Mouse Macrophage Galactose-type Lectin (mMGL) is Critical for Host Resistance against Trypanosoma cruzi Infection

Abstract

The C-type lectin receptor mMGL is expressed exclusively by myeloid antigen presenting cells (APC) such as dendritic cells (DC) and macrophages (Mφ), and it mediates binding to glycoproteins carrying terminal galactose and α- or β-N-acetylgalactosamine (Gal/GalNAc) residues. Trypanosoma cruzi (T. cruzi) expresses large amounts of mucin (TcMUC)-like glycoproteins. Here, we show by lectin-blot that galactose moieties are also expressed on the surface of T. cruzi. Male mMGL knockout (-/-) and wild-type (WT) C57BL/6 mice were infected intraperitoneally with 104 T. cruzi trypomastigotes (Queretaro strain). Following T. cruzi infection, mMGL-/- mice developed higher parasitemia and higher mortality rates compared with WT mice. Although hearts from T. cruzi-infected WT mice presented few amastigote nests, mMGL-/- mice displayed higher numbers of amastigote nests. Compared with WT, Mφ from mMGL-/- mice had low production of nitric oxide (NO), interleukin (IL)-12 and tumor necrosis factor (TNF)-α in response to soluble T. cruzi antigens (TcAg). Interestingly, upon in vitro T. cruzi infection, mMGL-/- Mφ expressed lower levels of MHC-II and TLR-4 and harbored higher numbers of parasites, even when mMGL-/- Mφ were previously primed with IFN-γ or LPS/IFN-γ. These data suggest that mMGL plays an important role during T. cruzi infection, is required for optimal Mφ activation, and may synergize with TLR-4-induced pathways to produce TNF-α, IL-1β and NO during the early phase of infection.

MGL1 Receptor Plays a Key Role in the Control of T. cruzi Infection by Increasing Macrophage Activation through Modulation of ERK1/2, c-Jun, NF-κB and NLRP3 Pathways

“…Consistent with previous reports that demonstrated that MGL can modulate TLR activation [22,31], we observed significantly lower expression levels of TLR-2 and TLR-4 in MGL1 −/− PE-Mφ compared to WT PE-Mφ treated with TcAg or T. cruzi parasites (Figure 4a,b). Importantly, we also found reduced expression of MHC-II and CD40 in MGL1 −/− Mφ (Figure 4c,d).…”

“…Having demonstrated that MGL1 −/− Mφ infected in vitro with T. cruzi presented greater numbers of internalized parasites than WT Mφ [22], we extended this observation by showing that internalized parasites in MGL1 −/− Mφ remain alive. Moreover, following overnight incubation of MGL1 −/− Mφ with IFN-γ, LPS or both, there was not a significant reduction in the number of intracellular parasites, as occurred in the WT Mφ.…”

“…The generation of MGL1 −/− mice allows for investigating the immunological functions of MGL1 separately from that of MGL2 at the cellular level; using these mice, it has been possible to establish that MGL1 is capable of recognize glycosylated structures expressed in parasites including protozoa and helminths [8,22]. Our previous studies, conducted in a mouse model, demonstrated that the interaction of MGL1 with highly glycosylated structures of T. cruzi (as a natural ligand) plays an essential role in immunity by increasing Mφ activation and parasite killing during in vivo T. cruzi infection [22,43]. Despite this evidence pointing to a role for MGL1 in the immune response, how MGL1 modulates the immune response against this pathogen remains unclear.…”

“…We have previously reported that most TcAg bind to lectin Jacalin, which recognizes Gal residues; therefore, TcAg are glycosylated with Gal residues. In addition, we showed that MGL1 −/− mice were highly susceptible to T. cruzi infection, and they developed higher parasitemia and mortality rates than WT mice [22]. Since TcAg contains Gal residues and MGL1 −/− Mφ showed an impaired ability to eliminate this parasite, we hypothesized that MGL1 could play an important role in optimal Mφ activation.…”

Canine Macrophage DH82 Cell Line As a Model to Study Susceptibility to Trypanosoma cruzi Infection

“…In in vitro models of macrophages infection by T. cruzi , the resistance to infection is closely associated with activation and consequent increase in the microbicidal activity of macrophages (37, 38). Our results showed that resistance of the DH82 cells to T. cruzi infection was increased after stimulation, indicating that pretreatment with classical activators can modulate these macrophages.…”