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Published on: January 20, 2017
Caveolin-1 limits human influenza A virus (H1N1) propagation in mouse embryo-derived fibroblasts
Katrin Bohm1, Lijing Sun1, Divyeshsinh Thakor1
1Department of Gene Regulation and Differentiation, Helmholtz Center for Infection Research, D-38124 Braunschweig, Germany.
Abstract:
Caveolin expression supports the multiplication of retro-, ortho- and paramyxoviruses in susceptible cells. However, human influenza A virus (IAV), an orthomyxovirus, does not multiply efficiently in mouse embryo fibroblasts (MEFs), which are abundant in caveolin-1 (Cav-1). Surprisingly, the absence of Cav-1 in a MEF cell line removed the block for IAV replication and raised the infectious titer 250-fold, whereas the re-introduction of Cav-1 reversed the effect. The monitoring of cellular pathways revealed that Cav-1 loss considerably increased activities of p53. Furthermore, infection of MEF Cav-1 (-/-) induced reactive oxygen species (ROS) and pronounced apoptosis in the late phase of viral multiplication, but no type I IFN response. Strikingly, pharmacological inactivation showed that the elevated levels of ROS together with apoptosis caused the increase of virus yield. Thus, Cav-1 represents a new negative regulator of IAV infection in MEF that diminishes IAV infectious titer by controlling virus-supportive pathways.
Insights
Caveolin-1 (Cav-1) normally restricts influenza A virus (IAV) replication in mouse cells. Removing Cav-1 boosts IAV infectious titers by increasing reactive oxygen species and apoptosis, revealing Cav-1 as a novel IAV negative regulator.
Area of Science:
- Virology
- Cell Biology
- Molecular Biology
Background:
- Caveolin expression generally supports viral replication in various cell types.
- Human influenza A virus (IAV) exhibits inefficient replication in mouse embryo fibroblasts (MEFs) due to abundant caveolin-1 (Cav-1).
Purpose of the Study:
- To investigate the role of caveolin-1 (Cav-1) in regulating influenza A virus (IAV) replication in mouse embryo fibroblasts (MEFs).
- To elucidate the cellular mechanisms by which Cav-1 influences IAV infectious titers.
Main Methods:
- Generated and utilized Cav-1 knockout (Cav-1-/-) MEF cell lines.
- Assessed IAV replication efficiency and infectious titers in MEFs with and without Cav-1.
- Monitored cellular pathways, including p53 activity, reactive oxygen species (ROS) production, and apoptosis.
- Investigated the impact of ROS and apoptosis on viral yield.
Main Results:
- Absence of Cav-1 significantly enhanced IAV replication, increasing infectious titers by 250-fold.
- Cav-1 loss led to increased p53 activity, elevated ROS levels, and pronounced apoptosis.
- Pharmacological inhibition confirmed that increased ROS and apoptosis contribute to higher IAV yield.
- No type I interferon response was detected in Cav-1 deficient MEFs during IAV infection.
Conclusions:
- Caveolin-1 acts as a novel negative regulator of influenza A virus infection in mouse embryo fibroblasts.
- Cav-1 diminishes IAV infectious titer by controlling pathways that support viral replication, including those involving ROS and apoptosis.
- Targeting Cav-1 or associated pathways may offer new strategies for controlling IAV infections.
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