Roles of galectins in viral infection of mucosal epithelia using the zebrafish model system

Viral diseases can have a severe impact on both human and animal populations, including farmed and natural fish populations. Viruses such as influenza A virus, rabies, respiratory syncytial virus, coronaviruses (COVID19), use a wide variety of strategies to attach to and enter their hosts’ epithelial cells. In many of these examples, however, the detailed mechanisms still remain unclear and urgent research is needed to gain the key information that would enable the development of innovative preventive and therapeutic strategies for viral disease. This research project uses the zebrafish model system to address questions about the mechanisms involved in viral infection, with focus on the role(s) of sugar-binding proteins (galectins) in viral adhesion. Several galectin types are present in both fish and humans, and function in defense against viral infection. A recent study by the investigators revealed that a particular galectin type (galectin-9) promotes viral infectivity. These observations established a new paradigm for the role of galectins as anti-viral defense factors, as they suggest that some viruses have evolved to “hijack” galectins to facilitate viral host entry. By the use of innovative experimental approaches and state-of-the-art molecular tools, this project is aimed at elucidating the molecular mechanisms by which galectin-9 promotes viral infection. The research will provide critical and useful information for viral infections relevant to human and veterinary medicine, including commercial aquaculture. Importantly, these studies will also contribute to the education and hands-on training of graduate, undergraduate, and high school students, including students from underrepresented minorities. The infectious hematopoietic necrosis virus (IHNV) is one of the most important fish pathogens in natural and farmed populations worldwide. Environmental stress and high-density aquaculture can lead to catastrophic IHNV outbreaks. Infection by IHNV involves interaction of the viral envelope glycoprotein spikes with glycoprotein receptor(s) on the fish epithelia, but the mechanisms remain unknown. The investigator’s lab addresses structural/functional aspects of sugar-binding proteins expressed by the host, such as galectins, in infectious disease using both murine and non-mammalian models, such as zebrafish. Several structurally different galectin types have been described (e.g. galectin-1, Gal1; Gal3; and Gal9). While the zebrafish Gal1 and Gal3 hinder IHNV viral adhesion, Gal9, which houses two sugar-recognition domains, promotes viral infectivity. This led to the hypothesis that zebrafish Gal9 enhances viral attachment by crosslinking the viral envelope glycoprotein to fish epithelial glycans, and that under environmental stress the protective role of epidermal mucus is diminished. The hypothesis will be tested by investigating though state-of-the-art biochemical, molecular, and genetic experimental approaches the mechanism(s) involved in Gal9-mediated enhancement of IHNV entry into the host epithelial cell, and potential increase of viral replication, the epidermal mucus’ protective role, and the detrimental effect of stressful environmental conditions. This research will be examine the long-held concept of galectins as defense factors against infectious disease, and will unravel basic infection mechanisms pertinent to other enveloped viruses (e.g. influenza, rabies, and coronavirus) of human and veterinary relevance. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.