Influenza virus receptors on human airway epithelial cells

Project: Research project

Project Details

Description

Influenza virus causes seasonal infections during the winter all over the world and occasionally pandemics with high mortality rate. It is a global health problem. There are several strains of this virus classified based on hemagglutinin and neuraminidase antigens. The viral hemagglutinin binds to sialic acid receptors on airway epithelial cells to allow virus entry into cells, whereas neuraminidase cleaves this binding releasing newly formed virus for shedding and spread of infection. Although we know in general that influenza hemagglutinins bind to sialic acids, not much is known about binding specificity between the ever increasing subtypes of hemagglutinin antigens (H1 through H18) and sialic acids (43 derivatives). This proposal combines transcontinental expertise in glycobiology, glycomics and airway clinical research to address the overall goal of determining variation in sialic acid components from the upper to the lower airway in humans and to identify specific airway sialic acid receptors for specific hemagglutinin subtypes. We hypothesize that sialic acid composition varies from the nasal passages to the distal lower airways and that there is specificity between subtypes hemagglutinins and sialic acids. We will address this hypothesis in 3 aims. In aim 1, to identify sialic acid receptors for specific hemagglutinins, we will synthesize influenza hemagglutinins in vitro using genetic engineering of virus genomic RNA and examine binding of hemagglutinins to a sialic acid array. In aim 2, to localize influenza virus hemagglutinin receptors in the upper and lower airways, we will tag influenza hemagglutinins for immunohistochemistry to locate specific sialic acids in upper and lower airway samples and will also perform glycomics of lower airway samples. This aim will also explore the hypothesis that more virulent viruses possess hemagglutinins that bind preferentially to lower airways. In aim 3, to assess functional specificity of sialic acid receptors for influenza virus subtypes, we will synthesize specific hemagglutinins and sialic acids to perform inhibition binding assays of influenza virus subtypes to airway tissue sections and to cultures of primary airway epithelial cells from the upper and lower airways. In aim 4, to determine whether underlying chronic airway disease may alter glycomics of airway, we will compare glycomic profiling of upper and lower airway samples from healthy and asthmatic subjects. These aims will significantly advance our understanding of glycobiology of influenza virus infection and airway glycomics establishing the background for future development of small molecule inhibitors of influenza binding to airway cells. A mixture of relevant inhibitors could then be used to prevent or treat seasonal and pandemic influenza infections
StatusFinished
Effective start/end date9/3/152/29/20

Funding

  • Scripps Research Institute (5-53557//5R01AI114730-04)
  • National Institute of Allergy and Infectious Diseases (5-53557//5R01AI114730-04)

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