Advances in the glycobiology and immunology fields have provided many insights into the role of carbohydrate-protein interactions in the immune system. We aim to present a comprehensive review of the effects that some plant lectins exert as immunomodulatory agents, showing that they are able to positively modify the immune response to certain pathological conditions, such as cancer and infections. The present review comprises four main themes: (1) an overview of plant lectins that exert immunomodulatory effects and the mechanisms accounting for these activities; (2) general characteristics of the immunomodulatory lectin ArtinM from the seeds of Artocarpus heterophyllus; (3) activation of innate immunity cells by ArtinM and consequent induction of Th1 immunity; (4) resistance conferred by ArtinM administration in infections with intracellular pathogens, such as Leishmania (Leishmania) major, Leishmania (Leishmania) amazonensis, and Paracoccidioides brasiliensis. We believe that this review will be a valuable resource for more studies in this relatively neglected area of research, which has the potential to reveal carbohydrate targets for novel prophylactic and therapeutic strategies.

Trichoderma harzianum species are well known as biocontrol agents against important fungal phytopathogens. Mycoparasitism is one of the strategies used by this fungus in the biocontrol process. In this work, we analyzed the effect of Epl-1 protein, previously described as plant resistance elicitor, in expression modulation of T. harzianum genes involved in mycoparasitism process against phytopathogenic fungi; self cell wall protection and recognition; host hyphae coiling and triggering expression of defense-related genes in beans plants. The results indicated that the absence of Epl-1 protein affects the expression of all mycoparasitism genes analyzed in direct confrontation assays against phytopathogen Sclerotinia sclerotiorum as well as T. harzianum itself; the host mycoparasitic coiling process and expression modulation of plant defense genes showing different pattern compared with wild type strain. These data indicated the involvement T. harzianum Epl-1 in self and host interaction and also recognition of T. harzianum as a symbiotic fungus by the bean plants.

The signaling second messenger cyclic AMP (cAMP) regulates many aspects of cellular function in all organisms. Previous studies have suggested a role for cAMP in the regulation of gene expression of cellulolytic enzymes in Trichoderma reesei (anamorph of Hypocrea jecorina). The effects of cAMP in T. reesei were analyzed through both activity and expression of cellulase, intracellular cAMP level measurement, western blotting, indirect immunofluorescence and confocal microscopy. To elucidate the involvement of cAMP in the cellulase expression, we analyzed the growth of the mutant strain ∆acy1 and its parental strain QM9414 in the presence of the inducers cellulose, cellobiose, lactose, or sophorose, and the repressor glucose. Our results indicated that cAMP regulates the expression of cellulase in a carbon source-dependent manner. The expression cel7a, and cel6a genes was higher in the presence of sophorose than in the presence of cellulose, lactose, cellobiose, or glucose. Moreover, intracellular levels of cAMP were up to four times higher in the presence of sophorose compared to other carbon sources. Concomitantly, our immunofluorescence microscopy and western blot data suggest that in the presence of sophorose, cAMP may regulate secretion of cellulolytic enzymes in T. reesei. These results allow us to better understand the role of cAMP and expand our knowledge on the signal transduction pathways involved in the regulation of cellulase expression in T. reesei. Finally, our data may help develop new strategies to improve the expression of cel7a and cel6a genes, and therefore, favor their application in several biotechnology fields.

We have reported that some lectins act as agonists of TLRs and have immunomodulatory properties. The plant lectin ArtinM 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. These interactions trigger cell signaling that leads to NF-kB activation and production of the Th1 polarizing cytokine IL-12. In vivo, the administration of an active lectin to mice infected with an intracellular pathogen is followed by the same sequence of events, conferring resistance to the pathogen. The human pathogens Toxoplasma gondii (TgMIC1 and TgMIC4) and Paracoccidioides brasiliensis (Paracoccin, PCN) by recognition and activation of TLR2 and TLR4 induce cell events and in vivo effects comparable to the promoted by ArtinM. In this article, we highlight these two distinct mechanisms for activating antigen presenting cells. TLRs act as sensors for the presence of conventional pathogen-associated molecular patterns such as microbial lipids. On the other hand, our results show that there is an alternative way to trigger TLR-mediated cell activation, in which lectins bind to receptor N-glycans and stimulate activation of cells, leading to expression of pro-inflammatory cytokines. This process may lead to the development of new pharmaceutical tools that are effective promoters of protective immune responses directed against intracellular pathogens and potentially tumors.

ArtinM, a D-mannose binding lectin from Artocarpus heterophyllus, has immunomodulatory activities through its interaction with N-glycans of immune cells, culminating with the establishment of T helper type 1 (Th1) immunity. This interaction protects mice against intracellular pathogens, including Leishmania major and Leishmania amazonensis. ArtinM induces neutrophils activation, which is known to account for both resistance to pathogens and host tissue injury. Although exacerbated inflammation was not observed in ArtinM-treated animals, assessment of neutrophil responses to ArtinM is required to envisage its possible application to design a novel immunomodulatory agent based on carbohydrate recognition. Herein, we focus on the mechanisms through which neutrophils contribute to ArtinM-induced protection against Leishmania, without exacerbating inflammation. For this purpose, human neutrophils treated with ArtinM and infected with Leishmania major were analyzed together with untreated and uninfected controls, based on their ability to eliminate the parasite, release cytokines, degranulate, produce reactive oxygen species (ROS), form neutrophil extracellular traps (NETs) and change life span. We demonstrate that ArtinM-stimulated neutrophils enhanced L. major clearance and at least duplicated tumor necrosis factor (TNF) and interleukin-1beta (IL-1β) release; otherwise, transforming growth factor-beta (TGF-β) production was reduced by half. Furthermore, ROS production and cell degranulation were augmented. The life span of ArtinM-stimulated neutrophils decreased and they did not form NETs when infected with L. major. We postulate that the enhanced leishmanicidal ability of ArtinM-stimulated neutrophils is due to augmented release of inflammatory cytokines, ROS production, and cell degranulation, whereas host tissue integrity is favored by their shortened life span and the absence of NET formation. Our results reinforce the idea that ArtinM may be considered an appropriate molecular template for the construction of an efficient anti-infective agent. Vaccination is a successful way to eliminate infectious diseases. The generated antibodies neutralize the invading microbe and avoid the establishment of infection. Vaccines are efficient to prevent infections by pathogens living outside rather than inside the host`s cells. This occurs because protection against intracellular pathogens requires the engagement of T lymphocytes. The discovery of receptors on innate immunity cells opened new perspectives in trying manners to stimulate effective response against intracellular pathogens. Frequently the microbial sensing by Toll-like receptors (TLRs) besides triggering immediate defense also orchestrates adaptative immunity towards T-cell response. Therefore, TLR ligands started to be assayed in new anti-infective approaches. Our laboratory has been investigating the immunomodulation induced by lectins, which are ubiquitous sugar-binding proteins. Our primary model is ArtinM, from the seeds of jackfruit, a lectin that binds to TLR2 sugar chains on macrophages and dendritic cells and promotes production of cytokines that engages T lymphocytes in a process that culminate with elimination of intracellular pathogens. Concomitantly, ArtinM activates other immune cells, including neutrophils, which contributes to the pathogen elimination, but may also account for tissue damage. This last possibility led us to investigate the lectin effects on neutrophils deeply. We analyzed neutrophils treated with ArtinM and infected with Leishmania major. We concluded that the leishmanicidal ability of ArtinM-stimulated neutrophils was due to augmented release of inflammatory cytokines, ROS production, and cell degranulation. Otherwise, host tissue integrity is favored by shortened cells lifespan and absence of NET formation. This work reinforces the idea that ArtinM can be an appropriate molecular template for the construction of an efficient anti-infective agent.