How Different Pathologies Are Affected by IFIT Expression

Abstract

The type-I interferon (IFN) system represents the first line of defense against viral pathogens. Recognition of the virus initiates complex signaling pathways that result in the transcriptional induction of IFNs, which are then secreted. Secreted IFNs stimulate nearby cells and result in the production of numerous proinflammatory cytokines and antiviral factors. Of particular note, IFN-induced tetratricopeptide repeat (IFIT) proteins have been thoroughly studied because of their antiviral activity against different viral pathogens. Although classically studied as an antiviral protein, IFIT expression has recently been investigated in the context of nonviral pathologies, such as cancer and sepsis. In oral squamous cell carcinoma (OSCC), IFIT1 and IFIT3 promote metastasis, while IFIT2 exhibits the opposite effect. The role of IFIT proteins during bacterial/fungal sepsis is still under investigation, with studies showing conflicting roles for IFIT2 in disease severity. In the setting of viral sepsis, IFIT proteins play a key role in clearing viral infection. As a result, many viral pathogens, such as SARS-CoV-2, employ mechanisms to inhibit the type-I IFN system and promote viral replication. In cancers that are characterized by upregulated IFIT proteins, medications that decrease IFIT expression may reduce metastasis and improve survival rates. Likewise, in cases of viral sepsis, therapeutics that increase IFIT expression may improve viral clearance and reduce the risk of septic shock. By understanding the effect of IFIT proteins in different pathologies, novel therapeutics can be developed to halt disease progression.

Keywords: IFIT protein; IFNβ; cancer; type-I IFNs; viral sepsis.

Figure 1

Overview of RLR and TLR pathway during viral infection. The recognition of viral nucleic acids by RLRs and TLRs induces activation of IRF-3/7 and NF-κB by phosphorylation, thus upregulating the expression of type-I IFNs and proinflammatory cytokines, respectively. This figure was created with BioRender.com (accessed on 20 January 2023).

Figure 2

Overview of canonical type-I IFN pathway. PRRs within infected cells recognize the virus and induce IFNα/β production. The type-I IFNs are secreted and act on IFNα receptors, which facilitate the transcription of ISGs and proinflammatory cytokines. The generation of ISG proteins in uninfected cells confers greater protection against the virus. This figure was created with BioRender.com (accessed on 20 January 2023).

Figure 3

Summary of human and mouse IFIT function. Both human IFIT1/2 and mouse Ifit1/2 reduce viral protein translation by binding to eIF3, thus inhibiting the preinitiation complex. Similar to human IFIT3, mouse Ifit1c enhances the function of other IFIT proteins. IFIT1 is responsible for targeting cap 0/1 RNA in human cells, while mouse cells utilize Ifit1 and Ifit1b to target cap 0 and cap 1 RNA, respectively. IFIT5 binds to phosphorylated RNA and promotes the activity of MAVS. In contrast to IFIT3/5, IFIT1 acts as a negative regulator of the type-I IFN response. The function of mouse Ifit3 and Ifit3b has yet to be fully characterized. This figure was created with BioRender.com (accessed on 20 January 2023).