Human Type I Interferon Antiviral Effects in Respiratory and Reemerging Viral Infections

Abstract

Type I interferons (IFN-I) are a group of related proteins that help regulate the activity of the immune system and play a key role in host defense against viral infections. Upon infection, the IFN-I are rapidly secreted and induce a wide range of effects that not only act upon innate immune cells but also modulate the adaptive immune system. While IFN-I and many IFN stimulated genes are well-known for their protective antiviral role, recent studies have associated them with potential pathogenic functions. In this review, we summarize the current knowledge regarding the complex effects of human IFN-I responses in respiratory as well as reemerging flavivirus infections of public health significance and the molecular mechanisms by which viral proteins antagonize the establishment of an antiviral host defense. Antiviral effects and immune modulation of IFN-stimulated genes is discussed in resisting and controlling pathogens. Understanding the mechanisms of these processes will be crucial in determining how viral replication can be effectively controlled and in developing safe and effective vaccines and novel therapeutic strategies.

Figure 1

Type I interferon immune response. (a) Detection of viral infection by pathogen recognition receptors and signaling cascades resulting in the production of IFN-I. (b) IFN-I-α/β receptor (IFNAR) and activation of the JAK/STAT pathway leading to the induction of IFN-stimulated genes.

Figure 2

Induction of IFN-I by influenza virus. PRRs involved in viral recognition include TLR-3, TLR-7/8, MDA5, and RIG-I that can detect viral products to signal IFN-α/β production in infected cells.

Figure 3

Evasion and inhibition of respiratory virus-induced IFN-I signaling. Many respiratory viruses can inhibit and modulate their detection using diverse strategies, thereby inhibiting the IFN-I production. Circular boxes in black background represent the viral protein involved in the pathway inhibition. Abbreviations: NS: nonstructural protein; V: V protein; C: C protein; SH: small hydrophobic protein.

Figure 4

Induction of IFN-I by RSV. RSV is detected by different PRRs that include TLR-2, TLR-4, TLR-3, TLR-7/8, MDA5, and RIG-I and leads to the IFN-I pathway activation.

Figure 5

Induction of IFN-I by flaviviruses. The TLR and RLR signaling cascades converge with the activation of transcription factors, which are critical for the induction of IFN-α∕β.

Figure 6

Inhibition of the IFN-I pathway by flaviviruses. Different viral proteins are involved in the modulation of the IFN-I activation pathway. Circular boxes in black background represent the viral protein involved in the pathway inhibition. Abbreviations: nonstructural protein (NS) 1, 2, 3, 4, and 5; E: envelope protein.