Toll-Like Receptor 2 Deficiency Is Associated with Enhanced Severity of Group B Streptococcal Disease

Abstract

Group B streptococcus (GBS) has been recognized as an ever-growing cause of serious invasive infections in nonpregnant adults, in particular, in association with severe underlying diseases. The most common manifestations include primary bacteremia, urinary tract infections, pneumonia, meningitis, peritonitis, and osteoarticular infections. Toll-like receptor-2 (TLR2) mediates host responses to gram-positive bacteria. TLR2 function was investigated in murine GBS-induced sepsis and arthritis in wild-type (wt) and TLR2-deficient (TLR2 ؊/؊ ) mice. Mice were infected with different doses of GBS (10 7 , 5 ؋ 10 6 , or 10 6 CFU per mouse). Mortality, appearance of arthritis, GBS growth in the organs, and local and systemic cytokine and chemokine production were examined. TLR2؊/؊ mice showed earlier and higher mortality rates and increased incidence and severity of arthritis than wt mice at all the infecting doses employed. Histopathological analysis of the joints confirmed clinical observations. TLR2 ؊/؊ mice exhibited a higher microbial load in blood, kidneys, and joints than wt animals. In vitro experiments performed with peritoneal polymorphonuclear cells and macrophages showed a significantly lower bactericidal ability of cells from TLR2 ؊/؊ mice. Increased systemic and local levels of interleukin-1␤ (IL-1␤), IL-6, tumor necrosis factor alpha, macrophage inflammatory protein-1␣ (MIP-1␣), and MIP-2 accompanied the more severe development of sepsis and arthritis in TLR2 ؊/؊ mice. In conclusion, the lack of TLR2 was associated with an impaired host resistance to GBS infection, likely due to a diminished bacterial clearing and a consequent enhanced inflammatory response.

Evaluating the role of Toll-like receptors in diseases of the central nervous system

“…Furthermore GBS can trigger microglial apoptosis in a pathway dependent upon TLR2 and caspase 8 [101]. A functional interaction between TLR2 and GBS is consistent with other studies which indicate that TLR2 is required for host defence against GBS in other disease settings such as arthritis and sepsis [102].…”

Transmission of endoplasmic reticulum stress and pro-inflammation from tumor cells to myeloid cells

“…3 A and B). Of note, we found that TLR2 KO BMDM secreted increased amounts of MIP-1α, MIP-1β, and monocyte chemoattractant protein-1 (MCP-1) in response to the ER stressconditioned medium relative to WT BMDM, suggesting that TLR2 may normally function as a negative regulator in response to proinflammatory stimuli (22,23). Next, we turned our attention to the IL-6R based on the following: (i) both cancer cells and macrophages secrete IL-6, a proliferative antiapoptotic proinflammatory cytokine; (ii) IL-6 production can be amplified by autocrine/paracrine mechanisms via IL-6 receptor (IL-6R) signaling (2); and (iii) the supernatant of LLC cells up-regulates IL-6 production in myeloid cells (6).…”

Aryl hydrocarbon receptor control of a disease tolerance defence pathway

“…Next, we evaluated the impact of endotoxin tolerance on group B Streptococcus (GBS)-induced multifocal septic arthritis, a condition in which functional TLR2 signaling is necessary for attenuating the severity of group B streptococcal disease 33 . Mice preconditioned as in the Salmonella model were infected i.v.…”

“…Morphological investigation the lungs, livers and ceca of mice treated with different doses of LPS or l -kynurenine were as described 33 , and so were measurements of IDO1 functional activity in terms of l -kynurenine production 18 . In Fig.…”