Galectin-1–Driven Tolerogenic Programs Aggravate <i>Yersinia enterocolitica</i> Infection by Repressing Antibacterial Immunity

Abstract

<i>Yersinia enterocolitica</i> is an enteropathogenic bacterium that causes gastrointestinal disorders, as well as extraintestinal manifestations. To subvert the host's immune response, <i>Y. enterocolitica</i> uses a type III secretion system consisting of an injectisome and effector proteins, called <i>Yersinia</i> 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 <i>Y. enterocolitica</i> 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 <i>Y. enterocolitica</i> serotype O:8 compared with noninfected hosts. This effect was prevented when mice were infected with <i>Y. enterocolitica</i> lacking YopP or YopH, two critical effectors involved in bacterial immune evasion. Consistent with a regulatory role for this lectin during <i>Y. enterocolitica</i> 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 <i>Y. enterocolitica</i> infection. Thus, targeting Gal-1-glycan interactions may contribute to reinforce antibacterial responses by reprogramming innate and adaptive immune mechanisms.