@article{6784,
  abstract     = {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.},
  author       = {Ruess, Jakob and Pleska, Maros and Guet, Calin C and Tkačik, Gašper},
  issn         = {1553-7358},
  journal      = {PLoS Computational Biology},
  number       = {7},
  publisher    = {Public Library of Science},
  title        = {{Molecular noise of innate immunity shapes bacteria-phage ecologies}},
  doi          = {10.1371/journal.pcbi.1007168},
  volume       = {15},
  year         = {2019},
}

@article{457,
  abstract     = {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},
  author       = {Pleska, Maros and Lang, Moritz and Refardt, Dominik and Levin, Bruce and Guet, Calin C},
  journal      = {Nature Ecology and Evolution},
  number       = {2},
  pages        = {359 -- 366},
  publisher    = {Springer Nature},
  title        = {{Phage-host population dynamics promotes prophage acquisition in bacteria with innate immunity}},
  doi          = {10.1038/s41559-017-0424-z},
  volume       = {2},
  year         = {2018},
}

@phdthesis{202,
  abstract     = {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.},
  author       = {Pleska, Maros},
  issn         = {2663-337X},
  pages        = {126},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{Biology of restriction-modification systems at the single-cell and population level}},
  doi          = {10.15479/AT:ISTA:th_916},
  year         = {2017},
}

@article{561,
  abstract     = {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.},
  author       = {Pleska, Maros and Guet, Calin C},
  issn         = {1744-9561},
  journal      = {Biology Letters},
  number       = {12},
  publisher    = {The Royal Society},
  title        = {{Effects of mutations in phage restriction sites during escape from restriction–modification}},
  doi          = {10.1098/rsbl.2017.0646},
  volume       = {13},
  year         = {2017},
}

@article{1243,
  abstract     = {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.},
  author       = {Pleska, Maros and Qian, Long and Okura, Reiko and Bergmiller, Tobias and Wakamoto, Yuichi and Kussell, Edo and Guet, Calin C},
  journal      = {Current Biology},
  number       = {3},
  pages        = {404 -- 409},
  publisher    = {Cell Press},
  title        = {{Bacterial autoimmunity due to a restriction-modification system}},
  doi          = {10.1016/j.cub.2015.12.041},
  volume       = {26},
  year         = {2016},
}