ABSTRACT
Inflammasome activation exacerbates infectious disease caused by pathogens such as Listeria monocytogenes, Staphylococcus aureus, and severe acute respiratory syndrome coronavirus 2. Although these pathogens activate host inflammasomes to regulate pathogen expansion, the mechanisms by which pathogen toxins contribute to inflammasome activation remain poorly understood. Here we show that activation of inflammasomes by Listeria infection is promoted by amino acid residue T223 of listeriolysin O (LLO) independently of its pore-forming activity. LLO T223 is critical for phosphorylation of the inflammasome adaptor ASC at amino acid residue Y144 through Lyn-Syk signaling, which is essential for ASC oligomerization. Notably, a Listeria mutant expressing LLO T223A is impaired in inducing ASC phosphorylation and inflammasome activation. Furthermore, the virulence of LLO T223A mutant is markedly attenuated in vivo due to impaired ability to activate the inflammasome. Our results reveal a function of a pathogen toxin that exacerbates infection by promoting phosphorylation of ASC.
Subject(s)
Bacterial Proteins/metabolism , Bacterial Toxins/metabolism , CARD Signaling Adaptor Proteins/metabolism , Heat-Shock Proteins/metabolism , Hemolysin Proteins/metabolism , Inflammasomes/metabolism , Listeria monocytogenes/pathogenicity , Signal Transduction , Amino Acid Sequence , Animals , Bacterial Proteins/genetics , Bacterial Toxins/chemistry , Bacterial Toxins/genetics , CARD Signaling Adaptor Proteins/chemistry , CARD Signaling Adaptor Proteins/deficiency , CARD Signaling Adaptor Proteins/genetics , Gene Editing , Heat-Shock Proteins/chemistry , Heat-Shock Proteins/genetics , Hemolysin Proteins/chemistry , Hemolysin Proteins/genetics , Interleukin-18/metabolism , Listeria monocytogenes/metabolism , Macrophages, Peritoneal/cytology , Macrophages, Peritoneal/metabolism , Macrophages, Peritoneal/microbiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutagenesis, Site-Directed , Phosphorylation , Syk Kinase/genetics , Syk Kinase/metabolism , Virulence , src-Family Kinases/genetics , src-Family Kinases/metabolismABSTRACT
Bacterial toxins play a key role in the pathogenesis of lung disease. Based on their structural and functional properties, they employ various strategies to modulate lung barrier function and to impair host defense in order to promote infection. Although in general, these toxins target common cellular signaling pathways and host compartments, toxin- and cell-specific effects have also been reported. Toxins can affect resident pulmonary cells involved in alveolar fluid clearance (AFC) and barrier function through impairing vectorial Na+ transport and through cytoskeletal collapse, as such, destroying cell-cell adhesions. The resulting loss of alveolar-capillary barrier integrity and fluid clearance capacity will induce capillary leak and foster edema formation, which will in turn impair gas exchange and endanger the survival of the host. Toxins modulate or neutralize protective host cell mechanisms of both the innate and adaptive immunity response during chronic infection. In particular, toxins can either recruit or kill central players of the lung's innate immune responses to pathogenic attacks, i.e., alveolar macrophages (AMs) and neutrophils. Pulmonary disorders resulting from these toxin actions include, e.g., acute lung injury (ALI), the acute respiratory syndrome (ARDS), and severe pneumonia. When acute infection converts to persistence, i.e., colonization and chronic infection, lung diseases, such as bronchitis, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) can arise. The aim of this review is to discuss the impact of bacterial toxins in the lungs and the resulting outcomes for pathogenesis, their roles in promoting bacterial dissemination, and bacterial survival in disease progression.