Inhibition of inflammasome activation by a clinical strain of Klebsiella pneumoniae impairs efferocytosis and leads to bacterial dissemination

Abstract

Klebsiella pneumoniae is a Gram-negative bacterium responsible for severe cases of nosocomial pneumonia. During the infectious process, both neutrophils and monocytes migrate to the site of infection, where they carry out their effector functions and can be affected by different patterns of cell death. Our data show that clinical strains of K. pneumoniae have dissimilar mechanisms for surviving within macrophages; these mechanisms include modulation of microbicidal mediators and cell death. The A28006 strain induced high IL-1β production and pyroptotic cell death in macrophages; by contrast, the A54970 strain induced high IL-10 production and low IL-1β production by macrophages. Pyroptotic cell death induced by the A28006 strain leads to a significant increase in bacterial sensitivity to hydrogen peroxide, and efferocytosis of the pyroptotic cells results in efficient bacterial clearance both in vitro and in vivo. In addition, the A54970 strain was able to inhibit inflammasome activation and pyroptotic cell death by inducing IL-10 production. Here, for the first time, we present a K. pneumoniae strain able to inhibit inflammasome activation, leading to bacterial survival and dissemination in the host. The understanding of possible escape mechanisms is essential in the search for alternative treatments against multidrug-resistant bacteria.

Cross talk between intracellular pathogens and cell death

“…Furthermore, by S. aureus secretes alpha‐toxin that reduces CCN1 expression in the lung and alters surface localization of DD1α in aveolar macrophages, both of which reduce efferocytosis of infected neutrophils and thus promote bacterial dissemination 125 . K. pneumoniae on the other hand evades killing by inducing IL‐10 production, which reduces pyroptosis of infected cells and subsequent efferocytosis 126 . In summary, these findings reveal highly context depended outcomes for the efferocytosis of infected cells.…”

The Role of IgG Subclass in Antibody-Mediated Protection against Carbapenem-Resistant Klebsiella pneumoniae

“…It is possible that coordination of macrophages with additional immune cells and cytokines in concert may be required for the full capability of antibody-mediated opsonophagocytosis to be realized (50)(51)(52)(53). Additionally, alveolar macrophages or inflammatory monocytes may have improved lysosomal capabilities relative to standard BMDMs (54), or macrophages may clear phagocytized bacteria self-destruction via autophagy or pyroptosis (50,51).…”

Increased Plasma Levels of Mitochondrial DNA and Normal Inflammasome Gene Expression in Monocytes Characterize Patients With Septic Shock Due to Multidrug Resistant Bacteria

“…However, we were unable to obtain tissue samples and had to concentrate on circulating monocytes, which are simple enough to obtain, and study gene expression rather than protein levels due to the lack of biological material. In addition to the inability of studying macrophages we must also add that unfortunately, only anecdotical reports (20,21) have dealt with the role of inflammasomes regarding strains of resistant bacteria, so our hypothesis of "abnormal normality" has to be verified with a more conspicuous number of patients.…”