Life Sciences Seminar: Defining the Role of the β6 Integrin During Influenza A Virus Infection

Life Sciences Seminar
Defining the Role of the β6 Integrin in the Regulation of Epithelial-Derived Innate Antiviral Responses During Influenza A Virus Infection

Maria Smith ’18
Ph.D. Candidate
St. Jude Graduate School of Biomedical Sciences
St. Jude Children’s Research Hospital

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Detection of influenza A viral (IAV) pathogens by lung epithelial cells and the induction of innate antiviral responses are essential for immune defenses to limit viral replication and spread. Our studies demonstrated the significant upregulation of the epithelial-specific β6 integrin subunit in early during IAV infection impairs viral recognition and inhibits innate responses during IAV infection.

Abstract:
Influenza A virus (IAV) primarily targets the epithelial cells of the respiratory tract. As a result, detection of invasive viral pathogens by lung epithelial cells and the induction of innate antiviral responses are essential for stimulating immune defenses to limit viral replication and spread. However, dysregulation of these antiviral responses can exacerbate lung epithelial destruction and hence tight regulation of epithelial-induced innate responses is necessary to maintain lung homeostasis and prevent tissue damage. Our studies demonstrated the significant upregulation of the epithelial-specific β6 integrin subunit in diverse epithelial cell populations early during IAV infection. Interestingly, loss of the β6 integrin (β6KO) substantially improved type I IFN responses that reduced viral spread and improved survival outcomes during IAV challenge. Single-cell RNA sequencing (scRNA-Seq) of CD45-negative cells from IAV-infected wildtype (WT) mice revealed that β6-positive lung epithelial cells are more susceptible to infection due to dampened Nuclear Factor Kappa B Subunit 1 (NFκB1) and Interferon Regulatory Factor (IRF1) expression. Moreover, RNA sequencing (RNA-seq) of primary respiratory cells derived from IAV-infected β6KO mice indicated an increased resistance to infection via a type I IFN-dependent mechanism. Through scRNA-Seq and RNA-Seq data analyses, I identified elevated IFN signaling in β6-negative lung epithelial cells, with highest transcriptional expression of an innate viral sensor, the Toll Like Receptor 7 (TLR7). My studies indicated significantly higher NFκB1, IRF1 and TLR7 transcripts in β6KO mice than WT mice at baseline and post-infection. Additionally, immunofluorescence microscopy revealed substantially higher expression of NFκB1 in β6KO mTECs at baseline and early post-infection, with NFκB1 activation evident at 8 hpi. Collectively, these data suggest that the elevated expression of the β6 integrin in the respiratory epithelium during IAV infection impairs viral recognition by downregulating TLR7-mediated activation of NFκB1 and IRF1 transcription factors, which deter IFN induction and inhibit productive innate responses during IAV infection. Future studies will investigate how the β6 integrin regulates TLR7 signaling to further decipher the mechanisms that dampen intrinsic antiviral responses and exacerbate susceptibility to IAV infection.

Speaker Bio:
Maria Smith was born and raised in the Commonwealth of Dominica, located in the Caribbean. In 2014, she moved to Rochester, NY to major in Biotechnology and Molecular Bioscience at RIT. During her undergraduate studies, she worked in the labs of Dr. Robert Osgood in the College of Biomedical Sciences as well as Dr. Feng Cui in the Department of Bioinformatics. Soon after graduating in 2018, she joined the St. Jude Graduate School of Biomedical Sciences in Memphis, TN. Currently, Maria is a fourth-year PhD candidate in the Department of Infectious Diseases working at the St. Jude Children’s Research Hospital. Her work investigates host-viral interactions, focusing on elucidating the mechanistic interactions at the respiratory epithelium that potentiate influenza virus pathogenesis in high-risk hosts.

Intended Audience:
Beginners, undergraduates, graduates. Those with interest in the topic.

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