Date Published: April 12, 2019
Publisher: Public Library of Science
Author(s): Brian J. McHugh, Rongling Wang, Hsin-Ni Li, Paula E. Beaumont, Rebekah Kells, Holly Stevens, Lisa Young, Adriano G. Rossi, Robert D. Gray, Julia R. Dorin, Emily L. Gwyer Findlay, David Brough, Donald J. Davidson, Igor Eric Brodsky.
Pulmonary infections are a major global cause of morbidity, exacerbated by an increasing threat from antibiotic-resistant pathogens. In this context, therapeutic interventions aimed at protectively modulating host responses, to enhance defence against infection, take on ever greater significance. Pseudomonas aeruginosa is an important multidrug-resistant, opportunistic respiratory pathogen, the clearance of which can be enhanced in vivo by the innate immune modulatory properties of antimicrobial host defence peptides from the cathelicidin family, including human LL-37. Initially described primarily as bactericidal agents, cathelicidins are now recognised as multifunctional antimicrobial immunomodulators, modifying host responses to pathogens, but the key mechanisms involved in these protective functions are not yet defined. We demonstrate that P. aeruginosa infection of airway epithelial cells promotes extensive infected cell internalisation of LL-37, in a manner that is dependent upon epithelial cell interaction with live bacteria, but does not require bacterial Type 3 Secretion System (T3SS). Internalised LL-37 acts as a second signal to induce inflammasome activation in airway epithelial cells, which, in contrast to myeloid cells, are relatively unresponsive to P. aeruginosa. We demonstrate that this is mechanistically dependent upon cathepsin B release, and NLRP3-dependent activation of caspase 1. These result in LL-37-mediated release of IL-1β and IL-18 in a manner that is synergistic with P. aeruginosa infection, and can induce caspase 1-dependent death of infected epithelial cells, and promote neutrophil chemotaxis. We propose that cathelicidin can therefore act as a second signal, required by P. aeruginosa infected epithelial cells to promote an inflammasome-mediated altruistic cell death of infection-compromised epithelial cells and act as a “fire alarm” to enhance rapid escalation of protective inflammatory responses to an uncontrolled infection. Understanding this novel modulatory role for cathelicidins, has the potential to inform development of novel therapeutic strategies to antibiotic-resistant pathogens, harnessing innate immunity as a complementation or alternative to current interventions.
Pulmonary diseases caused by bacterial or viral infections are a common cause of morbidity and account for 1 in 5 deaths in the UK . There is an increasing global threat from antibiotic-resistant bacterial infections and newly emerging viral infections. In this context, therapeutic interventions aimed at protectively modulating host responses, to enhance defence against infection, take on greater significance as alternative or complementary future approaches. An important component of first line defences against such infections is the innate immune response of airway epithelial cells, which constitute the principal barrier first encountered by respiratory pathogens. These innate epithelial cell responses include the secretion of antimicrobial host defence peptides (HDP) [2, 3], and the release of chemokines and cytokines to help orchestrate the response of other immune effector cells. HDP are produced by innate immune effector cells in response to infection, damage and inflammation  Understanding their effect on epithelial cell responses to infection is important in elucidating the potential of HDP as targets for development of future antimicrobial interventions.
Pseudomonas aeruginosa is an important, opportunistic, multidrug-resistant human pathogen. It is associated with a wide range of serious acute and chronic infections, including ventilator-associated pneumonia and sepsis syndromes, and is the predominant pulmonary infection leading to fatal deterioration of lung function in patients with CF . New interventional approaches for the treatment of P. aeruginosa are urgently needed in the context of the increasing global threat of antimicrobial resistance, and may be informed by a greater knowledge of effective innate host defence. Cathelicidins are a vital, non-redundant antimicrobial host defence peptide component of innate host defence, necessary for in vivo protection against infections of the lung, skin, intestinal tract, urinary tract and eye (reviewed in ). We have previously demonstrated that innate antimicrobial host defence peptides of the cathelicidin family can enhance the clearance of pulmonary P. aeruginosa in vivo by amplifying the protective neutrophilic inflammatory response . However, the mechanism by which cathelicidin promotes protective pulmonary inflammation in the context of an infectious threat, but not when delivered to the quiescent lung, remained unclear.