Enterococcus faecalis modulation of NF-kB signaling in macrophages
Tagore, Soumili Bhaduri
Date of Issue2016-10-07
Interdisciplinary Graduate School
Singapore Center on Environmental Life Science and Engineering
Enterococcus faecalis is a gram-positive commensal of the mammalian gastrointestinal tract as well as an opportunistic pathogen that can lead to endocarditis, bacteraemia, wound infections, pelvic and soft tissue infections and urinary tract infections. E. faecalis has an intrinsic and acquired resistance to several antibiotics and a high mortality rate in immune-compromised patients. It is imperative to understand how E. faecalis bacteria evade host immune response and establishes robust opportunistic infections in order to identify novel therapeutic intervention points. In this thesis, we applied a model system to study NF-κB activity in response to E. faecalis and to identify bacterial factors which modulate NF-κB activity. Employing this model system, we have shown that E. faecalis prevents NF-κB activity in murine macrophages in a dose-dependent manner and prevents NF-κB activation in response to potent activators like lipopolysaccharide and lipoteichoic acid. We established that the E. faecalis NF-κB suppressing molecule is bacterial surface-associated, heat modifiable and not secreted. We have shown that bacterial virulence factors sortase A and autolysin are important to prevent NF-κB suppression in macrophages. Furthermore, we identified a novel function for an uncharacterized sortase substrate in preventing NF-κB activity. Finally, we have identified a previously undescribed function for E. faecalis gDNA as an immunosuppresor molecule in murine immune cells. Taken together this work helps to better understand enterococcal pathogenesis and immune modulatory capability.