Although alteration in host cellular translation machinery occurs in virus-infected cells, the role of such alteration and the precise pathogenic processes are not well understood. Influenza A virus (IAV)
infection shuts off host cell gene expression at transcriptional and translational levels. Here, we found that the
protein level of eukaryotic translation
initiation factor 4B (
eIF4B), an integral component of the translation initiation apparatus, was dramatically reduced in A549 cells as well as in the lung, spleen, and thymus of mice infected with IAV. The decrease in
eIF4B level was attributed to lysosomal degradation of
eIF4B, which was induced by viral NS1
protein. Silencing
eIF4B expression in A549 cells significantly promoted IAV replication, and conversely, overexpression of
eIF4B markedly inhibited the viral replication. Importantly, we observed that
eIF4B knockdown transgenic mice were more susceptible to IAV
infection, exhibiting faster
weight loss, shorter survival time, and more-severe organ damage. Furthermore, we demonstrated that
eIF4B regulated the expression of
interferon-induced transmembrane
protein 3 (IFITM3), a critical
protein involved in immune defense against a variety of RNA viruses, including influenza virus. Taken together, our findings reveal that
eIF4B plays an important role in host defense against IAV
infection at least by regulating the expression of IFITM3, which restricts viral entry and thereby blocks early stages of viral production. These data also indicate that influenza virus has evolved a strategy to overcome host innate immunity by downregulating
eIF4B protein.
IMPORTANCE: Influenza A virus (IAV)
infection stimulates the host innate immune system, in part, by inducing
interferons (IFNs). Secreted IFNs activate the
Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, leading to elevated transcription of a large group of IFN-stimulated genes that have
antiviral function. To circumvent the host innate immune response, influenza virus has evolved multiple strategies for suppressing the production of IFNs. Here, we show that IAV
infection induces lysosomal degradation of
eIF4B protein; and
eIF4B inhibits IAV replication by upregulating expression of
interferon-induced transmembrane
protein 3 (IFITM3), a key
protein that protects the host from
virus infection. Our finding illustrates a critical role of
eIF4B in the host innate immune response and provides novel insights into the complex mechanisms by which influenza virus interacts with its host.