Project C03

The lung as a pathogen-specific entry site for systemic infection

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Prof. Dr. Oliver Karzai & PD Dr. Knut Ohlsen

 

Although the lung is the most frequent entry site for human bloodstream infection (BSI) and sepsis, not all pathogens are equally able to use the respiratory tract as a portal for invasion and systemic spreading. We aim to characterise molecular decision points that govern this distinct, pathogen- and site-specific potential for invasion and dissemination. Candida albicans and Staphylococcus aureus are leading causes of BSI and readily disseminate to multiple anatomical sites. However, whereas S. aureus is a relevant cause of pneumonia and regularly spreads from the lung to cause bacteraemia and sepsis, C. albicans nearly never causes invasive lung infection. Even massive deep airway colonisation with C. albicans, which frequently occurs in ventilated patients, poses no risk for pneumonia or secondary dissemination. We hypothesise that (i) site-specific interaction with host factors (molecular decision points) prevents C. albicans but not S. aureus from pulmonary invasion, and that ii) mutual interactions between S. aureus and C. albicans can modulate invasiveness and inflammatory responses in the lung. In vivo data for lung infection using a candidalysin-deficient C. albicans mutant suggest that multiple host signalling pathways triggered by this pore-forming toxin are prime candidates for identification of such molecular decision points. These pathways include EGFR receptor signalling and the initiation of Th2 and Th17 responses. Furthermore, in our own preliminary work, we have identified cytokine signatures triggered by S. aureus that are associated with invasion and spreading compared to clearance of infection. Based on these findings, we will compare patterns of host pathogen interaction between S. aureus and C. albicans in lung and bloodstream infection and determine molecular decision points governing site-specific entry capacity of these two model pathogens. In addition, we will analyse physical and immunological interaction of S. aureus and C. albicans in the lung to identify potential modulatory effects of Candida airway colonisation for the risk for invasive staphylococcal infection.