Timing of Galectin-1 Exposure Differentially Modulates Nipah Virus Entry and Syncytium Formation in Endothelial Cells

Abstract

Nipah virus (NiV) is a deadly emerging enveloped paramyxovirus that primarily targets human endothelial cells. Endothelial cells express the innate immune effector galectin-1 that we have previously shown can bind to specific N-glycans on the NiV envelope fusion glycoprotein (F). NiV-F mediates fusion of infected endothelial cells into syncytia, resulting in endothelial disruption and hemorrhage. Galectin-1 is an endogenous carbohydrate-binding protein that binds to specific glycans on NiV-F to reduce endothelial cell fusion, an effect that may reduce pathophysiologic sequelae of NiV infection. However, galectins play multiple roles in regulating host-pathogen interactions; for example, galectins can promote attachment of HIV to T cells and macrophages and attachment of HSV-1 to keratinocytes but can also inhibit influenza entry into airway epithelial cells. Using live Nipah virus, in the present study, we demonstrate that galectin-1 can enhance NiV attachment to and infection of primary human endothelial cells by bridging glycans on the viral envelope to host cell glycoproteins. In order to exhibit an enhancing effect, galectin-1 must be present during the initial phase of virus attachment; in contrast, addition of galectin-1 postinfection results in reduced production of progeny virus and syncytium formation. Thus, galectin-1 can have dual and opposing effects on NiV infection of human endothelial cells. While various roles for galectin family members in microbial-host interactions have been described, we report opposing effects of the same galectin family member on a specific virus, with the timing of exposure during the viral life cycle determining the outcome. IMPORTANCENipah virus is an emerging pathogen that targets endothelial cells lining blood vessels; the high mortality rate (up to 70%) in Nipah virus infections results from destruction of these cells and resulting catastrophic hemorrhage. Host factors that promote or prevent Nipah virus infection are not well understood. Endogenous human lectins, such as galectin-1, can function as pattern recognition receptors to reduce infection and initiate immune responses; however, lectins can also be exploited by microbes to enhance infection of host cells. We found that galectin-1, which is made by inflamed endothelial cells, can both promote Nipah virus infection of endothelial cells by "bridging" the virus to the cell, as well as reduce production of progeny virus and reduce endothelial cell fusion and damage, depending on timing of galectin-1 exposure. This is the first report of spatiotemporal opposing effects of a host lectin for a virus in one type of host cell. N ipah virus (NiV) is an emerging zoonotic paramyxovirus that targets endothelial and neural cells. Infection with NiV can result in a severe encephalitic or respiratory syndrome with case fatality rates ranging from 40 to 100% in humans (1, 2). Although initial outbreaks involved transmission from bats to pigs and then from pigs to humans, more recent outbreaks have been shown to involve...

The zebrafish galectins Drgal1-L2 and Drgal3-L1 bind in vitro to the infectious hematopoietic necrosis virus (IHNV) glycoprotein and reduce viral adhesion to fish epithelial cells

“…Our observation that exposure of the fish epithelial cells to IHNV has negligible effects on expression of Drgal1-L2 and Drgal3-L1 during the viral adhesion stage, but strongly downregulates galectin expression at later infection stages. Recently, human galectins have been shown to be induced in vivo in response to several different viral infections, including influenza (Katoh et al 2014), Nipah (Garner et al 2015), and human immunodeficiency virus (Tandon et al 2014). It is tempting to speculate that the downregulation of galectin expression observed at 48h may reflect a viral-mediated mechanism for subversion of galectin function at the later stages of viral infection, and current studies in our laboratory are addressing this intriguing observation.…”

Molecular recognition of human ephrinB2 cell surface receptor by an emergent African henipavirus

“…NiV and GhV pseudotyped particles (NiVpp and GhVpp) were produced as described (12,19,65). Glycoprotein expression on NiVpp and GhVpp was determined by Western blotting for F and G using anti-AU1 and -HA tag antibodies, respectively.…”

Chicken galectin-1B inhibits Newcastle disease virus adsorption and replication through binding to hemagglutinin–neuraminidase (HN) glycoprotein

“…Besides contributing to the immune homeostasis as an important regulatory factor (17,21), mammalian galectin-1 can also mediate the host-pathogen interaction via binding glycans on the surface of pathogens (8,9,24,29). During infection, mammalian galectin-1 may participate in host antiviral defense or promote the course of virus invasion through specific interaction with glycans on the viral envelope glycoprotein (8,9,23,24,29,30). To date, whether CG-1A and CG-1B, which are closely related to human galectin-1 (31,32), play a role in avian virus infection has not been reported.…”

“…Viral infection can modulate the expression and function of galectin-1, and the complex interplay between galectin-1 and virus may ultimately determine the outcome of infection (7,8,19,24,29). Although the expression of CG-1B was up-regulated in target organs of chickens infected with both lentogenic La Sota and velogenic F48E9, the outcomes of the clinical illness caused by these two viruses were distinct.…”

“…Galectin-1 binds directly to envelope glycoproteins of influenza virus and inhibits viral infection (8). However, galectin-1 facilitates Nipah virus and HIV-1 adsorption and infection through direct interaction with N-glycans on viral glycoproteins and host receptors (9,23,24).…”