3.Interferons role in COVID-19 Infection:
Interferons are one of the key mediators in limiting viral invasion to the cells, but activation of inhibitory responses like CD200:CD200R1 signaling pathway by specific viral pathogens such as COVID-19 limit their antiviral activity(17). As mentioned before, using novel agents such as CD200 inhibitors might not yet be optimized for this situation. So, how about taking one step further in the signaling pathway and trying interferons for supporting the virus clearance system?
Intrinsic viral resistance of the cells is highly dependent on IFN I & IFN III. One of the cellular attack strategies by coronavirus is to suppress the IFN response (18). As expected, a serum analysis study of COVID-19 patients revealed suppressed levels of type I & type III interferon and elevated inflammatory and proinflammatory cytokines and chemokines (19). However, some researchers suggest that the virus induce a late interferon response rather than a complete absence (20). An animal study on a mouse model of SARS-CoV infection also showed that IFN-1 was detectable in the lung until several hours after the viral load peak(21). A small COVID-19 patients cohort revealed surprising results. In this study, a strong association between IFN-α and viral load, as well as disease severity, was discovered. This study concluded that high interferon levels in the late stages of the infection could not successfully bring down the viral load, and interferon probably acts optimally in the early stages of the disease (22).
So, according to all these details, can IFN be a therapeutic strategy in COVID-19 infection?
Actually, the efficacy of the interferons as a therapeutic option for COVID-19 is a subject of debate. Numerous in vitro and in vivo studies candidate IFN-I as a promising therapeutic option for SARS and MERS infections (23). The knowledge from SARS-CoV and MERS-CoV studies on interferon efficacy can be a valuable guide for determining interferons’ position in COVID-19 treatment guidelines. Several randomized clinical trials are registered to test this. These studies include the DisCoVeRy trial (NCT04315948, the first clinical trial by the WHO Solidarity consortium) that is aimed to evaluate the therapeutical efficacy of subcutaneous injection of IFN-b1a in combination with lopinavir-ritonavir, lopinavir-ritonavir alone, hydroxychloroquine, or remdesivir. Another phase II clinical trial on inhaled IFN-b1a as a single agent is ongoing in the UK (NCT04385095) (24). A retrospective study of 77 COVID-19 patients in Wuhan, China compared nebulized IFN-a2b with arbidol or a combination of the two and claimed that nebulized IFN-a2b significantly reduced the level of inflammatory markers, interleukin-6 and C-reactive protein (CRP) as well as the duration of the detectable virus (25). A case series in Hubei Province evaluated the efficacy of recombinant IFN-a nasal drops in preventing COVID-19 incidence. In this study, 2944 healthcare workers received the IFN-a nasal drop. After 28 days, the rate of COVID-19 infection among them was zero (26). Fortunately, the primary results of ongoing clinical studies on interferons are encouraging. However, studies on different animal models and larger sample sizes are required to obtain more precise details on the safety and efficacy of IFN-I as a therapy in COVID-19.