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Social Evolution and Social Engineering of bacterial Infections

Periodic Reporting for period 3 - SESE (Social Evolution and Social Engineering of bacterial Infections)

Reporting period: 2018-08-01 to 2020-01-31

"Micro-organisms were believed until recently to live independent, unicellular lives but are now understood to rely on complex systems of social behaviours for survival. In pathogenic bacteria, cooperation and communication between cells leads to increased virulence and the understanding of how these behaviours evolve is of fundamental importance to the future of human health. The aim of my ERC-funded research project is to understand the role of social interactions in shaping behaviour of bacterial cells infecting human hosts. I have taken an interdisciplinary approach, in collaboration with clinical microbiologists, towards completion of three primary objectives: (1) I have developed Pseudomonas aeruginosa infections of the cystic fibrosis lungs as a model system for investigating social behaviour in long-term bacterial infections and aim now to extend this work to Staph. aureus infections of nasal passages; (2) I have provided the first definitive evidence in support of social interactions driving dynamics of social behaviour in long-term infections and (3) I have worked to provide proof of principle for a strategy to exploit social dynamics in the treatment of bacterial infection. This third objective applies evolutionary theory to the clinical challenge of bacterial infection to develop novel intervention strategies beyond the scope of conventional medicine, which is based primarily on understanding of bacteria at the cellular level. The WHO recently published a list of bacterial species of special concern due to the emergence of antibiotic resistance (www.who.int/mediacentre/news/releases/217/bacteria-antibiotics-needed/en/). The ERC has funded me to work on one of three species listed under ""critical priority"" - Pseudomonas aeruginosa."
"Objective 1: Developing a model system for studying long-term dynamics of social behaviour in bacteria

This objective is mainly completed. I have worked with collaborators Professor Soeren Molin and Dr Helle Krogh Johansen in the Danish Technical University to characterise social traits of interest in over 300 clinical isolates from sputa samples of patients with cystic fibrosis. These traits are of clinical interest but are also amenable to experimental evolution study in the lab. We have characterised (1) iron uptake systems both experimentally and through genome sequence analysis. This includes the pyoverdine system that relies on sharing of public goods, as outlined in my proposal but has also been expanded to include alternative iron uptake systems that rely on other non-social mechanisms. This line of research has expanded to explore the evolution of iron uptake in the lung in more detail and also to explore potential co-evolutionary processes occurring between different iron uptake systems.. (2) antibiotic resistance profiles: to date, this work has focussed on beta-lactamase production that involves the release of enzymes that destroy beta-lactam antibiotics into the environment surrounding the cell. Through our collaboration with Prof Molin and Dr Krogh Johansen, we have been able to analyse antibiotic resistance behaviour in relation to duration of infection and treatment regime experienced by patients from whom they were isolated. We have recently arranged to spend time working the laboratory of Professor Derrick Crook at the John Radcliffe Hospital in Oxford (brought forward due to the loss of our building! (www.bbc.co.uk/news/uk-england-oxfordshire-38934959) to establish a similar collect of Staphylococcus aureus isolates collected as part of a carriage study in the nasal passages of subjects that may or not be symptomatic of infection. this will allow us to broaden the scope of our project to other species of bacteria, beyond a single study system.


Objective 2: To investigate effects of social evolution in pathogenic bacteria

In brief, we have already shown that the answer to this question is yes. We were able to provide definitive evidence from sequence analysis of genes involved in pyoverdine-mediated iron uptake system to show that reduced pyoverdine production over time was due to invasion by cheats (see Andersen et al. 2015 PNAS). We are now developing this line of research towards the understanding of what happens to ""iron starved' populations of bacterial cells in the lung, once pyoverdine has been lost from the population. The implications of this finding are potentially far-reaching: behaviour observed in bacterial cells is typically interpreted as a response to the host environment and assumed to be optimised for survival in the host environment. We were able to show that competition with conspecifics can drive beneficial traits (such as pyoverdine production) extinct. This is a well-known consequence of cooperator cheat dynamics, also captured in the Prisoner's Dilemma and the so-called Tragedy of the Commons.

As well as cooperative behaviour, we have also examined consequence of harming social behaviours in clinical strains. Specifically, we have produced evidence to show how bacteriocin production changes through duration of infection. We have found that cells become less toxic to one another through time in infection and are working to explain this pattern in terms of selection pressures operating on maintenance of effective but potentially costly ""protection"" mechanisms. We have recently expanded this line of enquiry to include alternative killing mechanisms - specifically contact dependent killing involving the Type VI secretion system.

We are currently finalising experiments designed to investigate consequences of social interaction on another trait - antibiotic resistance through beta-lactamase production. It is possible, that cooperation facilitates the persistence of ""susceptible"" cells"
ERC support has already supported work in my lab which demands broad questioning of assumptions in the interpretation of behaviour in bacterial cells causing infection. This could have implications for the development of future anti-bacterial treatment strategies. For example, as iron systems are shut-down in bacteria over time in long-term lung infection, we might assume that a drug designed to withhold iron would be ineffective - bacterial cells do not appear to be scavenging iron. However, our results show that such a drug is likely to be highly effective - iron uptake systems are shut down despite a metabolic demand for iron. We have provided evidence for this through analysis of genome sequence in situ.