DESCRIPTION (provided by applicant): Type III, or-lambda, interferons (IFN) make up a newly discovered family of cytokines which, like the type I IFNs (alpha/beta), are induced by virus infection. IFN-lambda's signaling, through a unique receptor, leads to formation of the same interferon stimulated gene factor 3 (ISGF3) transcription complex activated by IFN- alpah/beta, and therefore has very similar effects. The primary difference noted so far between the type I and type III IFNs is the very limited distribution of the IFN-lambda receptor, in contrast to the IFN-alpha/beta receptor which is ubiquitously expressed. As the IFN-lambda receptor is expressed primarily by epithelial cells and dendritic cells, it has been suggested that this cytokine may be of particular importance in protection from mucosal infections by viral pathogens. In a mouse model of influenza A virus infection we have made the novel observation that IFN-lambda is the primary IFN induced by intranasal infection, and have found that this induction can occur even in the absence of IFN-alpha/beta signaling. It is our hypothesis that this alternatively regulated family of anti-viral IFNs has a unique role in protecting the host from respiratory virus infection. We will test this hypothesis using gene-targeted mice and primary airway epithelial cell cultures to investigate the ways in which type I and type III IFNs have overlapping versus distinctive functions in protection of respiratory tract. We propose the following aims: 1) Demonstrate the requirement for IFN signaling via ISGF3, and investigate the relative importance of type I and type III IFNs for effective innate immune protection against influenza virus. 2) Identify the source(s) of IFN-lambda in influenza virus infection, as well the responding cell types. 3) Characterize production of, and responsiveness to, type I and type III IFNs by polarized airway epithelial cells. 4) Determine the role of IFN-lambda in pDC maturation and function during influenza virus infection.
|Effective start/end date||9/17/09 → 8/31/12|
- National Institute of Allergy and Infectious Diseases: $827,095.00
- National Institute of Allergy and Infectious Diseases: $809,880.00
- Immunology and Microbiology(all)
- Pulmonary and Respiratory Medicine