The OAS Genes Play A Key Role In SARS-CoV-2 Induced Heart Failure

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Researchers from Shanxi Medical University – China have found that the OAS genes plays a key role in COVID-19 induced heart failure.

The OAS gene family in the human genome includes OAS1, OAS2, OAS3, and OASL. As an important immune regulator, OAS gene family participates in antiviral biological process and innate immune.
https://pubmed.ncbi.nlm.nih.gov/34100287/

The study findings were published in on a preprint server and are currently being peer reviewed for publication in the Journal of Translational Medicine (BMC).
https://www.researchsquare.com/article/rs-2142806/v1

The highlight of this study was the discovery of an important role of OAS gene family in the process of COVID-19 induced HF.

HF is one of the major adverse consequences of COVID-19 [35]. The fact that OAS genes were highly expressed in both SARS-CoV-2-infected cardiomyocytes and human HF tissues provides us a reason to believe that some similar signaling molecules may mediate the developments of COVID-19 and HF.

Or in other words, there may be some similar or common molecular mechanisms in the two diseases, and OAS genes may be the common genetic factors. Based on the present bioinformatics analysis (shown in Fig. 1 and Fig. 3) and previous reports, OAS genes are highly expressed in SARS-CoV-2 infected cardiomyocytes and COVID-19 patients [36–39], and our qPCR experiments further verified the high expressions of OAS genes in the myocardium of COVID-19-free HF cases (shown in Fig. 2 and Fig. 4).

Previous studies have reported that OAS cluster variants are associated with greater risk of severe COVID-19, and OAS gene family plays an important role in the innate antiviral mechanisms linking to SARS-CoV-2 infection [37, 39–41].

These findings may be associated with the immune dysregulation and cytokine storm leading to HF in COVID-19 patients [42, 43]. During the cytokine storm, a large number of inflammatory factors are produced, such as TNF-α, IL-1, IL-6, and IFN-γ, leading to severe inflammation, multi-organ failure and even death.

Several previous studies have reported that cytokine storm can occur in COVID-19 patients, and the level of pro-inflammatory factors is positively correlated with disease severity [44, 45]. This may be a crucial reason for developing HF in COVID-19 cases.

To corelate OAS gene family with COVID-19 associated HF, it is worthy to mention the important roles of IFN and IFN-stimulated genes (ISGs) in the endogenous anti-virus processes. OAS gene family is closely related to the induction of IFN [21].

In COVID-19 patients, SARS-CoV-2 strongly triggers the expressions of many ISGs and activates immune cells. ISGs have immunopathogenic potentials, including overexpression of inflammatory genes. In some COVID-19 cases, the level of IFN-I is low at the early stage, leading to excessive viral proliferation; when the IFN-I reaches a high level at the advanced stage, it may be too late to be rescued. Massive viral replication and early immune escape result in hyperactivation of pro-inflammatory responses [46–48].

In severe COVID-19 cases, IFN-I response arouses an excessive inflammatory response by promoting TNF/IL-1β-driven inflammation leading to cytokine storm [49]. As the critical members of innate immunity, OAS genes play important roles in immune responses and even the cytokine storm, this may one reason why COVID-19 can develop to HF. Zhang et al. [50] found a highly preserved transcriptional profile of IFN-I dependent genes for COVID-19 complementary diagnosis, and OAS genes were included in the profile.

These evidences suggest the important role of OAS gene family in COVID-19. Adeghate et al. [51] reported that SARS-CoV-2 invasion can damage the heart via the following mechanisms:

1) inflammatory cells infiltrate into the myocardium;

2) pro-inflammatory cytokines cause cardiomyocyte death;

3) viruses damage the endothelial cells coupled with micro-thrombosis;

4) hypoxia caused by respiratory failure indirectly contributes to HF. Among these mechanisms, OAS genes may take roles at least in some of them, for example, the immune responses.

COVID-19 is associated with many inflammation-related signaling pathways, such as interleukin-6/Janus kinase/STAT (IL-6/JAK/STAT) pathway, interferon (IFN) cell signaling pathway, tumor necrosis factor-α/nuclear factor-kappa (TNFα/NF-κB) pathway, toll-like receptor (TLR) pathway, T-cell receptor (TCR) pathway, etc. [52–54]. Our study on COVID-19 dataset reveals that inflammation-related pathways, such as hsa04668 (TNF signaling pathway), hsa04210 (Apoptosis), and hsa04630 (JAK-STAT signaling pathway), are consistent with the above viewpoint.

These signaling pathways also have important biological functions in HF [55–57]. In addition, our results show that after cardiomyocytes being infected by SARS-CoV-2, some HF-associated biological pathways became prevalent, such as hsa04260 (cardiac muscle contraction) and hsa05415 (diabetic cardiomyopathy), which directly indicates the signaling by which COVID-19 causes HF. By analyzing the DEGs in HF dataset GSE120852, we found that some signaling pathways associated with the DEGs, such as GO:0002252 (BP: immune effector process), GO:0002683 (BP: negative regulation of immune system process), GO:0050727 (BP: regulation of inflammatory response), hsa05171 (coronavirus disease-COVID-19), hsa04210 (apoptosis), and hsa04064 (NF-kappa B signaling pathway), are COVID-19 or inflammation related pathways. Especially, the term hsa05171 (coronavirus disease-COVID-19) from the HF dataset fully illustrates the close relationship of COVID-19 with HF.

Currently, there is no specific and effective drug for COVID-19. Thus, development of this kind of drugs is in urgent need. Some antiviral drugs have the potential to treat COVID-19, such as remdesivir, lopinavir/ritonavir, interferon β-1a, and hydroxychloroquine/chloroquine [58].

In the present study, we predicted some potential chemicals or ingredients which regulate the expression of OAS genes by analyzing the CTD and SymMap databases (shown in Fig. 8). Notably, we found that estradiol is one of them. Except for regulating the sexual system, estradiol plays an important role in anti-inflammation and suppression of virus-induced innate immune inflammatory response.

High physiological concentration of estradiol can reduce the production of pro-inflammatory cytokines, such as IL-6, IL-1β, TNF-α, and CCL2, and prevent migration of monocytes and neutrophils into inflamed tissues.

Therefore, under the influence of estradiol, immune dysregulation caused by cytokine storm in COVID-19 is ameliorated [59, 60]. Women generally show better immune responses to viruses than men, men are more susceptible to severe COVID-19 [61, 62]. A study proposed that a combination of estradiol with vitamin D and quercetin can be used to relieve COVID-19 [63].

Estradiol also has a certain protective effect on cardiovascular diseases [64, 65]. Estradiol can rescue severe HF through the classical estrogen receptor beta (ERβ), which is present in the heart [66]. Frump et al. [67] reported that estradiol can protect the function of right ventricle in pulmonary hypertension via BMPR2 and apelin.

These evidences suggest the protective effect of estradiol on the heart, including the heart damage in COVID-19.

The study has some limitations. We were unable to obtain cardiac tissues from COVID-19 and HF patients to verify the expression and mechanism of OAS gene family in these diseases. These issues warrant future studies.

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