Abstract
Enterococcus faecalis is a commensal bacterium residing in the gastrointestinal tract of mammals, but in certain situations it is also an opportunistic pathogen which can cause serious disease. Macrophages have been shown to play a critical role in controlling infections by commensal enterococci and also have an important role in mediating chromosomal instability and promoting colon cancer during high-level enterococcal colonization in genetically susceptible mice. However, the molecular mechanisms involved in the interaction of macrophages with enterococci during infection are not fully understood. In this study, using BMDM and RAW264.7 macrophages we show that enterococcal infection activates ERK, JNK and p38 MAPK as well as NF-κB, and drives polarization of macrophages towards the M1 phenotype. Inhibition of NF-κB activation significantly reduced the expression of TNF-α and IL-1β, as did the inhibition of ERK, JNK and p38 MAPK, although to differing extent. Enterococci-induced activation of these pathways and subsequent cytokine expression was contact dependent, modest compared to activation by E. coli and, required the adaptor protein MyD88. Phagocytosis of enterococci by macrophages was enhanced by preopsonization with E. faecalis antiserum and involved the ERK and JNK signaling pathways, with the adaptor protein MyD88 as an important mediator. This study of the interaction of macrophages with enterococci could provide a foundation for studying the pathogenesis of infection by this opportunistic pathogen and to developing new therapeutic approaches to combat enterococcal infection.
Highlights
Enterococci are commensal organisms colonizing the gastrointestinal tract of all human and animals [1]
The mRNA of TNF-α, IL-1β, inducible NO synthase (iNOS) and INF-γ were measured as cytokines expressed by M1 type macrophages, whereas arginase and IL-4 mRNA were monitored as M2 phenotype-related cytokines
We treated bone marrow derived macrophage (BMDM) with E. faecalis E99 strain for 1 or 5 h, and found that the level of TNF-α, IL-1β, iNOS and INF-γ were significantly increased, while the M2-related cytokines including arginase and IL-4 gradually declined during enterococcal infection (Fig 1)
Summary
Enterococci are commensal organisms colonizing the gastrointestinal tract of all human and animals [1]. Despite being a commensal organism, E. faecalis is endowed with traits that make it an opportunistic pathogen, especially in the immunocompromised host. E. faecalis Infection and Host Cell Signaling enterococcal disease include urinary tract infections, hepatobiliary sepsis, endocarditis, surgical wound infections, bacteremia and neonatal sepsis [2]. Treatment options for these infections can often be an insurmountable challenge in the clinical setting on account of the high levels of intrinsic antibiotic resistance encountered in E. faecalis and E. faecium, the two most common enterococcal species associated with infections. Despite the clinical importance of enterococci, little is known about innate defense mechanisms that protect the normal host against invasive enterococcal infections
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