Important Role for Toll-Like Receptor 9 in Host Defense against Meningococcal Sepsis

Abstract

Neisseria meningitidis is a leading cause of meningitis and sepsis. The pathogenesis of meningococcal disease is determined by both bacterial virulence factors and the host inflammatory response. Toll-like receptors (TLRs) are prominent activators of the inflammatory response, and TLR2, -4, and -9 have been reported to be involved in the host response to N. meningitidis. While TLR4 has been suggested to play an important role in early containment of infection, the roles of TLR2 and TLR9 in meningococcal disease are not well described. Using a model for meningococcal sepsis, we report that TLR9 ؊/؊ mice displayed reduced survival and elevated levels of bacteremia compared to wild-type mice. In contrast, TLR2؊/؊ mice controlled the infection in a manner comparable to that of wild-type mice. TLR9 deficiency was also associated with reduced bactericidal activity in vitro, which was accompanied by reduced production of nitric oxide by TLR9-deficient macrophages. Interestingly, TLR9؊/؊ mice recruited more macrophages to the bloodstream than wild-type mice and produced elevated levels of cytokines at late time points during infection. At the cellular level, activation of signal transduction and induction of cytokine gene expression were independent of TLR2 or TLR9 in macrophages and conventional dendritic cells. In contrast, plasmacytoid dendritic cells relied entirely on TLR9 to induce these activities. Thus, our data demonstrate an important role for TLR9 in host defense against N. meningitidis.

Polysaccharide-Specific Memory B Cells Generated by Conjugate Vaccines in Humans Conform to the CD27+IgG+ Isotype–Switched Memory B Cell Phenotype and Require Contact-Dependent Signals from Bystander T Cells Activated by Bacterial Proteins To Differentiate into Plasma Cells

“…meningitidis also contains functional CpG DNA motifs that drive B MEM activation via the intracellular receptor TLR9, constitutively expressed by human B MEM although also upregulated on cross-linking of the BCR (34,63,64). The stimulation of human B MEM with CpG DNA results in both the proliferation of the population and also in their subsequent differentiation into PC (17,65).…”

Activation of Human and Chicken Toll-Like Receptors by Campylobacter spp

“…In strains that artificially express TLR4-stimulating LPS, virulence is completely overcome by an activated host immune system (39). Likewise, studies with knockout mice clearly show the need for TLR activation to control bacterial virulence: TLR5 knockout mice exhibit increased bacterial load and inflammation in the intestine (56), TLR9 deficiency leads to uncontrolled Neisseria meningitidis infection (47), and MyD88-deficient mice are more sensitive to a wide range of bacterial infections (16,36,51). The extent to which TLR activation influences Campylobacter infection in humans and animal species is currently unknown.…”

Toll-Like Receptor 9 Contributes to Defense against Acinetobacter baumannii Infection

“…Signaling through TLR9 has various effects on disease outcomes in murine models of acute bacterial infections. Mice lacking TLR9 have increased mortality and increased bacterial burdens in Klebsiella pneumoniae, Legionella pneumophila, and Streptococcus pneumoniae models of pneumonia, as well as a Neisseria meningitides model of sepsis (22)(23)(24)(25)(26). However, TLR9-mediated pathogen detection is detrimental in a Staphylococcus aureus murine pneumonia model, as well as a cecal ligation and puncture model of polymicrobial sepsis (27,28).…”