Evolution of cooperative resistance in microbial populations subject to fluctuating environments

Why does cooperation abound in Nature? Why are there so many coexisting species? These are issues of paramount importance and challenges to Darwinian evolution. In many microbial communities, it has been found that cooperative behaviour is associated with variation of environmental conditions.

Microbial communities evolve in volatile environments that often fluctuate between mild and harsh conditions, e.g. with sudden and radical changes in the concentration of toxins and nutrients. The resulting environmental variability greatly influences the population evolution, and the ability of species to cooperate and coexist. These are key characteristics of ecosystems that have direct applications in subjects of great societal concern, like the evolution of antimicrobial resistance (AMR). Drug resistance can often be viewed as a cooperative behaviour that is critically influenced by environmental and demographic fluctuations. Understanding how the coexistence of resistant and sensitive cells is affected by environmental changes and randomness variability are thus central questions in the effort of modelling the evolution of AMR.

While population dynamics is classically studied using differential equations in static environments, we will mathematically model the evolution of microbial communities subject to environmental and demographic fluctuations. Motivated by the application to the evolution of AMR, we will focus on models of competing species in the presence of varying toxin and/or nutrient concentrations. The main features of our modelling approach are the fluctuating size of populations, and eco-evolutionary coupling.

Objectives/methods:

By combining analytical techniques and simulations, we will study the eco-evolutionary dynamics of cooperative AMR in 1) well-mixed and 2) metapopulation settings.

1) The mechanism of AMR can often be regarded as a cooperative behaviour. Resistant cells may carry resistance plasmids expressing a "resistance enzyme" inactivating the drug, and offering them immunity for a metabolic cost. Sensitive cells do not pay this metabolic cost, but their growth is hampered by antibiotics. Yet, above a certain concentration threshold of resistant cells, the protection offered by the enzymes is shared with sensitive cells at no metabolic cost, yielding a cooperative behaviour. Hence, below a cooperation threshold, only the resistant cells benefit from the resistance enzymes: They outcompete sensitive bacteria and spread. However, when there are enough resistant cells (above the threshold), enzymes become a public good and protect also the sensitive cells that then have a fitness advantage.

We will study how fluctuations shape the eco-evolutionary dynamics of this cooperative AMR mechanism in well-mixed set-ups with time-varying concentrations of nutrients and drugs (harsh/mild conditions).

In particular, we are interested in following questions:
- How does the abundance of resistant cells change in time and with the environment?
- When and how can resistant cells be eradicated?

We plan to introduce novel realistic ingredients: (i) the concentration of antibiotics is non-constant but decreases with that of resistant cells; (ii) the carrying capacity and fitness of the species both vary with the environmental conditions.

2) The life cycle of some microbial communities can be described as a metapopulation model in which a large colony regularly splits into small groups of time-varying sizes. These grow independently and are reunited to form a new generation, restarting the cycle. While metapopulation models have mostly been investigated in static environments, we will study the eco-evolutionary above AMR cooperative behaviour in a life-cycle metapopulation setting with time-varying concentrations of toxin and resources. We will focus on the differences and similarities with the well-mixed case when cells are allowed to migrate from one group to another.