Immune stimulation and immunometabolism of the first line of defense in the lung

Pneumonia is an acute respiratory infection of the bronchial tree and alveoli of the lungs that can be classified as community-acquired pneumonia (CAP), or hospital-acquired pneumonia (HAP), the latter often affecting the immunocompromised or patients on an intensive care unit. In this context, the emergence of multidrug-resistant (MDR) bacteria, such as Klebsiella (K.) pneumoniae or Pseudomonas (P.) aeruginosa, poses a major risk. Apart from the development of new antibiotic agents, there is an increasing interest in drugs that can modulate or “boost” the host immune response; one of such agents is flagellin, a Toll-like receptor (TLR)5 ligand that induces an inflammatory reaction in respiratory epithelial cells upon topical administration. Next to the airway epithelium, alveolar macrophages (AMs) play an important role in the first line of defense in the lung, by phagocytosing pollutants and pathogens, and secreting inflammatory cytokines. Immunometabolic features of AMs, however, are largely unknown, while these could provide targets for improving immune cell function.
This thesis seeks to enhance our understanding of innate immunity in the lung, with the specific aim to improve local host defense in the context of pneumonia.
In Part I, we investigate the effect of local flagellin administration on the immune response of the airway epithelium, and whether this could serve as an adjunctive therapeutic to antibiotic treatment of bacterial lung infections. Part II focuses on the immunometabolic requirements of human AMs upon stimulation with lipopolysaccharide (LPS), component of the Gram-negative bacterial cell wall, and evaluates a model to generate AM-like cells from human monocytes.