Targeting and Recognition of Toll-Like Receptors by Plant and Pathogen Lectins

Abstract

We have reported that some lectins act as agonists of toll-like receptors (TLRs) and have immunomodulatory properties. The plant lectin ArtinM, for example, interacts with N-glycans of TLR2, whereas other lectins of microbial origin interact with TLR2 and TLR4. Expression of the receptors on the surface of antigen-presenting cells exposes N-glycans that may be targeted by lectins of different structures, specificities, and origins. In vitro, these interactions trigger cell signaling that leads to NF-κB activation and production of the Th1 polarizing cytokine IL-12. In vivo, a same sequence of events follows the administration of an active lectin to mice infected with an intracellular pathogen, conferring resistance to the pathogen. The lectins of the human pathogens Toxoplasma gondii (TgMIC1 and TgMIC4) and Paracoccidioides brasiliensis (Paracoccin), by recognition and activation of TLR2 and TLR4, induce cell events and in vivo effects comparable to the promoted by the plant lectin ArtinM. In this article, we highlight these two distinct mechanisms for activating antigen-presenting cells. On the one hand, TLRs act as sensors for the presence of conventional pathogen-associated molecular patterns, such as microbial lipids. On the other hand, we showed that TLR-mediated cell activation might be triggered by an alternative way, in which lectins bind to TLRs N-glycans and stimulate cells to increase the expression of pro-inflammatory cytokines. This process may lead to the development of new pharmaceutical tools that promote protective immune responses directed against intracellular pathogens and tumors.

Keywords: N-glycosylation; carbohydrate recognition domain; innate immune response; lectins; toll-like receptors.

Figure 1

Glycans N-linked to TLR2, expressed on the surface of antigen-presenting cells, are targeted by carbohydrate recognition domain (CRD) of some lectins. The established interactions are followed by intracellular signaling and production of cytokines. Fully glycosylated TLR2 molecules can be targeted by lectins CRDs (shown at the right side of the figure), besides recognizing pathogen-associated molecular patterns (PAMPs) and synthetic ligands. Either interaction induces activation of NF-κB signaling pathway and production of cytokines. Most constructed TLR2 glycomutants (exhibiting isolated or combined elimination of N-glycans) preserve the capacity to recognize PAMPs, whereas some of the glycomutants become selectively unresponsive to a specific lectin stimulus (shown at the left side of this figure). This approach allows defining which N-glycans are critically required to trigger TLR2 activation by a lectin. In this illustration, the TLR2 N-glycans (numbered 1–4 and linked to Asn116, Asn199, Asn416, and Asn442) are not rigorously localized in the TLR2 backbone. For a more realistic representation of N-glycans position on TLR2, see the article authored by Weber et al. (13).