The Role of Type I Interferons in the Pathogenesis and Treatment of COVID-19

Abstract

Type I interferons (IFN-I) were first discovered over 60 years ago in a classical experiment by Isaacs and Lindenman, who showed that IFN-Is possess antiviral activity. Later, it became one of the first approved protein drugs using heterologous protein expression systems, which allowed its large-scale production. It has been approved, and widely used in a pleiotropy of diseases, including multiple-sclerosis, hepatitis B and C, and some forms of cancer. Preliminary clinical data has supported its effectiveness against potential pandemic pathogens such as Ebola and SARS. Still, more efficient and specific drugs have taken its place in treating such diseases. The COVID-19 global pandemic has again lifted the status of IFN-Is to become one of the more promising drug candidates, with initial clinical trials showing promising results in reducing the severity and duration of the disease. Although SARS-CoV-2 inhibits the production of IFNb and thus obstructs the innate immune response to this virus, it is sensitive to the antiviral activity of externally administrated IFN-Is. In this review I discuss the diverse modes of biological actions of IFN-Is and how these are related to biophysical parameters of IFN-I-receptor interaction and cell-type specificity in light of the large variety of binding affinities of the different IFN-I subtypes towards the common interferon receptor. Furthermore, I discuss how these may guide the optimized use IFN-Is in combatting COVID-19.

Shared and Unique Features of Human Interferon-Beta and Interferon-Alpha Subtypes

“…Table 2 shows the nine IFN-I licensed in the United States along with indications for use. As discussed elsewhere in this series of reviews ( 84 ), there are several ongoing clinical studies to test efficacy of IFN-I and IFN-III to treat Covid19.…”

Understanding the implications of SARS-CoV-2 re-infections on immune response milieu, laboratory tests and control measures against COVID-19

“…One justification may be that they are not a crucial aspect of recovery, but are limited to acute and chronic viral infection. This part will require additional studies to explain the processes involved [ 56 , 57 , 58 , 59 ]. Alternative explanation for the increased convalescent rates with higher amount of memory B cells is that these cells form part of a bigger pool, resulting to better T cell facilitation of B cell germinal center responses in unexposed individuals during primary infection.…”

“…Alternative explanation for the increased convalescent rates with higher amount of memory B cells is that these cells form part of a bigger pool, resulting to better T cell facilitation of B cell germinal center responses in unexposed individuals during primary infection. This elucidation is plausible since memory production is strictly connected to the production of specific antibodies against the responsible agent [ 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ].…”

Potentin vitroanti-SARS-CoV-2 activity by gallinamide A and analogues via inhibition of cathepsin L

“…Whilst this molecule has been reported to show some efficacy during early infection, the drug has performed poorly in a number of trials where it was deemed ineffective, ( 6, 7 ) including a recent report from the World Health Organization that suggested remdesivir provided little to no effect in the outcome of COVID-19 infections in hospitalized patients ( 8 ). Examples of other repurposing approaches that have been explored, include the use of the hydroxychloroquine, ( 9–11 ) the HIV therapy Lopinavir-ritonavir, ( 12, 13 ) as well as type I interferon regimens; ( 14, 15 ) however, these too have shown no improvement over standard care in hospitalized COVID-19 patients. At the present time, one of the most effective means of improving COVID-19 patient outcomes has been through the use of the glucocorticoid dexamethasone which serves to reduce inflammation-mediated lung injury ( 16 ).…”