Pseudomonas aeruginosa proteolytically alters the interleukin 22-dependent lung mucosal defense

Abstract

The IL-22 signaling pathway is critical for regulating mucosal defense and limiting bacterial dissemination. IL-22 is unusual among interleukins because it does not directly regulate the function of conventional immune cells, but instead targets cells at outer body barriers, such as respiratory epithelial cells. Consequently, IL-22 signaling participates in the maintenance of the lung mucosal barrier by controlling cell proliferation and tissue repair, and enhancing the production of specific chemokines and anti-microbial peptides. Pseudomonas aeruginosa is a major pathogen of ventilator-associated pneumonia and causes considerable lung tissue damage. A feature underlying the pathogenicity of this bacterium is its capacity to persist and develop in the host, particularly in the clinical context of nosocomial lung infections. We aimed to investigate the ability of P. auruginosa to disrupt immune-epithelial cells cross-talk. We found that P. aeruginosa escapes the host mucosal defenses by degrading IL-22, leading to severe inhibition of IL-22-mediated immune responses. We demonstrated in vitro that, protease IV, a type 2 secretion system-dependent serine protease, is responsible for the degradation of IL-22 by P. aeruginosa. Moreover, the major anti-proteases molecules present in the lungs were unable to inhibit protease IV enzymatic activity. In addition, tracheal aspirates of patients infected by P. aeruginosa contain protease IV activity which further results in IL-22 degradation. This so far undescribed cleavage of IL-22 by a bacterial protease is likely to be an immune-evasion strategy that contributes to P. aeruginosa-triggered respiratory infections.

Interleukin-22 Immunotherapy during Severe Influenza Enhances Lung Tissue Integrity and Reduces Secondary Bacterial Systemic Invasion

“…In the pulmonary compartment, IL-22 protects against acute and chronic airway inflammation, including ventilator-induced lung injury and lung fibrosis, whereas its role in asthma is more ambiguous (26)(27)(28)(29)(30)(31). IL-22 plays a role in pulmonary mucosal defenses against intracellular and extracellular bacteria, including Klebsiella pneumoniae, Chlamydia muridarum, Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae, and Mycobacterium tuberculosis (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). The positive role of IL-22 in respiratory fungal infections has also been reported (45,46).…”

The best defense is a good (Protease) offense: HowPseudomonas aeruginosaevades mucosal immunity in the lung

“…study was the definitive identification of P. aeruginosa-derived protease IV as an enzymatic mediator of IL-22 degradation. 13,23 As a corollary to their in vitro results, the authors reported that protease IV activity could not be inhibited by antiproteases found in the lung and also demonstrated protease IV activity in tracheal aspirates obtained from P. aeruginosa-infected patients. While the findings from the Guillon et.…”

“…further suggests that airway supplementation with IL-22 may enhance recovery of the injured lung following P. aeruginosa infection. 13 Reduced levels of airway IL-22 expression has been documented for patient populations outside of those afflicted with ventilator-induced pneumonia, including subjects with acute respiratory distress syndrome and sarcoidosis. 24 It would be expected that cystic fibrosis patients, who are highly susceptible to P. aeruginosa, would have reduced IL-22 levels, but there is currently no evidence of quantitative differences in this cytokine from nasal lavages.…”

“…study hypothesized that the human host may be limited in ability to combat P. aeruginosa infection if the immunomodulatory properties of IL-22 are compromised, possibly by direct action from bacterial products. 13 Through a series of elegant in vitro studies, Guillon, et. al.…”

“…al. in this issue proposes a new immunotherapeutic approach for attenuation of P. aeruginosa pathogenicity, centered upon identification of a virulence factor that may allow P. aeruginosa to evade mucosal host-pathogen defense mechanisms. 13 The basis for the Guillon, et. al.…”