Final Report Summary - ALLOSERGON (The role of TREM proteins in inflammatory lung disease)
Final publishable summary report:
Pneumococcal infections affect millions of people world-wide causing significant mortality/morbidity and an associated high economic burden. The main aim of this project was to provide the key tools to reduce the severity of bacterial complications and identify targets for prophylactics/therapeutics.
Secondary bacterial infections are a consequence of many lung inflammatory diseases and arise due to defective microbicidal responses in the remodeled airspaces. We reasoned that the release of the recently identified receptor Triggering receptor expressed on myeloid cells-1 (TREM-1) expressed on neutrophils is at least partly responsible for impaired innate immune responses to bacteria following influenza virus infection. TREM-1 amplifies Toll-like receptor (TLR)-mediated inflammation during infection and also exists in an antagonistic soluble form that has been used as a peripheral biomarker in sepsis, though the mechanisms of its release are not entirely clear. The requirement of TREM-1 in single microbial infections is controversial, with some studies showing a protective role and others a contribution to immunopathology. Furthermore, the role of membrane–bound and soluble TREM-1 in polygenic infections is currently unknown.
The overall scientific objective was to apply established models of secondary bacterial pneumonia in the mouse in order to identify the molecular mechanisms and the involvement of the novel surface receptor protein TREM-1. Airway neutrophils were analysed by high throughput flow cytometry and cytokines measured by ELISA to identify innate immune alterations.
In a mouse co-infection model where preceding viral infection greatly enhances bacteria infiltration, Gudrun Weiss determined a mechanism for the striking increase in soluble TREM-1 and the loss of TREM-1 on the surface of neutrophils. A matrix metalloproteinase (MMP)-9 cleavage site in TREM-1 was identified and that the increase of MMP-9 in bronchoalveolar lavage fluid mirrors sTREM-1 release. In vitro studies with neutrophils and MMP-9 and the reduction of sTREM-1 in vivo after MMP-9 inhibition verifies that this enzyme cleaves TREM-1. MMP-9 inhibition significantly reduces bacterial load and prevents sepsis ensuing immunopathology in this co-infection model. These results highlight MMP-9 inhibition as a potential therapeutic via blocking the cleavage of TREM-1. This work is accepted for publication in Mucosal Immunology.
An appropriate balance of anti- and pro-inflammatory mediators is essential for an effective immune response against respiratory syncytial virus (RSV). Gudrun Weiss established a murine co-infection model and discovered that RSV infection of adult mice with house dust mite (HDM) induced asthma prevents RSV-induced weight loss, epithelial damage, the pro-inflammatory cytokine and chemokine release in the airways, and significantly reduces viral load. RSV infection in HDM induced asthma causes a change of phenotype of alveolar macrophages from an alternatively active M2 type towards the classically activated M1 type important for resolution.
A manuscript is currently in preparation.
Pneumococcal infections affect millions of people world-wide causing significant mortality/morbidity and an associated high economic burden. The main aim of this project was to provide the key tools to reduce the severity of bacterial complications and identify targets for prophylactics/therapeutics.
Secondary bacterial infections are a consequence of many lung inflammatory diseases and arise due to defective microbicidal responses in the remodeled airspaces. We reasoned that the release of the recently identified receptor Triggering receptor expressed on myeloid cells-1 (TREM-1) expressed on neutrophils is at least partly responsible for impaired innate immune responses to bacteria following influenza virus infection. TREM-1 amplifies Toll-like receptor (TLR)-mediated inflammation during infection and also exists in an antagonistic soluble form that has been used as a peripheral biomarker in sepsis, though the mechanisms of its release are not entirely clear. The requirement of TREM-1 in single microbial infections is controversial, with some studies showing a protective role and others a contribution to immunopathology. Furthermore, the role of membrane–bound and soluble TREM-1 in polygenic infections is currently unknown.
The overall scientific objective was to apply established models of secondary bacterial pneumonia in the mouse in order to identify the molecular mechanisms and the involvement of the novel surface receptor protein TREM-1. Airway neutrophils were analysed by high throughput flow cytometry and cytokines measured by ELISA to identify innate immune alterations.
In a mouse co-infection model where preceding viral infection greatly enhances bacteria infiltration, Gudrun Weiss determined a mechanism for the striking increase in soluble TREM-1 and the loss of TREM-1 on the surface of neutrophils. A matrix metalloproteinase (MMP)-9 cleavage site in TREM-1 was identified and that the increase of MMP-9 in bronchoalveolar lavage fluid mirrors sTREM-1 release. In vitro studies with neutrophils and MMP-9 and the reduction of sTREM-1 in vivo after MMP-9 inhibition verifies that this enzyme cleaves TREM-1. MMP-9 inhibition significantly reduces bacterial load and prevents sepsis ensuing immunopathology in this co-infection model. These results highlight MMP-9 inhibition as a potential therapeutic via blocking the cleavage of TREM-1. This work is accepted for publication in Mucosal Immunology.
An appropriate balance of anti- and pro-inflammatory mediators is essential for an effective immune response against respiratory syncytial virus (RSV). Gudrun Weiss established a murine co-infection model and discovered that RSV infection of adult mice with house dust mite (HDM) induced asthma prevents RSV-induced weight loss, epithelial damage, the pro-inflammatory cytokine and chemokine release in the airways, and significantly reduces viral load. RSV infection in HDM induced asthma causes a change of phenotype of alveolar macrophages from an alternatively active M2 type towards the classically activated M1 type important for resolution.
A manuscript is currently in preparation.