Interleukin-1beta Participates in the Development of Pneumococcal Acute Lung Injury and Death by Promoting Alveolar Microvascular Leakage

Streptococcus pneumoniae (S. pneumoniae, also known as pneumococcus) infections are major causes of death worldwide. Despite the development and use of effective antibiotics, high, early mortality due to pneumococcal infections has not been decreased for the last few decades. Recent study found a deadly hemorrhagic acute lung injury (ALI) as a major cause of death at the early stage of severe pneumococcal infections. Interleukin (IL)-1beta was known to play critical roles not only for the development of ALI but also resolution of it. The role of IL-1beta on the pathogenesis of pneumococcal ALI, however, has not been well understood yet. This study aims to investigate the role of IL-1beta on the development of pneumococcal ALI and subsequent death. IL-1beta expression was upregulated in the lungs of pneumococcal ALI in wild-type (WT) mice, but not in the plasma. Despite an increased expression of pulmonary IL-1beta, no inflammatory cell infiltration into airway has been observed. Upregulation of IL-1beta expression was indeed dependent on pneumococcal cytoplasmic toxin pneumolysin and its cell surface receptor Toll-like receptor 4. Deficiency of IL-1R1, a cell surface receptor of IL-1beta, resulted in a markedly reduced hemorrhagic pulmonary edema and early death in pneumococcal ALI. Finally, IL-1beta neutralization in WT mice protects against pulmonary hemorrhagic edema and death. These data suggest that pulmonary expression of IL-1beta exacerbates pneumolysin-induced ALI and death by promoting alveolar hemorrhagic edema.

The in vivo and in vitro Roles of Epithelial Pattern Recognition Receptors in Pneumococcal Infections

Streptococcus pneumoniae, also called pneumococcus, is a major cause of infectious disease in human. Pneumococcus resides in the nasopharynx as an upper respiratory commensal, and most of pneumococcal colonizations are asymptomatic in immunocompetent individuals. When nasopharyngeal mucosal homeostasis is disrupted, pneumococcus migrates into middle ear and lower respiratory tract and causes detrimental colonization. In this regard, the epithelial cells of middle ear and lung act as first line of defense against pneumococcus to prevent invasive pneumococcal diseases. Respiratory epithelial cells express various cell-surface and intra-cellular receptors sensing microbial pathogens and respond to sensed pathogens by triggering intra-cellular signaling pathways and inducing pathogen-specific innate immune responses. Various epithelial cell-surface and intra-cellular receptors, such as Toll-like receptors (TLRs), Nod-like receptors (NLRs), intracellular DNA sensing receptors, and scavenger receptors (SRs), participate in sensing of pneumococcus, and the activation of these receptors by pneumococcal components induces anti-pneumococcal innate immune responses including epithelial apoptosis and inflammatory cytokine/chemokine expressions. Epithelial sensing of pneumococcus is a critical step for setting an early defense against pneumococcal infection, and also is required to recruit and activate innate immune cells and trigger adaptive immunity.