Toll-Like Receptors in Brain Abscess

Abstract

Brain abscesses arise from a localized parenchymal infection, typically elicited by pyogenic bacteria such as S. aureus. Despite improvements in detection and treatment strategies, brain abscesses continue to occur, with an increased prevalence in developing countries and immune compromised patients. Adding to the seriousness of these infections is the recent emergence of antibiotic-resistant strains of bacteria, which are becoming more commonly associated with brain abscesses. Recent studies using a mouse experimental brain abscess model have revealed a complex role for Toll-like receptors (TLRs) in disease pathogenesis. Interestingly, TLR2 has limited impact on the innate immune response during the acute stage of brain abscess formation induced by S. aureus but influences adaptive immunity. In contrast, mice deficient in MyD88, a central adaptor molecule for the majority of TLRs in addition to the IL-1R and IL-18R, demonstrate severe defects in innate immunity coupled with exaggerated tissue destruction. It is envisioned that understanding the roles for TLRs in both resident CNS glia as well as infiltrating immune cells will provide insights as to how the immune response to bacterial infection can be tailored to achieve effective pathogen destruction without inducing excessive bystander damage of surrounding non-infected brain parenchyma. A discussion of recent findings in this field is presented along with outstanding questions and the concept of a pathogen-necrosis-autoantigen triad for the amplification for TLR signaling is introduced.

Increased Disease Severity of Parasite-Infected TLR2−/−Mice Is Correlated with Decreased Central Nervous System Inflammation and Reduced Numbers of Cells with Alternatively Activated Macrophage Phenotypes in a Murine Model of Neurocysticercosis

“…Recent studies have demonstrated the role of TLRs in orchestrating an inflammatory cascade in various models of CNS infectious diseases (28,31), including bacterial meningitis (30), brain abscess (19,44), and viral (59) and parasitic infections (38). We have shown that TLR2 is upregulated within 1 to 2 days in the CNS of mice infected i.c.…”

Toll-like receptor (TLR) and inflammasome actions in the central nervous system

“…This may trigger the release of self-antigens or DAMPs, many of which would not typically be exposed to the extracellular milieu. For example, during CNS infection, TLRs might play a dual role in ligand recognition, first by facilitating responses to the inciting pathogen and upon tissue destruction, recognizing newly liberated self-antigens, a scenario termed the “pathogen-necrosis-autoantigen triad” [100]. Newly liberated self-antigens may serve as direct triggers for TLRs to perpetuate the inflammatory response.…”

Inflammasome activation and IL‐1β/IL‐18 processing are influenced by distinct pathways in microglia

“…Numerous pathophysiological processes occur during brain abscess development, including necrosis, apoptosis, and robust parenchymal inflammation (Stenzel et al. 2005b; Esen and Kielian 2009). One of the main pro‐inflammatory cytokines that is essential for generating a protective CNS anti‐bacterial immune response is IL‐1β (Kielian et al.…”