst date_created: 2018-12-17T12:55:31Z date_updated: 2020-07-14T12:48:10Z file_id: '5706' file_name: 2018_Plos_Chaudhry.pdf file_size: 4007095 relation: main_file file_date_updated: 2020-07-14T12:48:10Z has_accepted_license: '1' intvolume: ' 16' isi: 1 issue: '8' language: - iso: eng month: '08' oa: 1 oa_version: Published Version publication: PLoS Biology publication_status: published publisher: Public Library of Science publist_id: '7972' quality_controlled: '1' related_material: record: - id: '9810' relation: research_data status: public scopus_import: '1' status: public title: Leaky resistance and the conditions for the existence of lytic bacteriophage tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 volume: 16 year: '2018' ... --- _id: '9810' article_processing_charge: No author: - first_name: Waqas full_name: Chaudhry, Waqas last_name: Chaudhry - first_name: Maros full_name: Pleska, Maros id: 4569785E-F248-11E8-B48F-1D18A9856A87 last_name: Pleska orcid: 0000-0001-7460-7479 - first_name: Nilang full_name: Shah, Nilang last_name: Shah - first_name: Howard full_name: Weiss, Howard last_name: Weiss - first_name: Ingrid full_name: Mccall, Ingrid last_name: Mccall - first_name: Justin full_name: Meyer, Justin last_name: Meyer - first_name: Animesh full_name: Gupta, Animesh last_name: Gupta - first_name: Calin C full_name: Guet, Calin C id: 47F8433E-F248-11E8-B48F-1D18A9856A87 last_name: Guet orcid: 0000-0001-6220-2052 - first_name: Bruce full_name: Levin, Bruce last_name: Levin citation: ama: Chaudhry W, Pleska M, Shah N, et al. Numerical data used in figures. 2018. doi:10.1371/journal.pbio.2005971.s008 apa: Chaudhry, W., Pleska, M., Shah, N., Weiss, H., Mccall, I., Meyer, J., … Levin, B. (2018). Numerical data used in figures. Public Library of Science. https://doi.org/10.1371/journal.pbio.2005971.s008 chicago: Chaudhry, Waqas, Maros Pleska, Nilang Shah, Howard Weiss, Ingrid Mccall, Justin Meyer, Animesh Gupta, Calin C Guet, and Bruce Levin. “Numerical Data Used in Figures.” Public Library of Science, 2018. https://doi.org/10.1371/journal.pbio.2005971.s008. ieee: W. Chaudhry et al., “Numerical data used in figures.” Public Library of Science, 2018. ista: Chaudhry W, Pleska M, Shah N, Weiss H, Mccall I, Meyer J, Gupta A, Guet CC, Levin B. 2018. Numerical data used in figures, Public Library of Science, 10.1371/journal.pbio.2005971.s008. mla: Chaudhry, Waqas, et al. Numerical Data Used in Figures. Public Library of Science, 2018, doi:10.1371/journal.pbio.2005971.s008. short: W. Chaudhry, M. Pleska, N. Shah, H. Weiss, I. Mccall, J. Meyer, A. Gupta, C.C. Guet, B. Levin, (2018). date_created: 2021-08-06T12:43:44Z date_published: 2018-08-16T00:00:00Z date_updated: 2023-09-13T08:45:41Z day: '16' department: - _id: CaGu doi: 10.1371/journal.pbio.2005971.s008 month: '08' oa_version: Published Version publisher: Public Library of Science related_material: record: - id: '82' relation: used_in_publication status: public status: public title: Numerical data used in figures type: research_data_reference user_id: 6785fbc1-c503-11eb-8a32-93094b40e1cf year: '2018' ... --- _id: '457' abstract: - lang: eng text: Temperate bacteriophages integrate in bacterial genomes as prophages and represent an important source of genetic variation for bacterial evolution, frequently transmitting fitness-augmenting genes such as toxins responsible for virulence of major pathogens. However, only a fraction of bacteriophage infections are lysogenic and lead to prophage acquisition, whereas the majority are lytic and kill the infected bacteria. Unless able to discriminate lytic from lysogenic infections, mechanisms of immunity to bacteriophages are expected to act as a double-edged sword and increase the odds of survival at the cost of depriving bacteria of potentially beneficial prophages. We show that although restriction-modification systems as mechanisms of innate immunity prevent both lytic and lysogenic infections indiscriminately in individual bacteria, they increase the number of prophage-acquiring individuals at the population level. We find that this counterintuitive result is a consequence of phage-host population dynamics, in which restriction-modification systems delay infection onset until bacteria reach densities at which the probability of lysogeny increases. These results underscore the importance of population-level dynamics as a key factor modulating costs and benefits of immunity to temperate bacteriophages article_processing_charge: No author: - first_name: Maros full_name: Pleska, Maros id: 4569785E-F248-11E8-B48F-1D18A9856A87 last_name: Pleska orcid: 0000-0001-7460-7479 - first_name: Moritz full_name: Lang, Moritz id: 29E0800A-F248-11E8-B48F-1D18A9856A87 last_name: Lang - first_name: Dominik full_name: Refardt, Dominik last_name: Refardt - first_name: Bruce full_name: Levin, Bruce last_name: Levin - first_name: Calin C full_name: Guet, Calin C id: 47F8433E-F248-11E8-B48F-1D18A9856A87 last_name: Guet orcid: 0000-0001-6220-2052 citation: ama: Pleska M, Lang M, Refardt D, Levin B, Guet CC. Phage-host population dynamics promotes prophage acquisition in bacteria with innate immunity. Nature Ecology and Evolution. 2018;2(2):359-366. doi:10.1038/s41559-017-0424-z apa: Pleska, M., Lang, M., Refardt, D., Levin, B., & Guet, C. C. (2018). Phage-host population dynamics promotes prophage acquisition in bacteria with innate immunity. Nature Ecology and Evolution. Springer Nature. https://doi.org/10.1038/s41559-017-0424-z chicago: Pleska, Maros, Moritz Lang, Dominik Refardt, Bruce Levin, and Calin C Guet. “Phage-Host Population Dynamics Promotes Prophage Acquisition in Bacteria with Innate Immunity.” Nature Ecology and Evolution. Springer Nature, 2018. https://doi.org/10.1038/s41559-017-0424-z. ieee: M. Pleska, M. Lang, D. Refardt, B. Levin, and C. C. Guet, “Phage-host population dynamics promotes prophage acquisition in bacteria with innate immunity,” Nature Ecology and Evolution, vol. 2, no. 2. Springer Nature, pp. 359–366, 2018. ista: Pleska M, Lang M, Refardt D, Levin B, Guet CC. 2018. Phage-host population dynamics promotes prophage acquisition in bacteria with innate immunity. Nature Ecology and Evolution. 2(2), 359–366. mla: Pleska, Maros, et al. “Phage-Host Population Dynamics Promotes Prophage Acquisition in Bacteria with Innate Immunity.” Nature Ecology and Evolution, vol. 2, no. 2, Springer Nature, 2018, pp. 359–66, doi:10.1038/s41559-017-0424-z. short: M. Pleska, M. Lang, D. Refardt, B. Levin, C.C. Guet, Nature Ecology and Evolution 2 (2018) 359–366. date_created: 2018-12-11T11:46:35Z date_published: 2018-02-01T00:00:00Z date_updated: 2023-09-15T12:04:57Z day: '01' department: - _id: CaGu - _id: GaTk doi: 10.1038/s41559-017-0424-z ec_funded: 1 external_id: isi: - '000426516400027' intvolume: ' 2' isi: 1 issue: '2' language: - iso: eng month: '02' oa_version: None page: 359 - 366 project: - _id: 25681D80-B435-11E9-9278-68D0E5697425 call_identifier: FP7 grant_number: '291734' name: International IST Postdoc Fellowship Programme - _id: 251BCBEC-B435-11E9-9278-68D0E5697425 grant_number: RGY0079/2011 name: Multi-Level Conflicts in Evolutionary Dynamics of Restriction-Modification Systems (HFSP Young investigators' grant) - _id: 251D65D8-B435-11E9-9278-68D0E5697425 grant_number: '24210' name: Effects of Stochasticity on the Function of Restriction-Modi cation Systems at the Single-Cell Level (DOC Fellowship) publication: Nature Ecology and Evolution publication_status: published publisher: Springer Nature publist_id: '7364' quality_controlled: '1' related_material: record: - id: '202' relation: dissertation_contains status: public scopus_import: '1' status: public title: Phage-host population dynamics promotes prophage acquisition in bacteria with innate immunity type: journal_article user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 volume: 2 year: '2018' ... --- _id: '9847' abstract: - lang: eng text: information on culture conditions, phage mutagenesis, verification and lysate preparation; Raw data article_processing_charge: No author: - first_name: Maros full_name: Pleska, Maros id: 4569785E-F248-11E8-B48F-1D18A9856A87 last_name: Pleska orcid: 0000-0001-7460-7479 - first_name: Calin C full_name: Guet, Calin C id: 47F8433E-F248-11E8-B48F-1D18A9856A87 last_name: Guet orcid: 0000-0001-6220-2052 citation: ama: Pleska M, Guet CC. Supplementary materials and methods; Full data set from effects of mutations in phage restriction sites during escape from restriction–modification. 2017. doi:10.6084/m9.figshare.5633917.v1 apa: Pleska, M., & Guet, C. C. (2017). Supplementary materials and methods; Full data set from effects of mutations in phage restriction sites during escape from restriction–modification. The Royal Society. https://doi.org/10.6084/m9.figshare.5633917.v1 chicago: Pleska, Maros, and Calin C Guet. “Supplementary Materials and Methods; Full Data Set from Effects of Mutations in Phage Restriction Sites during Escape from Restriction–Modification.” The Royal Society, 2017. https://doi.org/10.6084/m9.figshare.5633917.v1. ieee: M. Pleska and C. C. Guet, “Supplementary materials and methods; Full data set from effects of mutations in phage restriction sites during escape from restriction–modification.” The Royal Society, 2017. ista: Pleska M, Guet CC. 2017. Supplementary materials and methods; Full data set from effects of mutations in phage restriction sites during escape from restriction–modification, The Royal Society, 10.6084/m9.figshare.5633917.v1. mla: Pleska, Maros, and Calin C. Guet. Supplementary Materials and Methods; Full Data Set from Effects of Mutations in Phage Restriction Sites during Escape from Restriction–Modification. The Royal Society, 2017, doi:10.6084/m9.figshare.5633917.v1. short: M. Pleska, C.C. Guet, (2017). date_created: 2021-08-09T13:54:38Z date_published: 2017-11-27T00:00:00Z date_updated: 2023-02-23T12:29:44Z day: '27' department: - _id: CaGu doi: 10.6084/m9.figshare.5633917.v1 main_file_link: - open_access: '1' url: https://doi.org/10.6084/m9.figshare.5633917.v1 month: '11' oa: 1 oa_version: Published Version publisher: The Royal Society related_material: record: - id: '561' relation: used_in_publication status: public status: public title: Supplementary materials and methods; Full data set from effects of mutations in phage restriction sites during escape from restriction–modification type: research_data_reference user_id: 6785fbc1-c503-11eb-8a32-93094b40e1cf year: '2017' ... --- _id: '561' abstract: - lang: eng text: Restriction–modification systems are widespread genetic elements that protect bacteria from bacteriophage infections by recognizing and cleaving heterologous DNA at short, well-defined sequences called restriction sites. Bioinformatic evidence shows that restriction sites are significantly underrepresented in bacteriophage genomes, presumably because bacteriophages with fewer restriction sites are more likely to escape cleavage by restriction–modification systems. However, how mutations in restriction sites affect the likelihood of bacteriophage escape is unknown. Using the bacteriophage l and the restriction–modification system EcoRI, we show that while mutation effects at different restriction sites are unequal, they are independent. As a result, the probability of bacteriophage escape increases with each mutated restriction site. Our results experimentally support the role of restriction site avoidance as a response to selection imposed by restriction–modification systems and offer an insight into the events underlying the process of bacteriophage escape. acknowledgement: This work was funded by an HFSP Young Investigators' grant RGY0079/2011 (C.C.G.). M.P. is a recipient of a DOC Fellowship of the Austrian Academy of Science at the Institute of Science and Technology Austria. article_number: '20170646' article_processing_charge: No article_type: original author: - first_name: Maros full_name: Pleska, Maros id: 4569785E-F248-11E8-B48F-1D18A9856A87 last_name: Pleska orcid: 0000-0001-7460-7479 - first_name: Calin C full_name: Guet, Calin C id: 47F8433E-F248-11E8-B48F-1D18A9856A87 last_name: Guet orcid: 0000-0001-6220-2052 citation: ama: Pleska M, Guet CC. Effects of mutations in phage restriction sites during escape from restriction–modification. Biology Letters. 2017;13(12). doi:10.1098/rsbl.2017.0646 apa: Pleska, M., & Guet, C. C. (2017). Effects of mutations in phage restriction sites during escape from restriction–modification. Biology Letters. The Royal Society. https://doi.org/10.1098/rsbl.2017.0646 chicago: Pleska, Maros, and Calin C Guet. “Effects of Mutations in Phage Restriction Sites during Escape from Restriction–Modification.” Biology Letters. The Royal Society, 2017. https://doi.org/10.1098/rsbl.2017.0646. ieee: M. Pleska and C. C. Guet, “Effects of mutations in phage restriction sites during escape from restriction–modification,” Biology Letters, vol. 13, no. 12. The Royal Society, 2017. ista: Pleska M, Guet CC. 2017. Effects of mutations in phage restriction sites during escape from restriction–modification. Biology Letters. 13(12), 20170646. mla: Pleska, Maros, and Calin C. Guet. “Effects of Mutations in Phage Restriction Sites during Escape from Restriction–Modification.” Biology Letters, vol. 13, no. 12, 20170646, The Royal Society, 2017, doi:10.1098/rsbl.2017.0646. short: M. Pleska, C.C. Guet, Biology Letters 13 (2017). date_created: 2018-12-11T11:47:11Z date_published: 2017-12-01T00:00:00Z date_updated: 2023-09-07T11:59:32Z day: '01' department: - _id: CaGu doi: 10.1098/rsbl.2017.0646 external_id: pmid: - '29237814' intvolume: ' 13' issue: '12' language: - iso: eng main_file_link: - open_access: '1' url: https://doi.org/10.1098/rsbl.2017.0646 month: '12' oa: 1 oa_version: Published Version pmid: 1 project: - _id: 251BCBEC-B435-11E9-9278-68D0E5697425 grant_number: RGY0079/2011 name: Multi-Level Conflicts in Evolutionary Dynamics of Restriction-Modification Systems (HFSP Young investigators' grant) - _id: 251D65D8-B435-11E9-9278-68D0E5697425 grant_number: '24210' name: Effects of Stochasticity on the Function of Restriction-Modi cation Systems at the Single-Cell Level (DOC Fellowship) publication: Biology Letters publication_identifier: issn: - 1744-9561 publication_status: published publisher: The Royal Society publist_id: '7253' quality_controlled: '1' related_material: record: - id: '9847' relation: research_data status: public - id: '202' relation: dissertation_contains status: public scopus_import: '1' status: public title: Effects of mutations in phage restriction sites during escape from restriction–modification type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 13 year: '2017' ... --- _id: '202' abstract: - lang: eng text: 'Restriction-modification (RM) represents the simplest and possibly the most widespread mechanism of self/non-self discrimination in nature. In order to provide bacteria with immunity against bacteriophages and other parasitic genetic elements, RM systems rely on a balance between two enzymes: the restriction enzyme, which cleaves non-self DNA at specific restriction sites, and the modification enzyme, which tags the host’s DNA as self and thus protects it from cleavage. In this thesis, I use population and single-cell level experiments in combination with mathematical modeling to study different aspects of the interplay between RM systems, bacteria and bacteriophages. First, I analyze how mutations in phage restriction sites affect the probability of phage escape – an inherently stochastic process, during which phages accidently get modified instead of restricted. Next, I use single-cell experiments to show that RM systems can, with a low probability, attack the genome of their bacterial host and that this primitive form of autoimmunity leads to a tradeoff between the evolutionary cost and benefit of RM systems. Finally, I investigate the nature of interactions between bacteria, RM systems and temperate bacteriophages to find that, as a consequence of phage escape and its impact on population dynamics, RM systems can promote acquisition of symbiotic bacteriophages, rather than limit it. The results presented here uncover new fundamental biological properties of RM systems and highlight their importance in the ecology and evolution of bacteria, bacteriophages and their interactions.' acknowledgement: "During my PhD studies, I received help from many people, all of which unfortunately cannot be listed here. I thank them deeply and hope that I never made them regret their kindness.\r\nI would like to express my deepest gratitude to Călin Guet, who went far beyond his responsibilities as an advisor and was to me also a great mentor and a friend. Călin never questioned my potential or lacked compassion and I cannot thank him enough for cultivating in me an independent scientist. I was amazed by his ability to recognize the most fascinating scientific problems in objects of study that others would find mundane. I hope I adopted at least a fraction of this ability.\r\nI will be forever grateful to Bruce Levin for all his support and especially for giving me the best possible example of how one can practice excellent science with humor and style. Working with Bruce was a true privilege.\r\nI thank Jonathan Bollback and Gašper Tkačik for serving in my PhD committee and the Austrian Academy of Science for funding my PhD research via the DOC fellowship.\r\nI thank all our lab members: Tobias Bergmiller for his guidance, especially in the first years of my research, and for being a good friend throughout; Remy Chait for staying in the lab at unreasonable hours and for the good laughs at bad jokes we shared; Anna Staron for supportively listening to my whines whenever I had to run a gel; Magdalena Steinrück for her pioneering work in the lab; Kathrin Tomasek for keeping the entropic forces in check and for her FACS virtuosity; Isabella Tomanek for always being nice to me, no matter how much bench space I took from her.\r\nI thank all my collaborators: Reiko Okura and Yuichi Wakamoto for performing and analyzing the microfluidic experiments; Long Qian and Edo Kussell for their bioinformatics analysis; Dominik Refardt for the λ kan phage; Moritz for his help with the mathematical modeling. I thank Fabienne Jesse for her tireless editorial work on all our manuscripts.\r\nFinally, I would like to thank my family and especially my wife Edita, who sacrificed a lot so that I can pursue my goals and dreams.\r\n" alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Maros full_name: Pleska, Maros id: 4569785E-F248-11E8-B48F-1D18A9856A87 last_name: Pleska orcid: 0000-0001-7460-7479 citation: ama: Pleska M. Biology of restriction-modification systems at the single-cell and population level. 2017. doi:10.15479/AT:ISTA:th_916 apa: Pleska, M. (2017). Biology of restriction-modification systems at the single-cell and population level. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:th_916 chicago: Pleska, Maros. “Biology of Restriction-Modification Systems at the Single-Cell and Population Level.” Institute of Science and Technology Austria, 2017. https://doi.org/10.15479/AT:ISTA:th_916. ieee: M. Pleska, “Biology of restriction-modification systems at the single-cell and population level,” Institute of Science and Technology Austria, 2017. ista: Pleska M. 2017. Biology of restriction-modification systems at the single-cell and population level. Institute of Science and Technology Austria. mla: Pleska, Maros. Biology of Restriction-Modification Systems at the Single-Cell and Population Level. Institute of Science and Technology Austria, 2017, doi:10.15479/AT:ISTA:th_916. short: M. Pleska, Biology of Restriction-Modification Systems at the Single-Cell and Population Level, Institute of Science and Technology Austria, 2017. date_created: 2018-12-11T11:45:10Z date_published: 2017-10-01T00:00:00Z date_updated: 2023-09-15T12:04:56Z day: '01' ddc: - '576' - '579' degree_awarded: PhD department: - _id: CaGu doi: 10.15479/AT:ISTA:th_916 file: - access_level: open_access checksum: 33cfb59674e91f82e3738396d3fb3776 content_type: application/pdf creator: system date_created: 2018-12-12T10:08:48Z date_updated: 2020-07-14T12:45:24Z file_id: '4710' file_name: IST-2018-916-v1+3_2017_Pleska_Maros_Thesis.pdf file_size: 18569590 relation: main_file - access_level: closed checksum: dcc239968decb233e7f98cf1083d8c26 content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document creator: dernst date_created: 2019-04-05T08:33:14Z date_updated: 2020-07-14T12:45:24Z file_id: '6204' file_name: 2017_Pleska_Maros_Thesis.docx file_size: 2801649 relation: source_file file_date_updated: 2020-07-14T12:45:24Z has_accepted_license: '1' language: - iso: eng month: '10' oa: 1 oa_version: Published Version page: '126' project: - _id: 251D65D8-B435-11E9-9278-68D0E5697425 grant_number: '24210' name: Effects of Stochasticity on the Function of Restriction-Modi cation Systems at the Single-Cell Level (DOC Fellowship) publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria publist_id: '7711' pubrep_id: '916' related_material: record: - id: '1243' relation: part_of_dissertation status: public - id: '561' relation: part_of_dissertation status: public - id: '457' relation: part_of_dissertation status: public status: public supervisor: - first_name: Calin C full_name: Guet, Calin C id: 47F8433E-F248-11E8-B48F-1D18A9856A87 last_name: Guet orcid: 0000-0001-6220-2052 title: Biology of restriction-modification systems at the single-cell and population level tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2017' ... --- _id: '1243' abstract: - lang: eng text: Restriction-modification (RM) systems represent a minimal and ubiquitous biological system of self/non-self discrimination in prokaryotes [1], which protects hosts from exogenous DNA [2]. The mechanism is based on the balance between methyltransferase (M) and cognate restriction endonuclease (R). M tags endogenous DNA as self by methylating short specific DNA sequences called restriction sites, whereas R recognizes unmethylated restriction sites as non-self and introduces a double-stranded DNA break [3]. Restriction sites are significantly underrepresented in prokaryotic genomes [4-7], suggesting that the discrimination mechanism is imperfect and occasionally leads to autoimmunity due to self-DNA cleavage (self-restriction) [8]. Furthermore, RM systems can promote DNA recombination [9] and contribute to genetic variation in microbial populations, thus facilitating adaptive evolution [10]. However, cleavage of self-DNA by RM systems as elements shaping prokaryotic genomes has not been directly detected, and its cause, frequency, and outcome are unknown. We quantify self-restriction caused by two RM systems of Escherichia coli and find that, in agreement with levels of restriction site avoidance, EcoRI, but not EcoRV, cleaves self-DNA at a measurable rate. Self-restriction is a stochastic process, which temporarily induces the SOS response, and is followed by DNA repair, maintaining cell viability. We find that RM systems with higher restriction efficiency against bacteriophage infections exhibit a higher rate of self-restriction, and that this rate can be further increased by stochastic imbalance between R and M. Our results identify molecular noise in RM systems as a factor shaping prokaryotic genomes. acknowledgement: This work was funded by an HFSP Young Investigators’ grant. M.P. is a recipient of a DOC Fellowship of the Austrian Academy of Science at the Institute of Science and Technology Austria. R.O. and Y.W. were supported by the Platform for Dynamic Approaches to Living System from MEXT, Japan. We wish to thank I. Kobayashi for providing us with the EcoRI and EcoRV plasmids, and A. Campbell for providing us with the λ vir phage. We thank D. Siekhaus and C. Uhler and members of the C.C.G. and J.P. Bollback laboratories for in-depth discussions. We thank B. Stern for comments on an earlier version of the manuscript. We especially thank B.R. Levin for advice and comments, and the anonymous reviewers for significantly improving the manuscript. author: - first_name: Maros full_name: Pleska, Maros id: 4569785E-F248-11E8-B48F-1D18A9856A87 last_name: Pleska orcid: 0000-0001-7460-7479 - first_name: Long full_name: Qian, Long last_name: Qian - first_name: Reiko full_name: Okura, Reiko last_name: Okura - first_name: Tobias full_name: Bergmiller, Tobias id: 2C471CFA-F248-11E8-B48F-1D18A9856A87 last_name: Bergmiller orcid: 0000-0001-5396-4346 - first_name: Yuichi full_name: Wakamoto, Yuichi last_name: Wakamoto - first_name: Edo full_name: Kussell, Edo last_name: Kussell - first_name: Calin C full_name: Guet, Calin C id: 47F8433E-F248-11E8-B48F-1D18A9856A87 last_name: Guet orcid: 0000-0001-6220-2052 citation: ama: Pleska M, Qian L, Okura R, et al. Bacterial autoimmunity due to a restriction-modification system. Current Biology. 2016;26(3):404-409. doi:10.1016/j.cub.2015.12.041 apa: Pleska, M., Qian, L., Okura, R., Bergmiller, T., Wakamoto, Y., Kussell, E., & Guet, C. C. (2016). Bacterial autoimmunity due to a restriction-modification system. Current Biology. Cell Press. https://doi.org/10.1016/j.cub.2015.12.041 chicago: Pleska, Maros, Long Qian, Reiko Okura, Tobias Bergmiller, Yuichi Wakamoto, Edo Kussell, and Calin C Guet. “Bacterial Autoimmunity Due to a Restriction-Modification System.” Current Biology. Cell Press, 2016. https://doi.org/10.1016/j.cub.2015.12.041. ieee: M. Pleska et al., “Bacterial autoimmunity due to a restriction-modification system,” Current Biology, vol. 26, no. 3. Cell Press, pp. 404–409, 2016. ista: Pleska M, Qian L, Okura R, Bergmiller T, Wakamoto Y, Kussell E, Guet CC. 2016. Bacterial autoimmunity due to a restriction-modification system. Current Biology. 26(3), 404–409. mla: Pleska, Maros, et al. “Bacterial Autoimmunity Due to a Restriction-Modification System.” Current Biology, vol. 26, no. 3, Cell Press, 2016, pp. 404–09, doi:10.1016/j.cub.2015.12.041. short: M. Pleska, L. Qian, R. Okura, T. Bergmiller, Y. Wakamoto, E. Kussell, C.C. Guet, Current Biology 26 (2016) 404–409. date_created: 2018-12-11T11:50:54Z date_published: 2016-02-08T00:00:00Z date_updated: 2023-09-07T11:59:32Z day: '08' department: - _id: CaGu doi: 10.1016/j.cub.2015.12.041 intvolume: ' 26' issue: '3' language: - iso: eng month: '02' oa_version: None page: 404 - 409 project: - _id: 251D65D8-B435-11E9-9278-68D0E5697425 grant_number: '24210' name: Effects of Stochasticity on the Function of Restriction-Modi cation Systems at the Single-Cell Level (DOC Fellowship) publication: Current Biology publication_status: published publisher: Cell Press publist_id: '6087' quality_controlled: '1' related_material: record: - id: '202' relation: dissertation_contains status: public scopus_import: 1 status: public title: Bacterial autoimmunity due to a restriction-modification system type: journal_article user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87 volume: 26 year: '2016' ...