Positive epistasis between co-infecting plasmids promotes plasmid survival in bacterial populations

Abstract

Plasmids have a key role in the horizontal transfer of genes among bacteria. Although plasmids are catalysts for bacterial evolution, it is challenging to understand how they can persist in bacterial populations over the long term because of the burden they impose on their hosts (the ‘plasmid paradox'). This paradox is especially perplexing in the case of ‘small' plasmids, which are unable to self-transfer by conjugation. Here, for the first time, we investigate how interactions between co-infecting plasmids influence plasmid persistence. Using an experimental model system based on interactions between a diverse assemblage of ‘large' plasmids and a single small plasmid, pNI105, in the pathogenic bacterium Pseudomonas aeruginosa, we demonstrate that positive epistasis minimizes the cost associated with carrying multiple plasmids over the short term and increases the stability of the small plasmid over a longer time scale. In support of these experimental data, bioinformatic analysis showed that associations between small and large plasmids are more common than would be expected owing to chance alone across a range of families of bacteria; more generally, we find that co-infection with multiple plasmids is more common than would be expected owing to chance across a wide range of bacterial phyla. Collectively, these results suggest that positive epistasis promotes plasmid stability in bacterial populations. These findings pave the way for future mechanistic studies aimed at elucidating the molecular mechanisms of plasmid–plasmid interaction, and evolutionary studies aimed at understanding how the coevolution of plasmids drives the spread of plasmid-encoded traits.

Fitness Costs of Plasmids: a Limit to Plasmid Transmission

“…These interactions are common; for example, plasmids can inhibit the conjugative transfer of other coresident plasmids in a process known as fertility inhibition (132). The coexistence of several plasmids in the same host can either potentiate or alleviate plasmidmediated costs, as recently reported for P. aeruginosa, E. coli, and Agrobacterium tumefaciens (21,92,93). In addition to direct MGE interactions, MGEs can influence each other indirectly through their effects on host elements.…”

“…Previous studies revealed that interactions between MGEs play an important part in the fitness effects produced by these elements (21,23,92,95). Moreover, interactions between plasmids and other MGEs can also alter the evolutionary trajectories of plasmid-carrying ASMscience.org/MicrobiolSpectrumbacteria, as recently shown for a plasmid-phage combination in P. fluorescens (129).…”

“…Plasmids can promote bacterial survival in the presence of antibiotics, but, as we have seen, they can also impose a fitness cost when they enter a new bacterial host. The past few years have witnessed growing interest in the fitness effects of plasmids (21)(22)(23)(24)(25)(26)(27)(28)115), and some of the general principles underlying these effects are now beginning to be identified. However, we still are a long way from understanding the specific molecular basis of these costs or being able to predict plasmid fitness effects in a bacterial host.…”

“…The idea underlying this hypothesis is that even if plasmids produce a cost when they first arrive in a new bacterial host, this cost could be alleviated over time through compensatory mutations in the plasmid and/or the host chromosome (20). In recent years, several studies have analyzed the molecular basis of the cost and compensation of plasmids in bacterial populations (21)(22)(23)(24)(25)(26)(27)(28), generating new models of the existence conditions of plasmids (22,24). These studies evaluate a number of selection, transfer, and compensation regimes that could explain plasmid survival in bacterial populations, and have revealed new evidence about the molecular mechanisms underlying the cost of and adaptation to plasmids.…”

Rebooting the genome: The role of negative feedback in horizontal gene transfer

“…Deploying all these systems has a cost, increasing the burden imposed to the host and thus plasmid physiology is conditioned by several trade-offs. 7,[9][10][11] The fundamental law that correlates replication, maintenance and conjugation with their negative effect on host burden is called the Stewart-Levin equilibrium. 12 This equation indicates that plasmid survival depends on a delicate balance between promoting plasmid multiplication and imposing a burden to the host.…”