Immunopathology of community-acquired pneumonia

This thesis comprises different studies on the pathophysiology and potential biomarkers of community-acquired pneumonia (CAP), with the overall aim to broaden our understanding of host immune responses during CAP in a clinical context. Firstly, we report that 9.8% of critically ill patients with CAP exhibited macrophage-activation-like syndrome (CAP-MALS), with plasma ferritin levels above 4420 ng/ml. CAP-MALS is associated with dysregulation of host response mechanisms implicated in sepsis pathogenesis. Secondly, systemic hyperferritinemia in patients with CAP admitted to a general ward, was associated with enhanced systemic inflammation, neutrophil activation, cytokine release, endothelial cell activation and dysfunction, and activation of the coagulation system. Next, we demonstrated that blood leukocytes obtained from CAP patients on hospitalization displayed an impaired ability to release pro-inflammatory cytokines in response to ex vivo stimulation with bacterial agonists. Leukocytes of patients exhibiting the most impaired capacity to produce Tumor Necrosis Factor (TNF)-α, concurrently had elevated levels of soluble mediators of inflammation, endothelial function and procoagulant responses in plasma. In addition, the extent of impairment in TNF-α production by blood leukocytes of critically ill patients was associated with enhanced systemic inflammatory responses, enhanced endothelial cell activation, loss of vascular integrity, and increased procoagulant responses. Finally, we integrated cytokine production capacities, RNA-sequencing and DNA methylation data gathered from circulating monocytes obtained from CAP patients, into a multi-omics model. In doing so, we unmasked a potentially essential link between DNA methylation dynamics at transcriptional enhancer elements and immune tolerance via a transcriptomic signature attuned to cholesterol biosynthesis.