Role of quorum sensing by Pseudomonas aeruginosa in microbial keratitis and cystic fibrosis

Abstract

Pseudomonas aeruginosa is a ubiquitous bacterium that causes opportunistic infections in a range of host tissues and organs. Infections by P. aeruginosa are difficult to treat and hence there is interest in the development of effective therapeutics. One of the key mechanisms that P. aeruginosa uses to control the expression of many virulence factors is the N-acylated homoserine lactone (AHL) regulatory system. Hence, there is considerable interest in targeting this regulatory pathway to develop novel therapeutics for infection control. P. aeruginosa is the principal cause of microbial keratitis and of infections in cystic fibrosis (CF) sufferers, and AHL-dependent cell-to-cell signalling has been shown to be important for both infection types. However, keratitis tends to be an acute infection whereas infection of CF patients develops into a chronic, lifelong infection. Thus, it is unclear whether AHL-regulated virulence plays the same role during these infections. This review presents a comparison of the role of AHL signalling in P. aeruginosamediated microbial keratitis and chronic lung infections of CF patients. IntroductionAll evidence to date indicates that we are losing the race to combat what have been for the last 40 years simple bacterial infections. This is primarily due to the emergence of, and strong selection for, antibiotic-resistant bacteria, which has led to the current situation where many bacteria are so antibiotic resistant that patients can only be treated with what are considered to be drugs of last defence. A contributing factor in this steady failure of current drugs has been the strategy of making simple modifications of existing classes of antimicrobials to maintain a drug's activity over the short term. This process is no longer working, and what needs to be done is to identify and develop new drug targets. This will take significant effort and may require a paradigm shift in thinking about how we deal with pathogenic bacteria, and the development of therapeutics that are highly specific for bacterial groups or even individual organisms. However, such outcomes should not be seen as limitations, but as benefits, reducing the likelihood of general resistance developing. Furthermore, bacterial control does not necessarily require bactericidal activity; it may be sufficient to target genetic pathways that are essential for virulence or the infection process, but that are otherwise non-essential systems. One such system is the acylated homoserine lactone (AHL) quorum sensing (QS) system found in a range of pathogenic Gram-negative bacteria, e.g. Pseudomonas aeruginosa, Burkholderia cepacia and Serratia marcescens. P. aeruginosa is of particular interest because it forms biofilms that contribute to the infection process and many of its virulence factors, including biofilm development, are QS regulated. Furthermore, it causes infections in wounds, eyes and lungs (both chronic and acute). In fact, P. aeruginosa infection is the most frequent cause of mortality in cystic fibrosis sufferers and is...

Chronic pulmonary pseudomonal infection in patients with cystic fibrosis: A model for early phase symbiotic evolution

“…QS-deficient lasR mutants have been detected in a significant proportion (30-63%) of CF Pa isolates (Feliziani et al, 2010;Hoffman et al, 2009). Moreover, isolates of Pa defective in lasR, lasI, and/or rhlI have been shown to be much less virulent than QS-positive strains in animal models (Willcox et al, 2008;Wu et al, 2001). Once more, such intraclonal de-regulation and isogenic role differentiation support the concept of pseudomonal multicellularity during symbiotic adaptation.…”

Dynamics in the mixed microbial concourse

“…The LasI/LasR and RhlI/RhlR pairs play roles analogous to LuxI/LuxR, transmitting and receiving two distinct AHL compounds. A wide range of virulence factors are induced when a quorum is detected, including proteases, exotoxins, and biofilm-formation pathways (Willcox et al 2008). …”

Evaluation of Cholera Toxin Expression in Different Populations of Vibrio cholera

“…In this system, as the number of bacterium increases, concentration of autoinducer will also increase; so, autoinducer concentration is directly related to the number of bacteria. Usually, among bacteria whenever, autoinducer concentration at its maximum level, quorum sensing process occurs; which may leads to the expression of bacterial virulence genes (6). However, this system in Vibrio cholerae is exactly the opposite (7).…”