Etiopathogenesis and biomarker discovery in P. aeruginosa ventilator-associated pneumonia

Datum: 30 juni 2016

Locatie: UAntwerp - Campus Drie Eiken - Building Q - Promotiezaal - Universiteitsplein 1 - 2610 WILRIJK

Tijdstip: 15 uur

Promovendus: Kenny Bielen

Promotor: Prof S. Kumar-Singh & Prof H. Goossens

Korte beschrijving: PhD defence Kenny Bielen - Faculty of Medicine and Health Sciences



Abstract

Nosocomial pneumonia is amongst the leading causes of mortality and morbidity in hospital settings with P. aeruginosa as one of the most important etiologies. Especially patients in intensive care units who receive mechanical ventilation (MV) are at high risk of developing ventilator-associated pneumonia (VAP). Lung injury induced by MV has been proposed as an important step in VAP pathogenesis, however, despite an acute upregulation of proinflammatory cytokines, we showed that different protective MV protocols led to a robust and sustained Th2 and Th17 type immune response resulting in increased eosinophil and M2 macrophage infiltration in lungs.

Moreover, MV caused a reduced phagocytic capacity of alveolar macrophages in ex vivo assays and MV followed by intratracheal instillation of P. aeruginosa led to an aggravated phenotype. We therefore believe that MV causes a local immunosuppression that could render patients receiving MV more vulnerable towards developing pneumonia. A similar phenotype is observed in a chronic pneumonia model where P. aeruginosa is embedded in agar beads to mimic biofilm.

However, we showed that the increased Th17-Th2 phenotype observed in this model is a consequence of the immune response towards biofilm itself rather than the pathogen and does not lead to a higher mortality most likely due to slow release of bacteria from the beads as well as the lowered metabolic state of P. aeruginosa when in a biofilm condition as has been shown previously. Detailed understanding of host responses during P. aeruginosa pneumonia could potentially lead to immunomodulatory treatments to reduce the risk of infection or attenuate the disease progression.

Additionally, early detection of infections by specific organisms is becoming more important with the recent development of compendium diagnostics. Using existing as well as newly established mass spectrometric tools, we have identified several potential P. aeruginosa VAP related markers in urine from VAP patients as well as in animal models that, if further validated, could be used to diagnose nosocomial infections.

Moreover, these approaches allowed us to identify potential targets co-expressed by P. aeruginosa under various antibiotics that could lead to new treatment strategies.

We believe that similar strategies on animal models will contribute in our understanding towards the pathogenesis as well as biomarker discovery in complex diseases such as pneumonia and similar strategies could lead to new treatments/diagnostics test that ultimately can save lives.