Novel Innate Immune Functions for Galectin-1: Galectin-1 Inhibits Cell Fusion by Nipah Virus Envelope Glycoproteins and Augments Dendritic Cell Secretion of Proinflammatory Cytokines

Abstract

Galectin-1 (gal-1), an endogenous lectin secreted by a variety of cell types, has pleiotropic immunomodulatory functions, including regulation of lymphocyte survival and cytokine secretion in autoimmune, transplant disease, and parasitic infection models. However, the role of gal-1 in viral infections is unknown. Nipah virus (NiV) is an emerging pathogen that causes severe, often fatal, febrile encephalitis. The primary targets of NiV are endothelial cells. NiV infection of endothelial cells results in cell-cell fusion and syncytia formation triggered by the fusion (F) and attachment (G) envelope glycoproteins of NiV that bear glycan structures recognized by gal-1. In the present study, we report that NiV envelope-mediated cell-cell fusion is blocked by gal-1. This inhibition is specific to the Paramyxoviridae family because gal-1 did not inhibit fusion triggered by envelope glycoproteins of other viruses, including two retroviruses and a pox virus, but inhibited fusion triggered by envelope glycoproteins of the related Hendra virus and another paramyxovirus. The physiologic dimeric form of gal-1 is required for fusion inhibition because a monomeric gal-1 mutant had no inhibitory effect on cell fusion. gal-1 binds to specific N-glycans on NiV glycoproteins and aberrantly oligomerizes NiV-F and NiV-G, indicating a mechanism for fusion inhibition. gal-1 also increases dendritic cell production of proinflammatory cytokines such as IL-6, known to be protective in the setting of other viral diseases such as Ebola infections. Thus, gal-1 may have direct antiviral effects and may also augment the innate immune response against this emerging pathogen.

Functions of cell surface galectin-glycoprotein lattices

“…It has been demonstrated that galectin-1 inhibits envelope-mediated cell-cell fusion of some paramyxoviruses by binding to specific N-glycans on viral glycoproteins and inducing its oligomerization [27]. However, galectin-1 can also promote human immunodeficiency virus infectivity by stabilizing viral attachment to host cells and cross-linking viral glycoproteins with the target cells [28].…”

A broad-spectrum antiviral targeting entry of enveloped viruses

“…Pseudotyped VSV viruses were prepared and assayed for infection as previously described (26,(29)(30)(31). Unless indicated otherwise, all infections were performed in 1% FBS in PBS.…”

Galectin-3 Induces Death of Candida Species Expressing Specific β-1,2-Linked Mannans

“…Galectins are PRRs in several types of organisms, and many mammalian pathogens express saccharide structures that are recognized by galectins. Galectin-1 binds saccharide ligands on envelope glycoproteins of Nipah virus and HIV (20,21). Galectin-3 and galectin-9 bind Leishmania major and galectin-9 promotes L. major-macrophage interactions (22,23).…”