< Terug naar vorige pagina

Publicatie

Biomarkers and molecular immunopathology of pneumonia

Boek - Dissertatie

Pneumonia remains worldwide the single largest infectious cause of death both in children and adults, as well as in hospitalised patients. One of the most important bacterial causes of hospital-related mortality is Pseudomonas aeruginosa (PA), which is high on the WHO priority list of pathogenic organisms. This is because of PA’s substantial ability to rapidly gain resistance against antibiotics, partly because of protective biofilm formation, and cause mortality in immunocompromised patients including patients on mechanical ventilation (MV). We studied the effect of MV on innate immune factors such as cytokines and its relation to development of ventilator-associated pneumonia (VAP). We showed both in a rat VAP model as well as in VAP patients that the pro-inflammatory Th17-related cytokines are substantially dampened. We concluded that this form of immune modulation caused by MV can be an important cause of VAP. We further elucidated how inducing dispersal of bacteria from a biofilm causes an increased in vivo dissemination and mortality in mice, thereby suggesting that biofilm dispersion as a potential anti-PA therapy should be treaded carefully. While performing these studies, we also identified a knowledge gap regarding temporal evolution of immune responses in animal infection models. We showed distinct temporal expression profiles of cytokines and, importantly, demonstrated that serum levels are representative of the local lung immune response in mice. We believe that these studies will have an important impact on pre-clinical research utilizing these rodent pneumonia models. With the emergence of SARS-CoV-2, the focus of this thesis shifted on COVID-19 pneumonia. In the search for biomarkers of disease severity, we first developed a model based on the cytokine, chemokine, and growth factors (CCG) to predict development of acute respiratory distress syndrome already at the time of hospital admission. This research also elucidated a significant role of TGF-β in COVID-19 whose function is linked both with normal healing, as with fibrosis seen in COVID-19 patients. Lastly, we showed in a SARS-CoV-2 exposed cancer population long-term alterations in levels of inflammatory CCGs, some of which are also tumour-promoting factors. These data prompt for increased vigilance in SARS-CoV-2-exposed cancer patients and long-COVID management. The work performed in this thesis has provided useful insights in our understanding of the molecular pathology of pneumonia and will form the basis for future translational research in development of early diagnostic tools as well as for new therapies directed towards the immune system targeting bacterial and viral pneumonia.
Aantal pagina's: 179
Jaar van publicatie:2022
Trefwoorden:Doctoral thesis
Toegankelijkheid:Open