Pseudomonas aeruginosa Biofilms: Host Response and Clinical Implications in Lung Infections

Abstract

Pseudomonas aeruginosa is a major health challenge that causes recalcitrant multidrug-resistant infections, especially in immunocompromised and hospitalized patients. P. aeruginosa is an important cause of nosocomial and ventilator-associated pneumonia characterized by high prevalence and fatality rates. P. aeruginosa also causes chronic lung infections in individuals with cystic fibrosis. Multidrug- and totally drug-resistant strains of P. aeruginosa are increasing threats that contribute to high mortality in these patients. The pathogenesis of many P. aeruginosa infections depends on its ability to form biofilms, structured bacterial communities that can coat mucosal surfaces or invasive devices. These biofilms make conditions more favorable for bacterial persistence, as embedded bacteria are inherently more difficult to eradicate than planktonic bacteria. The molecular mechanisms that underlie P. aeruginosa biofilm pathogenesis and the host response to P. aeruginosa biofilms remain to be fully defined. However, it is known that biofilms offer protection from the host immune response and are also extremely recalcitrant to antimicrobial therapy. Therefore, development of novel therapeutic strategies specifically aimed at biofilms is urgently needed. Here, we review the host response, key clinical implications of P. aeruginosa biofilms, and novel therapeutic approaches to treat biofilms relevant to lung infections. Greater understanding of P. aeruginosa biofilms will elucidate novel avenues to improve outcomes for P. aeruginosa pulmonary infections.

Keywords: Pseudomonas aeruginosa; anti-infective agents; biofilms; cystic fibrosis; ventilator-associated pneumonia.

Figure 1.

Disruption of host response to Pseudomonas aeruginosa biofilms. The host response to P. aeruginosa biofilms depends on the coordinated action of various cells of the innate and adaptive immune systems. P. aeruginosa biofilms disrupt this immune response through various actions on host cells detailed here. eDNA = extracellular DNA; PON2 = paraoxonase 2.

Figure 2.

Bacterial and host factors that contribute to acute and chronic Pseudomonas aeruginosa lung infections in cystic fibrosis (CF). The relationship between bacterial and host factors that contribute to the development of chronic P. aeruginosa infections is complex. Patients with CF will typically develop recurrent acute P. aeruginosa infections early in life that are treated aggressively with antibiotic therapy. Under significant selective pressure to survive in a hostile host environment, bacteria develop several important adaptations. Similarly, there are aspects of susceptible host biology that also promote persistent infections. Psl = polysaccharide synthesis locus; Th2 = T-helper type 2.

Figure 3.

Biofilm development and dispersal and site of action of various biofilm-directed therapies. Biofilm formation begins with the attachment of planktonic bacteria to biotic or abiotic surfaces. These bacterial colonies, under the regulation of cell-signaling molecules, including quorum sensing (QS) molecules and bis-(3′-5′) cyclic diguanosine monophosphate (c-di-GMP), secrete components of the extracellular polymeric substance matrix that form the bulk of the biofilm. QS molecules also rapidly diffuse into host cells, where they can be degraded by the enzyme PON2. Biofilm dispersal is induced by downregulation of c-di-GMP signaling. Within this dynamic process, there are multiple possible therapeutic targets that have clinical promise. These include biofilm adhesion inhibition, QS inhibition, quorum quenching, antibiofilm peptides, c-di-GMP inhibition, and activation of the host response. PPARγ = peroxisome proliferator–activated receptor γ.

Figure 4.

Chemical structures of QS molecules and selected QS inhibitors. The primary QS molecules used by Pseudomonas aeruginosa are the acylhomoserine lactones (AHLs), N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12-HSL) and N-butanoyl homoserine lactone (C4-HSL). These differ in the length of the acyl chain and the 3-oxo substituent. It has been found that natural halogenated furanones, which share a similar structure with AHLs, can inhibit QS signaling. Subsequently, synthetic furanones, such as C-30, have also been developed. In addition, a variety of natural chemicals, including patulin and ajoene, which have differing levels of structural similarity to QS molecules, have also been shown to exhibit QS inhibitory properties.