Abstract
The limited antiviral options and lack of an effective vaccine against human respiratory syncytial virus (RSV) highlight the need for a novel antiviral therapy. One alternative is to identify and target the host factors required for viral infection. Here, using RNA interference to knock down Rab proteins, we provide multiple lines of evidence that Rab5a is required for RSV infection: (a) Rab5a is upregulated both in RSV-A2-infected A549 cells and RSV-A2-challenged BALB/c mice's airway epithelial cells at early infection phase; (b) shRNA-mediated knockdown of Rab5a is associated with reduced lung pathology in RSV A2 challenged mice; (c) Rab5a expression is correlated with disease severity of RSV infection of infants. Knockdown of Rab5a increases IFN-λ (lambda) production by mediating IRF1 nuclear translocation. Our results highlight a new role for Rab5a in RSV infection, such that its depletion inhibits RSV infection by stimulating the endogenous respiratory epithelial antiviral immunity, which suggests that Rab5a is a potential target for novel therapeutics against RSV infection.Importance This study highlights the important role of Rab5a in RSV infection, such that its depletion inhibits RSV infection by stimulating the endogenous respiratory epithelial antiviral immunity and attenuates inflammation of the airway, which suggests that Rab5a is a powerful potential target for novel therapeutics against RSV infection.
Highlights
The limited antiviral options and lack of an effective vaccine against human respiratory syncytial virus (RSV) highlight the need for a novel antiviral therapy
Using specific small interfering RNA to knock down each Rab protein, we found that the micropinocytosisassociated Rab5a protein is required for RSV infection
We found that the small GTPase Rab5a, which is exclusively upregulated in RSV-infected airway epithelial cells, inhibits host responses against RSV infection by regulating the pathways related to IFN-l
Summary
The limited antiviral options and lack of an effective vaccine against human respiratory syncytial virus (RSV) highlight the need for a novel antiviral therapy. One alternative is to identify and target the host factors required for viral infection. Our results highlight a new role for Rab5a in RSV infection, such that its depletion inhibits RSV infection by stimulating the endogenous respiratory epithelial antiviral immunity, which suggests that Rab5a is a potential target for novel therapeutics against RSV infection. IMPORTANCE This study highlights the important role of Rab5a in respiratory syncytial virus (RSV) infection, such that its depletion inhibits RSV infection by stimulating the endogenous respiratory epithelial antiviral immunity and attenuates inflammation of the airway, which suggests that Rab5a is a powerful potential target for novel therapeutics against RSV infection. In order to identify cellular Rab proteins required for RSV infection, we interrogated the role of nine widely expressed Rab proteins (Rab1a, Rab2a, Rab4a, Rab5a, Rab6a, Rab7a, Rab8a, Rab9a, and Rab11a) that are involved in the endo- or exocytic pathways. Using specific small interfering RNA (siRNA) to knock down each Rab protein, we found that the micropinocytosisassociated Rab5a protein is required for RSV infection
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