Transregional Collaborative Research Center SFB-TR 84 - “Innate Immunity of the Lung: Mechanisms of Pathogen Attack and Host Defence in Pneumonia“

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A5-Subproject

Cross-talk of antimicrobial therapy, microbiota and innate immunity in pneumonia caused by multidrug-resistant Gram-negative bacteria
(Opitz / Chaput / Heimesaat)

 

Multidrug resistant (MDR) Gram-negative bacteria are a current medical defy. Particularly critically ill patients receiving antimicrobial therapy are at high risk to get colonized by e.g. MDR Pseudomonas aeruginosa and Klebsiella pneumoniae and develop invasive infections such as hospital-acquired pneumonia (HAP). Whereas the role of the microbiota in regulating local immunity in the gut is well established, little is known about if and how the antibacterial innate immunity in the lung is influenced systemically by the intestinal microbiota and/or locally by the microbiota of the respiratory tract. Moreover, our understanding of how a clinically used empirical antimicrobial therapy against HAP might affect the immunity in the lung by dysregulating the microbiota is sparse.

Based on preliminary data, we will test the following hypotheses: (i) Mice with a depleted microbiota and isolator-raised germ-free mice are more susceptible towards Gram-negative pneumonia as compared to conventionally colonized mice and mice recolonized with defined bacterial populations. (ii) The microbiota primes/regulates specific innate immune pathways or cells that are required for fighting Gram-negative bacterial infection in the lung. (iii) An empirical antimicrobial therapy against nosocomial pneumonia disturbs the commensal microbiota, weakens specific innate defense pathways, and worsens the outcome in pneumonia caused by MDR bacteria (that are resistant against the empirical therapy) in mice. (iv) An antimicrobial-mediated weakening of the antibacterial innate immunity in the lung can be rescued by application of synthetic innate response stimuli.