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Revisiting Pleiotropic Effects of Type I Interferons: Rationale for Its Prophylactic and Therapeutic Use Against SARS-CoV-2.

ABSTRACT: The pandemic distribution of SARS-CoV-2 together with its particular feature of inactivating the interferon-based endogenous response and accordingly, impairing the innate immunity, has become a challenge for the international scientific and medical community. Fortunately, recombinant interferons as therapeutic products have accumulated a long history of beneficial therapeutic results in the treatment of chronic and acute viral diseases and also in the therapy of some types of cancer. One of the first antiviral treatments during the onset of COVID-19 in China was based on the use of recombinant interferon alfa 2b, so many clinicians began to use it, not only as therapy but also as a prophylactic approach, mainly in medical personnel. At the same time, basic research on interferons provided new insights that have contributed to a much better understanding of how treatment with interferons, initially considered as antivirals, actually has a much broader pharmacological scope. In this review, we briefly describe interferons, how they are induced in the event of a viral infection, and how they elicit signaling after contact with their specific receptor on target cells. Additionally, some of the genes stimulated by type I interferons are described, as well as the way interferon-mediated signaling is torpedoed by coronaviruses and in particular by SARS-CoV-2. Angiotensin converting enzyme 2 (ACE2) gene is one of the interferon response genes. Although for many scientists this fact could result in an adverse effect of interferon treatment in COVID-19 patients, ACE2 expression contributes to the balance of the renin-angiotensin system, which is greatly affected by SARS-CoV-2 in its internalization into the cell. This manuscript also includes the relationship between type I interferons and neutrophils, NETosis, and interleukin 17. Finally, under the subtitle of "take-home messages", we discuss the rationale behind a timely treatment with interferons in the context of COVID-19 is emphasized.

SUBMITTER: Garcia-Del-Barco D

PROVIDER: S-EPMC8033157 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:New universal prophylactic vaccine platforms are needed to prevent or reduce the impact of future respiratory viral infections. While the attribute of T memory cells is particularly attractive in the context of vaccine design for viral infection, the efficiency of T and B memory cell-mediated protection generated under the adenoviral vector was tested. We studied the mechanism using the platform/ immunological factor combination (AdV1+rRBD): adenovirus AdV1 (adjuvant) armed with inducible co-stimulator ICOS and CD40 ligand in combination with recombinant spike protein rRBD (antigen) to promote the differentiation of memory T and B cells. Additionally, adenovirus AdV2 (adjuvant) without ICOS and CD40 ligand in combination with rRBD was tested. Investigating ex vivo T cell responses to the platform-specific stimuli, we found higher frequencies of CD8+ than CD4+ platform-specific T cells vs mock. The cytometric analysis showed that T cells confer protection against SARS-CoV-2 via elevated T cell subsets: CD8+TEMRA (57.6% ± SD 3.3 vs mock 39.6% ± SD 4.83) and CD4+TNAÏVE (59.6% ± SD 0.4 vs mock 50.8% ± SD 1.9). We found that CD8+TEM, CD8+TSCM, and CD8+TCM are antigen-experienced subpopulations generated via the platform after 7 days. When stimulated with the immunological factors, B cells changed from the production of IgM and IgD to isotype IgG. The CD40 gene was significantly expressed (RT-qPCR) in VERO E6 after stimulation with the platform. RNA-seq profiling identified Th1, Th2, and Th17 cell differentiation gene expression patterns that effectively protect against different pathogens. RNA-seq analysis determined signaling pathways that control immunological mechanisms by which the platform induces protective immunity: MAPK cascade, adipocytokine, cAMP, TNF, and Toll-like receptor (TLR) signaling pathway. The formulation (AdV1+rRBD) increased the production of IL-6, IL-8, and TNF vs the mock (P<0.0001). The whole-genome sequencing of VERO E6 showed differences in the expression of apoptosis gene stimulated with the platforms vs mock. Moreover, apoptotic hallmarks were identified and quantified using flow cytometry. We proved that immunogenic factors compromised plasma membrane integrity (RNA-seq). To sum up, the proposed adenoviral platform generated innate and adaptive immunity for the complex and robust regulatory system to prevent SARS-CoV-2 infections.

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Revisiting Pleiotropic Effects of Type I Interferons: Rationale for Its Prophylactic and Therapeutic Use Against SARS-CoV-2.

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