Galectin-1 is a 14-kDa protein that contains 135 amino acids and is encoded by the LGALS1 gene [13]. Human galectin-1 is soluble and exists in a dimeric form maintained by non-covalent binding [14]. This dimeric protein is composed of the 22-strand anti-parallel β-sandwich, and each monomer contains a CRD [15]. In addition to being found in the cytoplasm, galectin-1 is also found to be present on the cell membrane and can be secreted into the extracellular matrix. Of note, each monomer of galectin-1 contains six cysteine residues (Cys2, Cys16, Cys42, Cys60, Cys88, and Cys130), and the reduced or oxidized states of them play a significant impact on the function of this protein [16]. The oxidation of galectin-1, existing as a monomer, reduces the T-cell apoptosis activity [16] but shows an ability to promote axonal regeneration [17].

Galectin-1 is broadly expressed in a wide range of tissues as well as cell types and can exert its effects both intracellularly and extracellularly [18]. It was reported that intracellular galectin-1 is not only a functionally redundant splicing factor, which can bind splicing partners through weak protein-protein interactions [19] but is also involved in intracellular signaling [20]. Extracellular galectin-1 typically exists in the reduced state and performs function through carbohydrate recognition domains. By forming cross-linking heterodimers, extracellular galectin-1 can facilitate interactions between cells and cells as well as cells and extracellular matrix [21,22]. Interestingly, secreted galectin-1 bound to the cell surface or extracellular matrix has a more substantial effect than soluble galectin-1, as Jiale He et al. found that galectin-1 on Matrigel could kill T cells at Ten-fold less concentration than soluble galectin-1 [23]. Since its discovery, galectin-1 has been demonstrated to mediate diverse physiological and pathological processes, such as being involved in cell growth and migration, inflammation, angiogenesis and promoting nervous system development, muscle differentiation, and tumor progression, mediating evasion of cancer immune surveillance, immune tolerance in the early pregnancy and cell adhesion [18,24,25,26]. In recent years, there has been growing awareness that galectin-1 plays a vital role in modulating immune response.

It is often considered that galectin-1 performs an anti-inflammatory role in most cases, as Rabinovich et al. demonstrated that bee venom phospholipase A(2) induced acute inflammation was attenuated by galectin-1 in the rat hind paw edema test [27]. However, this may only sometimes be the case since the effect of galectin-1 may be changed by the stage of inflammation, the status of cell glycosylation, and many other factors [28,29]. The dual roles of galectin-1 in infection are discussed in the following three subsections.

In most instances, bacteria can take advantage of the anti-inflammatory effects of galectin-1 to circumvent protective host immunity. In the research by Davicino et al., endogenous galectin-1 regulate tolerogenic response by impairing the production of interferon-γ (IFN-γ) and interleukin (IL)-17, repressing synthesis of tumor necrosis factor (TNF) and nitric oxide (NO) as well as activation of nuclear factor kB (NF-kB), thereby promoting infection of Yersinia enterocolitica [30]. Interestingly, in the recent research of this same microorganism, Jofre et al. proposed a novel mechanism that galectin-1 could bind to virulence factors of Yersinia enterocolitica named Yops and protect them from trypsin digestion [31]. For intracellular bacteria such as Tropheryma whipplei, which can replicate in macrophages, crosslinking between bacterial glycans and cell surface glycans mediated by galectin-1 facilitate T. whipplei cell entry [32]. Of note, the anti-inflammatory effects of galectin-1 do not always play the role of “evildoer” in bacterial infection. It was reported that galectin-1 substantially attenuated CD4+ T cells, neutrophils, and CD45+ T infiltration as well as T helper (Th) 17 response, which diminished severe corneal immunoinflammatory impairment caused by infection of Pseudomonas aeruginosa [33].

However, galectin-1 also exerts pro-inflammatory effects in certain cases and promotes inflammatory lethality. Such dual effects appear to be most pronounced in neutrophils. It was shown that galectin-1 was capable of inducing phosphatidylserine (PS) exposure on the surface of human-activated, rather than resting, neutrophils, which promoted their phagocytosis by activated macrophages [34,35]. Nevertheless, Almkvist et al. demonstrated that galectin-1 contributed to the activation of the NADPH-oxidase in primed neutrophils [36]. These seemingly paradoxical roles of galectin-1 may be a protective mechanism that strengthens the bacterial killing capacity of neutrophils while protecting healthy tissues from inflammatory damage. However, the reactive oxygen species (ROS) production was not enhanced in naïve neutrophils following galectin-1 induction and pretreatment with galectin-1 attenuated the production of ROS upon stimulation of N-formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol myristate acetate (PMA), suggesting that the role of galectin-1 depended on the activation state of neutrophils as well as the stage of the inflammatory response [36,37]. Additionally, through binding to sialoglycoprotein CD43, galectin-1 was evidenced to induce the migration of human resting neutrophils under physiological conditions without additional inflammatory insults, whereas inhibition of polymorphonuclear leukocyte migration was observed following treatment with galectin-1 for 4 h in a murine acute inflammation model, accompanied by impaired expression of adhesion molecules [38,39]. Moreover, an updated study demonstrated that galectin-1 was an inflammatory damage-associated molecular pattern (DAMP) whose release was elicited by cytosolic lipopolysaccharide (LPS) sensing during Infections caused by Gram-negative bacteria. Additionally, it could accentuate lethal inflammation caused by sepsis through the inhibition of CD45 [28].

Overall, on the one hand, galectin-1 facilitates bacterial infection via diminishing the host immune response, protecting bacterial causative proteins as well as mediating the transport of bacteria. On the other hand, it is capable of promoting the development of inflammation in specific circumstances by enhancing the killing ability of neutrophils and augmenting inflammatory damage elicited by bacterial endotoxins.

Mounting evidence indicates that galectin-1 performs a number of functions via multiple mechanisms during virus infection. Take HIV infection as an example, galectin-1 was proved to facilitate interactions between viral envelope gp120 and host CD4+ T lymphocytes, thereby promoting attachment of the virus to target cells [40]. In addition to CD4+ T lymphocytes, monocyte-derived macrophages, which are usually one of the first target cells encountered by the virus, also provide a cellular environment for viral replication [41]. Additionally, galectin-1 mediates virus adhesion to macrophages in a glycan-binding manner [41,42]. As for the Nipah virus (NiV), it was reported that galectin-1 promoted NiV attachment to human epithelium [43].

However, during infection of the Dengue virus, galectin-1 seems to perform an anti-infection role. Toledo et al. found that galectin-1, rather than galectin-3, directly binding to dengue virus type 1 (DENV-1) causes inhibition of its internalization and adsorption to host cells, instead of facilitating adhesion [44]. Similarly, the infectivity and hemagglutination activity of the influenza virus was also diminished following galectin-1 binding to the viral envelope. Additionally, galectin-1 was applied as an intranasal treatment to attenuate inflammation, viral load as well as cell apoptosis caused by influenza in the lung [45]. Moreover, galectin-1 can bind to NiV-F and NiV-G, specific envelope glycoproteins of the Nipah virus, thereby thwarting endothelial cell fusion and syncytia formation [46,47]. This implies that galectin-1 is a protective factor during NiV infection, which seems to contradict what was mentioned above. The study of Garner et al. may explain this contradiction [43]. They found that the timing of virus exposure to galectin-1 could alter the effects. That is, pre-infective galectin-1 promotes NiV infection; in contrast, post-infective galectin-1 impairs syncytium formation as well as virus production, and this inhibition is unique to the Paramyxoviridae family [43,47]. These results suggest that the dual effects of galectin-1 are context-dependent and determined by multiple factors including species of virus and timing of exposure.

In parasitic infections, galectin-1 usually plays a pro-infection role. Endogenous galectin-1 was demonstrated to be a facilitator of parasitic infection by Poncini et al. in a Trypanosoma cruzi infection model. They found that a deficiency of galectin-1 thwarted the activation of dendritic cells (DCs) and regulatory T cells (Tregs), which meant galectin-1 fueled the immunotolerant circuits [48]. As for exogenous galectin-1, this glycan-binding protein secreted by Angiostrongylus cantonensis could bind to Annexin A2 and induce macrophage apoptosis [49]. In addition to exerting immunosuppressive properties, galectin-1 also mediates interactions between parasites and hosts. In the research of Okumura et al., they found that Trichomonas vaginalis were covered with lipophosphoglycan and contained a high abundance of galactose, which could serve as a binding site for galectin-1. Therefore, this parasite could attach to host cells through glycoconjugates [50]. Similarly, Petropolis demonstrated that human galectin-1 mediated the adhesion of Entamoeba histolytica to host endothelial cells in an in vitro human 3D-liver model [51]. Thus, the pro-infection abilities of galectin-1 are twofold. Firstly, both endo- and exogenous galectin-1 display immunosuppressive capability. Secondly, galectin-1 induces host-parasite interactions.