Galectin-1–Driven Tolerogenic Programs Aggravate Yersinia enterocolitica Infection by Repressing Antibacterial Immunity

Abstract

is an enteropathogenic bacterium that causes gastrointestinal disorders, as well as extraintestinal manifestations. To subvert the host's immune response, uses a type III secretion system consisting of an injectisome and effector proteins, called outer proteins (Yops), that modulate activation, signaling, and survival of immune cells. In this article, we show that galectin-1 (Gal-1), an immunoregulatory lectin widely expressed in mucosal tissues, contributes to pathogenicity by undermining protective antibacterial responses. We found higher expression of Gal-1 in the spleen and Peyer's patches of mice infected orogastrically with serotype O:8 compared with noninfected hosts. This effect was prevented when mice were infected with lacking YopP or YopH, two critical effectors involved in bacterial immune evasion. Consistent with a regulatory role for this lectin during pathogenesis, mice lacking Gal-1 showed increased weight and survival, lower bacterial load, and attenuated intestinal pathology compared with wild-type mice. These protective effects involved modulation of NF-κB activation, TNF production, and NO synthesis in mucosal tissue and macrophages, as well as systemic dysregulation of IL-17 and IFN-γ responses. In vivo neutralization of these proinflammatory cytokines impaired bacterial clearance and eliminated host protection conferred by Gal-1 deficiency. Finally, supplementation of recombinant Gal-1 in mice lacking Gal-1 or treatment of wild-type mice with a neutralizing anti-Gal-1 mAb confirmed the immune inhibitory role of this endogenous lectin during infection. Thus, targeting Gal-1-glycan interactions may contribute to reinforce antibacterial responses by reprogramming innate and adaptive immune mechanisms.

Galectin-1: A Jack-of-All-Trades in the Resolution of Acute and Chronic Inflammation

“…Within the immune system, Gal-1 is synthesized and secreted by a wide range of cells, including activated T and B cells (22,23), macrophages (24), Foxp3 + regulatory T cells (Tregs) (25,26), tolerogenic dendritic cells (DCs) (27,28), gd T cells (29), microglia (30), and myeloid-derived suppressor cells (29). Remarkably, Gal-1 expression is prominent in immuneprivileged sites, such as placenta (31,32), testis (33,34), and the eye (35), and is significantly up-or downmodulated in inflammatory conditions, including microbial infection (36)(37)(38), autoimmunity (27,39), allergy (40,41), cancer (19,29,(42)(43)(44), reproductive disorders (31,32,45,46), neurodegenerative diseases (30), and myocardial infarction (47). Interestingly, in experimental models, Gal-1 expression peaks during the recovery phase of autoimmune disease (27,30), indicating a major role for this lectin during resolution of inflammation.…”

“…Moreover, microbes may co-opt inhibitory pathways to subvert host protective immunity (1). Recently we found that Gal-1driven tolerogenic circuits can repress protective immunity during infection with Yersinia enterocolitica, an enteropathogenic bacterium, by targeting local immunity, including NO production, NF-kB activation, and TNF synthesis, as well as systemic Th1 and Th17 responses (38). Similarly, in a model of Trypanosoma cruzi infection, Gal-1 fueled the activation of immunoregulatory circuits that hindered antiparasite immunity, particularly those involving differentiation of tolerogenic DCs and Tregs (37).…”

Glycosylation-dependent galectin–receptor interactions promote Chlamydia trachomatis infection

“…Regarding bacterial infections, Gal4 and Gal8, two-CRD galectins, have been shown to recognize and kill bacteriaexpressing B− blood group antigens on their surface (54). Finally, pathogenic bacteria may also subvert recognition of host galectins to ensure successful attachment and invasion of target cells leading to alteration of immune responses (37). In conclusion, our study utilizes both in vitro and in vivo strategies to demonstrate that Gal1 favors the development of productive chlamydial infections by modulating attachment and internalization of bacteria into host cells via an N-glycandependent mechanism.…”

“…With regards to bacterial infections, desialylation of airway epithelial cells by neuraminidases enhances adhesion of Streptococcus pneumoniae by facilitating Gal1 binding to specific glycans (36). Moreover, we recently found that the enteropathogenic bacterium Yersinia enterocolitica represses protective immune programs via Gal1-dependent pathways (37). Furthermore, in a model of Pseudomonas aeruginosa infection, Gal1 suppresses corneal immunopathology by limiting pathogenic Th17 responses (38).…”

TrkB-Target Galectin-1 Impairs Immune Activation and Radiation Responses in Neuroblastoma: Implications for Tumour Therapy

“…Impaired tolerance in the allogeneic setting might be due to enhanced cytotoxic T cell activity in the absence of Gal-1, while Gal-1 derived from NK cells was sufficient to induce apoptosis in activated T cells [ 42 ]. A tolerogenic role of Gal-1 has also been described in the context of bacterial infections [ 43 ] and in T. cruzi infected mice, in which Gal-1 is produced and secreted by B cells [ 44 ]. While Gal-1 is dispensable for normal development, at least in mice, it has important functions in modulating innate and adaptive immune mechanisms.…”