Interfering with SARS-CoV-2: are interferons friends or foes in COVID-19?

Since November 2019 the SARS-CoV-2 pandemic has caused nearly 200 million infection and more than 4 million deaths globally (Updated information from the World Health Organization, as on 2nd Aug 2021). Within only one year into the pandemic, several vaccines were designed and reached approval for the immunization of the world population. The remarkable protective effects of the manufactured vaccines are demonstrated in countries with high vaccination rates, such as Israel and UK. However, limited production capacities, poor distribution infrastructures and political hesitations still hamper the availability of vaccines in many countries. In addition, due to the emergency of SARS-CoV-2 variants with immune escape properties towards the vaccines the global numbers of new infections as well as patients developing severe COVID-19, remains high. New studies reported that about 8% of infected individuals develop long term symptoms with strong personal restrictions on private as well as professional level, which contributes to the long socioeconomic problems caused by this pandemic. Until today, emergency use-approved treatment options for COVID-19 are limited to the antiviral Remdesivir, a nucleoside analogue targeting the viral polymerase, the glucocorticosteroide Dexamethasone as well as neutralizing antibodies. The therapeutic benefits of these treatments are under ongoing debate and clinical studies assessing the efficiency of these treatments are still underway. To identify new therapeutic treatments for COVID-19, now and by the post-pandemic era, diverse experimental approaches are under scientific evaluation in companies and scientific research teams all over the world. To accelerate clinical translation of promising candidates, repurposing approaches of known approved drugs are specifically fostered but also novel technologies are being developed and are under investigation. This review summarizes the recent developments from the lab bench as well as the clinical status of emerging therapeutic candidates and discusses possible therapeutic entry points for the treatment strategies with regard to the biology of SARS-CoV-2 and the clinical course of COVID-19.

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Beyond Vaccines: Clinical Status of Prospective COVID-19 Therapeutics.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10009586

Mechanistic insight into the protective and pathogenic immune-responses against SARS-CoV-2

Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies and have been successfully employed for the treatment of viral diseases. Humans express twelve IFN-alpha () subtypes, which activate downstream signalling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in type I IFN immunity and the presence of anti-IFN autoantibodies account for very severe courses of COVID-19, therefore, early administration of type I IFNs may be protective against life-threatening disease. Here we comprehensively analysed the antiviral activity of all IFN subtypes against SARS-CoV-2 to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFN subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate and low antiviral IFNs. In particular IFN5 showed superior antiviral activity against SARS-CoV-2 infection. Dose-dependency studies further displayed additive effects upon co-administered with the broad antiviral drug remdesivir in cell culture. Transcriptomics of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting and prototypical genes of individual IFN subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in type I IFN signalling pathways, negative regulation of viral processes and immune effector processes for the potent antiviral IFN5. Taken together, our data provide a systemic, multi-modular definition of antiviral host responses mediated by defined type I IFNs. This knowledge shall support the development of novel therapeutic approaches against SARS-CoV-2.

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Zehra Karakoese

Papers

Differential interferon-α subtype immune signatures suppress SARS-CoV-2 infection