Cutting Edge: TLR9 and TLR2 Signaling Together Account for MyD88-Dependent Control of Parasitemia in Trypanosoma cruzi Infection

Abstract

Activation of innate immune cells by Trypanosoma cruzi-derived molecules such as GPI anchors and DNA induces proinflammatory cytokine production and host defense mechanisms. In this study, we demonstrate that DNA from T. cruzi stimulates cytokine production by APCs in a TLR9-dependent manner and synergizes with parasite-derived GPI anchor, a TLR2 agonist, in the induction of cytokines by macrophages. Compared with wild-type animals, T. cruzi-infected Tlr9−/− mice displayed elevated parasitemia and decreased survival. Strikingly, infected Tlr2−/−Tlr9−/− mice developed a parasitemia equivalent to animals lacking MyD88, an essential signaling molecule for most TLR, but did not show the acute mortality displayed by MyD88−/− animals. The enhanced susceptibility of Tlr9−/− and Tlr2−/−Tlr9−/− mice was associated with decreased in vivo IL-12/IFN-γ responses. Our results reveal that TLR2 and TLR9 cooperate in the control of parasite replication and that TLR9 has a primary role in the MyD88-dependent induction of IL-12/IFN-γ synthesis during infection with T. cruzi.

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

“…This suggests that TLR2 and TLR4 cooperate during T. gondii infection. Similar conclusions have been made in relation to cooperation between TLR2-TLR9 in mediating protection against Trypanosoma cruzi infection in mice (Bafica et al 2006), as well as in models of Mycobacterium tuberculosis infection (Bafica et al 2005). T. gondii heat shock protein 70 has also been implicated in maturation of dendritic cells via TLR4 (Aosai et al 2006) and an important indirect effect of TLR4 stimulation is seen in induction of inflammation in the small intestine following oral infection of mice due to substantial overgrowth of commensals in the ileum (Heimesaat et al 2007).…”

Swimming against the current: genetic vaccination against Trypanosoma cruzi infection in mice

“…This latter phase is the period when most transmission to invertebrate hosts occurs. During the early stages of the acute phase, hosts survive because of strong innate immunity, mediated mostly by Toll-like receptors through the activation of the adaptor molecule MyD88 (Campos et al 2004, Bafica et al 2006, Bartholomeu et al 2008. However, to avoid elimination, the parasite manages to significantly delay the onset of the CD8 + T cell-mediated immunity (CMI) response (Martin et al 2006, Tzelepis et al 2006, 2007.…”

MyD88-Dependent Signals Are Essential for the Host Immune Response in Experimental Brain Abscess

“…A pivotal component of innate immunity is the intracellular protein MyD88, which represents the central adapter protein for the majority of the TLRs (1) identified to date (with the exception of TLR3) in addition to transducing activation signals emanating from the IL-1 and IL-18 receptors (14 -16). Previous studies have demonstrated that MyD88 knockout (KO) 3 mice exhibit dramatic defects in antibacterial immunity in a variety of infectious disease models, highlighting the importance of this adapter in influencing a wide array of host responses (17)(18)(19)(20)(21).…”