Interferon response constituted the major first line of defense against viruses. Here, in our bio-information analyse, it revealed that while type I ranking the main force against SARS-CoV-2, both type II, and III IFNs were concurrently involved in the process of the virus defense. This was identical with the report suggested that all the three type interferon contributed to suppression of the virus load, with the difference being that type I IFN more potent or rapid inducer of ISGs than type III IFN and type II IFN inducing the lowest levels and partial of ISGs. An recent investigation had heightened the role of interferon as a determinants of the disease progression for COVID-19. As illustrated that enriched type I and type II interferon (IFN) responses, distinguished mild to moderate patients from the other severe and critical patient groups. And it was observed in severe and critical patients, a highly impaired interferon (IFN) type I response, accompanied with persistent blood viral load and an exacerbated inflammatory response characterized by increased TNF-a and IL-6. Actually, there might be a balance between IFN responses and inflammation, with proper viral control IFN responses no inflammation, but inadequate, persistent and delayed IFN response leading to increased damaging inflammation. Based on this, when it came to applying endogenous IFNs towards the therapy for coronavirus disease 2019 (COVID-19),.it should be attached great importance about timing and duration for the IFNs usage[9, 22, 23].
The bio-information analyse present also demonstrated enrichment of neutrophi degranulation related activities. Consistent with this, A recent study reported the higher accumulation of neutrophils in severe COVID-19 patients compared to non-severe patients, which might be to blame defective type I response against SARS-COV-2 inducing various upregulated neutrophil chemoattractants and then neutrophil infiltrations. This was corresponding with execution of Neutrophils, who were initially restrained to make virus clearance, but persistent and prolonged virus presence might evoke the process of neutrophi degranulation and lysis[25, 26], which just further promoted cytokine and inflammation response and the disease severity[27, 28]. Additionally, Neutrophils degranulation accompanied with excessive ROS via the NADPH-oxidase system also acted as an important mediator of lung damage during acute lung injury[29, 30]. And it had been showed that loss of phagocyte NADPH-oxidase decreased lung pathology which could improve resolution of influenza virus infection. Thus, neutrophils accumulation seemed to be inevitable within the case of Covid-19 severity, which might served as the main part constituting the named cytokine storm, and with its nature of producing ROS, directly made great injury to the host cell.
What’ more, attention should also be attached to the enriched chemokines responsible for attracting inflammatory cells, which could release inflammatory factors and chemokines and by a feed-back loop aggravated immunopathogenesis. A research had just reported that CCL2 and CCL3 cytokines released by the lungs seemed to be correlated with mortality and older age because their inviting of Myeloid cells in COVID-19 airways, which featured hyperinflammatory signatures. Also, CXCL10 secreted by alveolar type II cells was reported to be effective disease markers in SARS, which recruited neutrophils within the alveolar spaces of the lungs[3, 15], suggesting their involvement in diffuse alveolar damage observed in COVID-19 pathology.
The discussion above could be simply summarized as following: if the first defense of type I IFN responses was committed to fulfil its duty fighting against SARS-COV-2, the symptom was mild and moderate; but conversely, genetic or elder-age induced type I IFN negligence of duty, the symptom would be severe and critically, characterized by excessive inflammatory response and cell injury. This brought to culmination of type I IFN responses suggestive of the subsequent course of the disease, which was also embodied in our analyse showing type I IFN responses as the hub gene module in Covid-19. Thus, agents aiming at the process of type I IFN response might been predominantly put as the first consideration over any other treatment of COVID-19.
In the key module network, OAS1 was outstanding and attractable for deep understanding, for that several studies revealed that the genetic SNP variation in OAS1 functioned as a determinants for COVID-19 susceptibility and severity, and a Neanderthal isoform of OAS1 in individuals of European ancestry affords the protection from SARS2 invasion. OAS1, which activated RNase L to directly cut off viral RNA , existed in two isoforms in humans—a longer isoform (p46) and a shorter version (p42)[33, 34]. The p46 OAS1 protein contains four more amino acid that forms a prenylation site, which could help to target proteins to membranes. And it was this membrane targeting deciding the host cell success defeat against SARS CoV-2, with the virus asked for double-membrane vesicle to replicates its genome[33, 34]. Genetic variation with a SNP causing alternative splicing of the OAS1 mRNA would lead to p46 expression, and an investigation displayed that within a cohort of 499 COVID-19 patients hospitalized in the UK, 42.5% of them did not express the antiviral p46 isoform. This pointed out that OAS1 is an important antiviral factor in SARS-CoV-2 infection and again emphasized the dominance of type 1 interferon to determinate the cell fate against SARS-CoV-2. These findings motivated strategies of increasing OAS1 p46 isoform to be prioritized for drug development, and the report that OAS1 could inhibit inflammation might add weight to this motivation.
Besides, the cerna regulatory network, which help to identify noncoding RNAs that directly acted upon the genome and control the transcriptome on a large scale, might also have the potential for success treatment for covid-19, though lots of trials needed to testify the efficacy.
The lncrna, serving as a sponge for mirna, could concurrently targeted the key components of type 1 interferon including OASL, IFIT1,IFIT2,IFIT3. Among these, OASL could enhance RIG-I-mediated IFN induction through its C-terminal ubiquitinlike domain specifically interacting with RIG-I. And the IFIT family, characterized by multiple repeats of tetratricopeptide repeat(TPR), were brought to the forefront by the the new paradigms put forth for how this family executing their effector functions, that was other than traditionally believed protein–protein interactions, the principal molecular role of IFITs might be to directly recognize foreign PPP-ssRNAs(single strand RNA) for downstream viral clearance[39, 40]. And it was found that IFITs formed large multiprotein complexes, with IFIT1, IFIT2 and IFIT3 all three proteins being the components and IFIT1 being central feature of the complex for its higher affinity to PPP RNA. In view of the fact that IFIT1 complex with TPR repeat might process the significance paralleling established receptors of the innate immune system such as LRR containing TLRs, and IFIT complex specifically antagonized single strand RNA as SARS-COV-2, it could be strongly purposed that agent targeting this complex might prove satisfactory, whether it be noncoding-RNA, or repurposed drugs like ribavirin in our analyse.
To sum up, our integrated bio-information analyse depicted the innate immune response landscape in Covid-19, which emphasized type 1 interferon a key defense against SARS-CoV-2 and suggestive of the disease progression. And regents aiming at the process of type 1 IFN were positively recommended for further treatment towards Covid-19, as displayed in this paper, agent toward OAS1 protein, noncoding RNA targeting OASL, IFIT1,IFIT2,IFIT3. or some other more ideal means.