Background: CD4+ T-cells are involved in the immune response to influenza infection by not only providing help for B-cells and CD8+ T-cells, but also by exhibiting direct antiviral effector functions. These antiviral functions could have a dramatic impact on the integrity of the airway epithelium by increasing the damage caused by the responding immune response to the surrounding epithelial cells in the lungs. CD4+ T-cells can secrete interferon-? (Th1) upon viral antigen encounter but the role of Th1 or other pro- inflammatory CD4+ T-cells, such as subsets secreting interleukin-17, in mediating immunopathology during influenza infection has not been fully delineated. Influenza infection generates robust CD4+ T-cell memory, with rapid antiviral effector functions, that cross-reacts with numerous conserved internal epitopes shared between viral strains. A comparative study of the key CD4+ T-cell subsets and their mechanisms that promote tissue damage and/or protection from virus during a primary versus secondary response is therefore warranted. Methods: C57BL/6NCr will be infected with influenza A/PR8/34 (PR8) and rested for six weeks post-infection to generate CD4+ T-cell memory for adoptive transfer. C57BL/6NCr mice with either no previous memory (primary infection) or having PR8 specific lung and spleen adoptively transferred CD4+ T-cell memory will be infected with the heterosubtypic strain of influenza A/HK-x31 (X31).
Specific Aims : We will investigate the role and mechanisms involved in the promotion of pulmonary inflammation by memory CD4 T-cells during secondary responses to influenza using the murine model. Therefore, we have generated two specific aims:
Aim I : Determine how memory CD4 T-cells interact with lung epithelium during influenza challenge to promote immunopathology and Aim II: Determine the pro-inflammatory role of memory CD4 T-cell subtypes and protective responses in lungs during a secondary response to influenza infection. Summary: This study will explore an immunopathologic and/or protective role for CD4+ T-cells during influenza infection and define the mechanisms involved that could enhance lung epithelial damage. This study could have a profound effect on vaccination or therapeutic strategies that enhance protection but limit immunopathologic responses.
Influenza infection has a tremendous impact on human health with many cases of severe illness and death each year associated with infection. We have determined that while memory immune responses (CD4 T-cells can provide partial protection to new strains of seasonal flu infection, some of the response can also exacerbate the disease symptoms and increase the amount of lung damage. We propose to study those mechanisms.
|Verhoeven, David; Xu, Qingfu; Pichichero, Michael E (2014) Differential impact of respiratory syncytial virus and parainfluenza virus on the frequency of acute otitis media is explained by lower adaptive and innate immune responses in otitis-prone children. Clin Infect Dis 59:376-83|
|Verhoeven, David; Nesselbush, Monica; Pichichero, Michael E (2013) Lower nasopharyngeal epithelial cell repair and diminished innate inflammation responses contribute to the onset of acute otitis media in otitis-prone children. Med Microbiol Immunol 202:295-302|