Title: Bacterial battles in the bid to dominate in chronic respiratory infections - colonisation warfare of Pseudomonas aeruginosa respiratory strains
Funder: The Academy of Medical Sciences

Abstract: This study aims to confirm the hypothesis that bacterial contact-dependent killing (CDK) systems enable Pseudomonas aeruginosa to dominate the lungs of Cystic Fibrosis (CF) patients through out-competition of the microbiota. My objectives will characterise CDK systems in clinical isolates by assessing: 1)their prevalence and expression; define if these systems are active in patient samples from chronic infections 2)determine their role in interbacterial competition against lung commensals Pseudomonas species or other pathogens 3)define their role in pathogenic bacterial communities or biofilms This project is important as P. aeruginosa is a WHO "priority pathogen" that causes deadly infections and is frequently multi-drug resistant. CF patients have compromised airway defences that lead to bacterial lung infections that become chronic. P. aeruginosa is the most prevalent pathogen in these patients, accelerating lung-function decline and driving mortality. Recently, several bacterial secretion systems have been shown to mediate CDK of rival bacteria and are bacterial virulence factors. These multiprotein nanomachines kill competitors through a mechanism akin to a poisoned spear. The role of these systems in chronic P. aeruginosa infection in humans is unknown. Building on my expertise and preliminary data, I hypothesize that these systems mediate interbacterial competition within the host and that this facilitates Pseudomonas to dominate the lungs of CF patients. This dominance drives declining clinical prognosis and mortality. Thus, an important unmet clinical need is to understand how Pseudomonas outcompetes other bacteria. Furthermore, this project will identify new CDK systems, their effectors and identify new therapeutic targets for intervention.

Lay abstract: In people with Cystic Fibrosis cells do not work properly. This is especially so in the lungs where impaired airway functions weaken the body’s defences to microscopic organisms like bacteria. The growth of bacteria leads to tissue damage, scarring and ultimately reduces lifespans. The most common bacteria in people with Cystic Fibrosis is Pseudomonas aeruginosa. Why this is so is unknown. However, this bacterium has competition systems that act like poisoned spears delivering toxic proteins into competing bacteria and killing them. This enables one bacterium to takeover a location. Bacteria can also band together forming communities called biofilms that are linked to worse patient outcomes. Bacteria in a biofilm make a slime, which acts as a protective coat, increasing survival. We currently do not know if bacteria use their competition systems to fight for their place in the lung environment, which systems they use and if biofilm protects them. To answer these critical questions, I will use my model organism P. aeruginosa. P. aeruginosa is an excellent biofilm former and has five known killing systems. In my position at the National Heart and Lung Institute, I will test which and when these systems are switched on during human infection. I will define the role of these bacterial competition systems in individual pathogens and against other bacteria. My work will reveal the importance of these systems, leading the way to target them with drugs or use them against pathogens for future novel therapies to combat bacteria and save human lives.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION