Abstract
Interferon (IFN) regulatory factor 3 (IRF3) is the key transcription factor for the induction of IFN and antiviral genes. The absence of antiviral genes in IRF3 deficiency leads to susceptibility to a wide range of viral infections. Previously, we uncovered a function for nontranscriptional IRF3 (nt-IRF3), RLR (RIG-I-like receptor)-induced IRF3-mediated pathway of apoptosis (RIPA), which triggers apoptotic killing of virus-infected cells. Using knock-in mice expressing a transcriptionally inactive, but RIPA-active, IRF3 mutant, we demonstrated the relative contribution of RIPA to host antiviral defense. Given that RIPA is a cellular antiviral pathway, we hypothesized that small molecules that promote RIPA in virus-infected cells would act as antiviral agents. To test this, we conducted a high throughput screen of a library of FDA-approved drugs to identify novel RIPA activators. Our screen identified doxorubicin as a potent RIPA-activating agent. In support of our hypothesis, doxorubicin inhibited the replication of vesicular stomatitis virus, a model rhabdovirus, and its antiviral activity depended on its ability to activate IRF3 in RIPA. Surprisingly, doxorubicin inhibited the transcriptional activity of IRF3. The antiviral activity of doxorubicin was expanded to flavivirus and herpesvirus that also activate IRF3. Mechanistically, doxorubicin promoted RIPA by activating the extracellular signal-regulated kinase (ERK) signaling pathway. Finally, we validated these results using another RIPA-activating compound, pyrvinium pamoate, which showed a similar antiviral effect without affecting the transcriptional activity of IRF3. Therefore, we demonstrate that the RIPA branch of IRF3 can be targeted therapeutically to prevent virus infection.
Highlights
The innate immune response is the first line of defense against microbial infection
We demonstrated that RIPA contributes to the optimal antiviral activity of IFN regulatory factor 3 (IRF3)
To identify small molecule activators of the antiviral RIPA branch of IRF3 (Figure 1A), we performed an unbiased high throughput screen using a library of FDA-approved compounds
Summary
The interferon (IFN) system represents a key antiviral innate immune response mechanism that dictates the outcome of a viral infection [1]. IRF3 remains as an inactive monomer in the cytosol of the uninfected cells; upon virus infection, it gets phosphorylated, dimerized, and translocated to the nucleus [2,4]. In contrast to the transcriptional pathway, nt-Irf in virus-infected cells functions as a chaperone protein by translocating the pro-apoptotic protein BCL2-associated X (BAX) to the mitochondria, thereby causing apoptotic cell death, which we named RLR (RIG-I-like receptor)-induced IRF3-mediated pathway of apoptosis (RIPA) (Figure 1A) [7,8,9,10,11,12,13]. We demonstrated that RIPA contributes to the optimal antiviral activity of IRF3
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