The role of plasmids in bacterial adaptation
Evolution and Systematics of Plants and Fungi
Metabolism, Biochemistry and Genetics of Microorganisms
Plant Cell and Developmental Biology
Final Report Abstract
Plasmids – extra-chromosomal self-replicating DNA elements – are common in bacteria and pivotal in bacterial evolution. While a priori a burden, they may code for adaptive traits, benefitting their host. Plasmids are highly relevant in the context of human health since clinically relevant antibiotic resistance is often encoded on plasmids. In the present work, we developed stochastic mathematical models to understand the role of plasmids in bacterial evolution. In our models, we focused on two key properties of plasmids – the plasmid copy number and horizontal gene transfer. Many plasmids exist in several or even many copies within the bacterial cell (‘multicopy plasmids’). This influences the rate of plasmid-mediated adaptation. With a copy number greater than one, different copies of the plasmid within the same cell may carry different alleles. At cell division, the plasmid copies are distributed to the daughter cells, which then in general have a new genetic composition. We developed a mathematical framework to study the evolutionary dynamics of alleles on multicopy plasmids. Among other results, we showed that a higher copy number increases the probability that rare new alleles, even if beneficial, get lost from the bacterial population due to stochasticity. In collaboration with an experimental group, we compared our theoretical predictions to data from evolution experiments. The comparison shows good agreement and thus confirms our understanding of the allele dynamics on multicopy plasmids. The results could have implications for the optimal drug dose during treatment to avoid resistance evolution. Many types of plasmids are not only vertically transmitted from the mother to the daughter cells but can also horizontally transfer to neighbouring cells through a process called conjugation. This transfer is even possible between cells of different species, enabling genes to cross species boundaries. Conjugation is usually considered to foster adaptation by facilitating the spread of adaptive alleles. Yet, this perspective ignores that plasmids may compete for host cells (so-called incompatible plasmids). This especially applies to wild-type and mutant variants of the same plasmid. We determined the probability that a bacterial population survives harsh environmental change (e.g. antibiotic treatment) due to the appearance of an adaptive ‘rescue’ plasmid, given that a resident plasmid with the same transfer rate is already present. The analysis reveals that under these circumstances, a higher conjugation rate can indeed sometimes reduce the probability of population survival. A caveat to the results is that they require transfer rates to be very high. Commensal bacteria might act as a reservoir of resistance genes, which – if on plasmids – could potentially be transferred to pathogens during treatment. Focusing on the influence of species interactions, we studied resistance evolution in a pathogen population in the presence of commensal bacteria. If commensals are at the same time competitors and donors of a resistance plasmid, it can be beneficial for the pathogen to either foster or hinder their growth, depending on the strengths of the various effects and the antibiotic concentration. Overall, the analysis clearly demonstrates how ecological interactions and feedbacks together with treatment variables such as the drug dose influence resistance evolution. In combination, by focusing on transfer within and across populations respectively, the two projects provide insight into the eco-evolutionary dynamics of bacterial populations in the presence of conjugative plasmid transfer. In the Covid pandemic, we could apply our expertise in evolutionary rescue theory and epidemic modeling to address a question of immediate relevance – vaccination strategies when doses are scarce. When vaccines became available in December 2020, supply was limited, which led Germany and other countries to extend the interval between the first and second doses. With this delay strategy, more people receive at least partial protection more quickly. However, concerns were raised that a large number of partially immune individuals might drive the evolution of vaccine escape mutants. Based on an epidemic model, we showed that such trade-offs do or do not exist, depending on the efficacies of the first doses for susceptibility and transmissibility and the relative resistance probabilities within unvaccinated and partially vaccinated individuals. By going beyond verbal arguments, our analysis thus builds the basis for a better informed discussion and for more detailed future models.
Publications
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Limits to evolutionary rescue by conjugative plasmids. (2022, 12, 11). American Geophysical Union (AGU).
Geoffroy, Félix & Uecker, Hildegard
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Vaccination strategies when vaccines are scarce: on conflicts between reducing the burden and avoiding the evolution of escape mutants. Journal of The Royal Society Interface, 19(191).
Geoffroy, Félix; Traulsen, Arne & Uecker, Hildegard
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Segregational drift hinders the evolution of antibiotic resistance on polyploid replicons. (2023, 2, 1). American Geophysical Union (AGU).
Garoña, Ana; Santer, Mario; Hülter, Nils F.; Uecker, Hildegard & Dagan, Tal
