The Immunological Response to Respiratory Syncytial Virus Infection Has Both Age-Related and Extracellular Matrix Provisions

• Main Author: Kellar, Gerald George
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2020
• Subjects: Immunology; Virology
• ISBN: 9798569995714

Early life respiratory syncytial virus (RSV) infection has been linked to the onset of asthma; despite this association knowledge as to the initial viral infection progression is limited while no safe or effective vaccine currently exists. Bronchioalveolar lavage, whole lung cellular isolation, and gene expression analysis were performed on 3-week (juvenile) and 8-week old (adult) RSV-infected C57BL/6 mice to investigate age-related differences in immunologic responses; juvenile mice displayed a sustained myeloid infiltrate (including monocytes and neutrophils) with increased RNA transcript production of Ccl2, Ccl3, and Ccl4, when compared to adult mice, at 72-hours post infection. Juvenile mice demonstrated αSma expression (which is indicative of myofibroblast activity), increased hyaluronan deposition in the lung parenchyma (which has been attributed to asthma progression), and a lack of CD64 upregulation on monocytes (which in conjunction with serum amyloid P is responsible for clearing residual hyaluronan (HA) and cellular debris). RSV infection of human airway epithelial cell/monocyte co-cultures (at air-liquid interface) were in concert with the CCL expression while suggesting matrix metalloproteinase-7 (MMP7) and MMP9 as possible matrix modifiers. Versican is an extracellular matrix component whose overexpression is often associated with exacerbations in asthma; however, RSV infection was shown to depress versican expression in human cell cultures. Therefore, we transferred our infection model into mice lacking versican in the epithelium (utilizing surfactant protein C-Cre (SPC-Cre) as the vehicle) to ascertain the impact; we found that our SPC-Cre versican floxed mice had a sustained myeloid recruitment at 72-hours, the CCL expression to support that recruitment, the expression of factors which would also impact HA metabolism (including hyaluronidase 1 (Hyal1) and Hyal2, hyaluronan synthase 1 (Has1) and Has2, and tumor necrosis factor stimulated gene-6), and an increase in the protein and hyaluronan content of the lavage fluid when compared to their RSV infected littermates and PBS controls. These data suggest that RSV infection supports the sustained influx of myeloid cells, hyaluronan deposition in the lungs of juvenile mice during acute infection and could potentiate a modification in extracellular matrix components facilitating the conditions necessary for airway remodeling and hyperresponsiveness.