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

Abstract

Severe bacterial (pneumococcal) infections are commonly associated with influenza and are significant contributors to the excess morbidity and mortality of influenza. Disruption of lung tissue integrity during influenza participates in bacterial pulmonary colonization and dissemination out of the lungs. Interleukin-22 (IL-22) has gained considerable interest in anti-inflammatory and anti-infection immunotherapy over the last decade. In the current study, we investigated the effect of exogenous IL-22 delivery on the outcome of pneumococcal superinfection postinfluenza. Our data show that exogenous treatment of influenza virus-infected mice with recombinant IL-22 reduces bacterial dissemination out of the lungs but is without effect on pulmonary bacterial burden. Reduced systemic bacterial dissemination was linked to reinforced pulmonary barrier functions, as revealed by total protein measurement in the bronchoalveolar fluids, intratracheal fluorescein isothiocyanate-dextran tracking, and histological approaches. We describe an IL-22-specific gene signature in the lung tissue of influenza A virus (IAV)-infected (and naive) mice that might explain the observed effects. Indeed, exogenous IL-22 modulates the gene expression profile in a way that suggests reinforcement of tissue integrity. Our results open the way to alternative approaches for limiting postinfluenza bacterial superinfection, particularly, systemic bacterial invasion.

Viral strategies predisposing to respiratory bacterial superinfections

“…With the resulting reduction of bacterial dissemination, IL‐22 protects against bacterial superinfections 86‐88 . This latter protective effect has been directly demonstrated by manipulation of the IL‐22/IL‐22 binding protein axis in murine models 87,88 . Th17 polarization in the lung is driven by IL‐23, a cytokine produced by DCs, which is also implicated in Th17 cell activation, proliferation, and cytokine production 89 .…”

Respiratory Barrier as a Safeguard and Regulator of Defense Against Influenza A Virus and Streptococcus pneumoniae

“…IL-22 is critical to epithelial repair following infection with A/PR/8/1934 (173), and in its absence, mice sustain significantly higher lung injury and loss of airway epithelial integrity during sublethal IAV infection followed by S. pneumoniae co-infection (167). Administration of exogenous IL-22 to mice with influenza causes the upregulation of genes encoding proteins involved in cell-cell adhesion such as Cldn24 and Pcdh15 (encoding claudin 24 and protocadherin 15, respectively) in the lungs, and reduces systemic dissemination of S. pneumoniae during secondary bacterial infection (174). Interestingly, although mice lacking the IL-22 decoy IL-22BP have significantly reduced bacterial outgrowth in the lungs during co-infection, dissemination is unaffected (175).…”

Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

“…Many studies have also demonstrated that restoration of critical signal transducers in these repair pathways, such as IL-6 (182), IL-22 (122), Fgf10 (183), and ADAMTS4 (184), are able to restore repair and help to rescue murine models of IAV infection via augmented host tolerance. In particular, Barthelemy et al demonstrated that the increase in tissue integrity resulting from IL-22 immunotherapy reduces secondary bacterial systemic invasion (185). Small molecule therapeutics, such as progesterone, which acts on the amphiregulin pathway to initiate tissue repair after IAV infection, have also been investigated with some success in a female murine model (186).…”