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Molecular noise of innate immunity shapes bacteria-phage ecologies.

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.

SUBMITTER: Ruess J

PROVIDER: S-EPMC6629147 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Molecular noise of innate immunity shapes bacteria-phage ecologies.

Ruess Jakob J Pleška Maroš M Guet Cǎlin C CC Tkačik Gašper G

PLoS computational biology 20190702 7

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 ...[more]

PMID: 31265463

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Project description:Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), together with associated genes (cas), form the CRISPR-cas adaptive immune system, which can provide resistance to viruses and plasmids in bacteria and archaea. Here, we use mathematical models, population dynamic experiments, and DNA sequence analyses to investigate the host-phage interactions in a model CRISPR-cas system, Streptococcus thermophilus DGCC7710 and its virulent phage 2972. At the molecular level, the bacteriophage-immune mutant bacteria (BIMs) and CRISPR-escape mutant phage (CEMs) obtained in this study are consistent with those anticipated from an iterative model of this adaptive immune system: resistance by the addition of novel spacers and phage evasion of resistance by mutation in matching sequences or flanking motifs. While CRISPR BIMs were readily isolated and CEMs generated at high rates (frequencies in excess of 10(-6)), our population studies indicate that there is more to the dynamics of phage-host interactions and the establishment of a BIM-CEM arms race than predicted from existing assumptions about phage infection and CRISPR-cas immunity. Among the unanticipated observations are: (i) the invasion of phage into populations of BIMs resistant by the acquisition of one (but not two) spacers, (ii) the survival of sensitive bacteria despite the presence of high densities of phage, and (iii) the maintenance of phage-limited communities due to the failure of even two-spacer BIMs to become established in populations with wild-type bacteria and phage. We attribute (i) to incomplete resistance of single-spacer BIMs. Based on the results of additional modeling and experiments, we postulate that (ii) and (iii) can be attributed to the phage infection-associated production of enzymes or other compounds that induce phenotypic phage resistance in sensitive bacteria and kill resistant BIMs. We present evidence in support of these hypotheses and discuss the implications of these results for the ecology and (co)evolution of bacteria and phage.

Project description:To study basal resistance we inoculated tobacco plants with Pseudomonas syringae pv. syringae 61 hrcC mutants (gift of A. Collmer). To compare the expression profiles of basal resistance to hypersensitive response, we used P. syringae pv. syringae 61. Gene activation triggered by the live compatible pathogen P. syringae pv. tabaci was compared to kanamycine-inactivated P. tabaci (10 min in 100 ug/ml KM, then washed 2x in H2O). Water-infiltrated control leaves were used. The aim of another set of experiments was to investigate the influence of various signal transduction pathways on basal resistance. Control plants were infiltrated with P. syringae pv syringae hrcC mutant bacteria. These were compared to treatments, in which the bacterial suspensions were supplemented with inhibitors that can block a specific type of signal transduction pathway. The inhibitors represented Ca2+ signaling, lipid derived signals generated by phospholipase C and A, protein phosphorilation (kinases) and protein degradation (degradation of transcription repressors or activators). The used inhibitors were LaCl3, neomycin, aristolochic acid, K252a and MG115 respectively. 2-2.5 months old tobacco plants (Nicotiana tabacum cv. Samsun nn) were grown in a greenhouse in soil with cca. 16/8 hr light/dark period at 20°C, then in a growth chamber 2 days before and during experiments, under identical conditions. A syringe was used for the injection of bacteria or chemical solutions into the tobacco leaves. At 6 or 48 hours post inoculation, leaf samples were taken, and frozen in liquid nitrogen. Every experiment was carried out in 3 independent replicates. Total RNA was extracted using the Quiagen RNeasy Plant Mini kit and the Quiagen Rnase-free Dnase Set, then re-purified and concentrated on Microcon-30 (Millipore) columns. The concentration and quality of isolated RNA was estimated by measuring its absorbency at 260 and 280 nm and running on 1% agarose gel. Keywords: Direct comparison

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Molecular noise of innate immunity shapes bacteria-phage ecologies.

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Molecular noise of innate immunity shapes bacteria-phage ecologies.

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