Protective and Pathogenic Roles of Type I IFNs during Coronavirus Infection
Both viral and host factors can affect the timing of IFN response. When the initial viral burden is low(left), IFNs can be induced early and clear theinfection effectively. High viral load (right) may
strongly suppress the IFN response due to viralevasion mechanisms, causing its delayed induction. Alternatively, IFN induction may be compromised in older hosts. When the IFN response is insufficient to control initial viral replication, lateonset IFN could lead to inflammation and lung

In this review, published in Cell Host & Microbe, it’s described the recent progress in understanding of both type I and type III IFN-mediated innate antiviral responses against human coronaviruses and discussed the potential use of IFNs as a treatment strategy for COVID-19.

Type I and type III IFNs establish the cellular state of viral resistance, as well as activate the adaptive immune responses to viruses. Successful viral pathogens therefore have evolved mechanisms to escape both immune recognition and suppress the functions of IFNs and ISGs. Many viral proteins are dedicated to modulating the host IFN response. These mechanisms have been extensively investigated for SARS-CoV and MERS-CoV. Both viral and host factors determine the outcome of IFN signaling. Type I IFN signaling in particular can be deleterious through its systemic, pro-inflammatory effects.

Innate viral recognition triggers a signaling cascade leading to both NF-κΒ-mediated induction of pro-inflammatory cytokines (e.g., IL-1, IL-6, TNF-α) and IRF3 and IRF7-mediated induction of type I and type III IFNs (IFN-I and IFN-III). Transcriptome profiling of various cell types revealed that SARS-CoV-2 infection elicits very low IFN-I or IFN-III and limited ISG response, while inducing chemokine and pro-inflammatory cytokine genes.

In addition to viral intrinsic suppression of IFN response, age of the host dictates the cytokine profiles. In a macaque model of SARS-CoV infection, aged macaques had more lung pathology and higher expression of pro-inflammatory cytokines but lower expression of IFN-Is compared to younger macaques. These results are consistent with older human monocytes having defective IFN-I and IFN-III production while maintaining intact pro-inflammatory cytokines in response to influenza A virus (IAV) infection. The defect in IFN induction in older monocytes was due to proteolytic degradation of TRAF3, a key signaling molecule downstream of many PRRs required for IFN transcription.

These collectively suggest that the imbalance between pro-inflammatory versus IFN response in aging may have important disease implications for COVID-19 pathogenesis.

Coronaviruses can interfere with any of the following processes in innate antiviral immunity: (1) innate sensing, (2) IFN production, (3) IFN signaling, and (4) ISG effector function

In the paper, are suggested several efforts that will help establish the feasibility as well as increase the versatility of IFN-I therapy. First, the prophylactic effects of IFNs that have been reported should be validated
by randomized clinical trials. The intervention should be tested
on healthcare workers and other individuals at risk for SARSCoV-2 infection. Second, in order to administer IFN in the early
stage of infection, robust public health measures including
testing and contact tracing need to be established to rapidly
identify those who have been exposed before symptom onset.
Furthermore, investigating cellular targets that can limit or

reverse IFN-I-associated inflammation will be valuable for potential therapeutic application with IFN-Is. Possible mechanisms
include inhibiting inflammatory genes downstream of IFN-I
signaling and promoting negative feedback of the IFN response.
Finally, identifying host factors that lead to delayed or reduced
IFN-I induction may instruct us on patient groups that may
particularly benefit or should be refrained from IFN-I treatment.
In addition to host age, genetic polymorphisms may affect IFN

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