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Published on: March 24, 2015
IFITM3 and type I interferons are important for the control of influenza A virus replication in murine macrophages
Sarah L Londrigan1, Linda M Wakim1, Jeffrey Smith1
1Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St, Victoria, 3000, Australia.
Abstract:
Abortive infection of macrophages serves as a "dead end" for most seasonal influenza A virus (IAV) strains, and it is likely to contribute to effective host defence. Interferon (IFN)-induced transmembrane protein 3 (IFITM3) restricts the early stages of IAV replication in epithelial cells, but IFITM3 restriction of IAV replication in macrophages has not been previously investigated. Herein, macrophages isolated from IFITM3-deficient mice were more susceptible to initial IAV infection, but late-stage viral replication was still controlled through abortive infection. Strikingly, IFNα/β receptor (IFNAR)-deficient macrophages infected with IAV were not only more susceptible to initial infection, but these cells also supported productive viral replication. Significantly, we have established that abortive IAV infection in macrophages is controlled through a type I IFN-dependent mechanism, where late-stage IAV replication can proceed in the absence of type I IFN responses. These findings provide novel mechanistic insight into macrophage-specific processes that potently shut down IAV replication.
Insights
Influenza A virus (IAV) infection in macrophages is typically abortive, controlled by type I interferon. IFITM3 protein is not essential for this macrophage antiviral defense against IAV.
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Seasonal influenza A virus (IAV) infection in macrophages usually results in abortive infection, contributing to host defense.
- Interferon-induced transmembrane protein 3 (IFITM3) is known to restrict IAV replication in epithelial cells, but its role in macrophages was unexplored.
Purpose of the Study:
- To investigate the role of IFITM3 and type I interferon in controlling IAV replication within macrophages.
- To elucidate the mechanisms underlying abortive IAV infection in macrophages.
Main Methods:
- Utilized macrophages from IFITM3-deficient and IFNAR-deficient mice for IAV infection experiments.
- Assessed susceptibility to initial infection and viral replication stages in these genetically modified macrophages.
Main Results:
- Macrophages from IFITM3-deficient mice showed increased susceptibility to initial IAV infection, but late-stage replication remained abortive.
- IFNAR-deficient macrophages supported productive IAV replication, indicating a crucial role for type I interferon signaling.
- Established that abortive IAV infection in macrophages is dependent on type I interferon, but late-stage replication can occur without it.
Conclusions:
- Abortive IAV infection in macrophages is a type I interferon-dependent process.
- IFITM3 is not the primary factor restricting IAV replication in macrophages; rather, type I interferon signaling is critical.
- These findings reveal novel macrophage-specific mechanisms that effectively inhibit IAV replication.
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