Activation of TLR2 and TLR4 by Glycosylphosphatidylinositols Derived from Toxoplasma gondii

Abstract

GPIs isolated from Toxoplasma gondii, as well as a chemically synthesized GPI lacking the lipid moiety, activated a reporter gene in Chinese hamster ovary cells expressing TLR4, while the core glycan and lipid moieties cleaved from the GPIs activated both TLR4- and TLR2-expressing cells. MyD88, but not TLR2, TLR4, or CD14, is absolutely needed to trigger TNF-α production by macrophages exposed to T. gondii GPIs. Importantly, TNF-α response to GPIs was completely abrogated in macrophages from TLR2/4-double-deficient mice. MyD88−/− mice were more susceptible to death than wild-type (WT), TLR2−/−, TLR4−/−, TLR2/4−/−, and CD14−/− mice infected with the ME-49 strain of T. gondii. The cyst number was higher in the brain of TLR2/4−/−, but not TLR2−/−, TLR4−/−, and CD14−/−, mice, as compared with WT mice. Upon infection with the ME-49 strain of T. gondii, we observed no decrease of IL-12 and IFN-γ production in TLR2-, TLR4-, or CD14-deficient mice. Indeed, splenocytes from T. gondii-infected TLR2−/− and TLR2/4−/− mice produced more IFN-γ than cells from WT mice in response to in vitro stimulation with parasite extracts enriched in GPI-linked surface proteins. Together, our results suggest that both TLR2 and TLR4 receptors may participate in the host defense against T. gondii infection through their activation by the GPIs and could work together with other MyD88-dependent receptors, like other TLRs or even IL-18R or IL-1R, to obtain an effective host response against T. gondii infection.

Recombinant Ov-ASP-1, a Th1-Biased Protein Adjuvant Derived from the Helminth Onchocerca volvulus, Can Directly Bind and Activate Antigen-Presenting Cells

“…But, they share a common activation pathway mediated through their Toll-IL-1R signaling domain resulting in activation of NF-B and MAPK. Previous results have also demonstrated that a number of pathogen-derived PAMP-containing ligands could simultaneously activate TLR2 and TLR4 (46 -48), such as the major surface protein of Wolbachia endosymbionts in filarial nematodes (43) and the glycosylphosphatidylinositols derived from T. gondii (46). Structural homology analyses of Ov-ASP-1 with the crystallized closely related hookworm-secreted protein Na-ASP-2 suggest that Ov-ASP-1 has three distinct functional domains (49).…”

Combined Effect of TLR2 Gene Polymorphism and Early Life Stress On the Age at Onset of Bipolar Disorders

“…the hypothalamic-pituitary-adrenal axis (FKBP5), the monoaminergic system (SLC6A4, COMT) and the neurotrophic support of the CNS (BDNF), provided logical candidate genes to test for gene-environment interactions in several studies and confirmed the suspected genetic vulnerability and epigenetic changes to stressful/traumatic life events in psychiatric settings [46][47][48][49][50][51][52][53]. However, these molecules are not in direct relationship with the potential environmental risk factors as it is the case with TLR2, a sensor of BD-associated neurotropic pathogens [54][55][56]. This is of importance as prenatal immune priming through the TLR-mediated pathway and peripubertal stress exposure synergistically induced behavioral changes, unbalanced neurotransmitter levels and enhanced the expression of markers of inflammation and of microglia activation in stress sensitive brain areas of mice [35].…”

Candidate gene analysis of ocular toxoplasmosis in Brazil: evidence for a role for toll-like receptor 9 (TLR9)

“…Core glycans and lipid moieties obtained from parasite GPI are recognized by both TLR2 and TLR4, both of which mediate recognition of T. gondii GPI in mouse macrophages as measured by induction of TNF-α (Debierre-Grockiego et al 2007). Mice deficient in both TLR2 and TLR4, but not TLR2 alone, show complete abrogation of TNF-α in response to GPI (Debierre-Grockiego et al 2007). This suggests that TLR2 and TLR4 cooperate during T. gondii infection.…”