SARS-CoV-2 NSP13 interacts with host IRF3, blocking antiviral immune responses.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an unprecedented threat to human health since late 2019. Notably, the progression of the disease is associated with impaired antiviral interferon (IFN) responses. Although multiple viral proteins were identified as potential IFN antagonists, the underlying molecular mechanisms remain to be fully elucidated. In this study, we firstly demonstrate that SARS-CoV-2 NSP13 protein robustly antagonizes IFN response induced by the constitutively active form of transcription factor IRF3 (IRF3/5D). This induction of IFN response by IRF3/5D is independent of the upstream kinase, TBK1, a previously reported NSP13 target, thus indicating that NSP13 can act at the level of IRF3 to antagonize IFN production. Consistently, NSP13 exhibits a specific, TBK1-independent interaction with IRF3, which, moreover, is much stronger than that of NSP13 with TBK1. Furthermore, the NSP13-IRF3 interaction was shown to occur between the NSP13 1B domain and IRF3 IRF association domain (IAD). In agreement with the strong targeting of IRF3 by NSP13, we then found that NSP13 blocks IRF3-directed signal transduction and antiviral gene expression, counteracting IRF3-driven anti-SARS-CoV-2 activity. These data suggest that IRF3 is likely to be a major target of NSP13 in antagonizing antiviral IFN responses and provide new insights into the SARS-CoV-2-host interactions that lead to viral immune evasion.

SARS-CoV-2 Evasion of the Interferon System: Can We Restore Its Effectiveness?

Type I and III Interferons (IFNs) are the first lines of defense in microbial infections. They critically block early animal virus infection, replication, spread, and tropism to promote the adaptive immune response. Type I IFNs induce a systemic response that impacts nearly every cell in the host, while type III IFNs' susceptibility is restricted to anatomic barriers and selected immune cells. Both IFN types are critical cytokines for the antiviral response against epithelium-tropic viruses being effectors of innate immunity and regulators of the development of the adaptive immune response. Indeed, the innate antiviral immune response is essential to limit virus replication at the early stages of infection, thus reducing viral spread and pathogenesis. However, many animal viruses have evolved strategies to evade the antiviral immune response. The Coronaviridae are viruses with the largest genome among the RNA viruses. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic. The virus has evolved numerous strategies to contrast the IFN system immunity. We intend to describe the virus-mediated evasion of the IFN responses by going through the main phases: First, the molecular mechanisms involved; second, the role of the genetic background of IFN production during SARS-CoV-2 infection; and third, the potential novel approaches to contrast viral pathogenesis by restoring endogenous type I and III IFNs production and sensitivity at the sites of infection.

Autoantibodies to Interferons in Infectious Diseases.

Anti-cytokine autoantibodies and, in particular, anti-type I interferons are increasingly described in association with immunodeficient, autoimmune, and immune-dysregulated conditions. Their presence in otherwise healthy individuals may result in a phenotype characterized by a predisposition to infections with several agents. For instance, anti-type I interferon autoantibodies are implicated in Coronavirus Disease 19 (COVID-19) pathogenesis and found preferentially in patients with critical disease. However, autoantibodies were also described in the serum of patients with viral, bacterial, and fungal infections not associated with COVID-19. In this review, we provide an overview of anti-cytokine autoantibodies identified to date and their clinical associations; we also discuss whether they can act as enemies or friends, i.e., are capable of acting in a beneficial or harmful way, and if they may be linked to gender or immunosenescence. Understanding the mechanisms underlying the production of autoantibodies could improve the approach to treating some infections, focusing not only on pathogens, but also on the possibility of a low degree of autoimmunity in patients.

Antiviral Therapy of COVID-19.

Since the beginning of the COVID-19 pandemic, the scientific community has focused on prophylactic vaccine development. In parallel, the experience of the pharmacotherapy of this disease has increased. Due to the declining protective capacity of vaccines against new strains, as well as increased knowledge about the structure and biology of the pathogen, control of the disease has shifted to the focus of antiviral drug development over the past year. Clinical data on safety and efficacy of antivirals acting at various stages of the virus life cycle has been published. In this review, we summarize mechanisms and clinical efficacy of antiviral therapy of COVID-19 with drugs based on plasma of convalescents, monoclonal antibodies, interferons, fusion inhibitors, nucleoside analogs, and protease inhibitors. The current status of the drugs described is also summarized in relation to the official clinical guidelines for the treatment of COVID-19. In addition, here we describe innovative drugs whose antiviral effect is provided by antisense oligonucleotides targeting the SARS-CoV-2 genome. Analysis of laboratory and clinical data suggests that current antivirals successfully combat broad spectra of emerging strains of SARS-CoV-2 providing reliable defense against COVID-19.

Interferon-Induced Transmembrane Protein 3 rs34481144 C/T Genotype and Clinical Parameters Related to Progression of COVID-19.

Recent research has associated the interferon-induced transmembrane protein 3 gene (IFITM3) with the outcomes of coronavirus disease 2019 (COVID-19), although the findings are contradictory. This study aimed to determine the relationship between IFITM3 gene rs34481144 polymorphism and clinical parameters with COVID-19 mortality. The tetra-primer amplification refractory mutation system-polymerase chain reaction assay was used to analyze IFITM3 rs34481144 polymorphism in 1,149 deceased and 1,342 recovered patients. The clinical parameters were extracted from the patients' medical records. In this study, the frequency of IFITM3 rs34481144 CT genotypes (OR 1.47, 95% CI 1.23-1.76, P < 0.0001) in both sexes was significantly higher in deceased patients than in recovered patients. Moreover, IFITM3 rs34481144 TT genotypes (OR 3.38, 95% CI 1.05-10.87, P < 0.0001) in women were significantly associated with COVID-19 mortality. The multivariable logistic regression model results indicated that mean age (P < 0.001), alkaline phosphatase (P = 0.005), alanine aminotransferase (P < 0.001), low-density lipoprotein (P < 0.001), high-density lipoprotein (P < 0.001), fasting blood glucose (P = 0.010), creatinine (P < 0.001), uric acid (P < 0.001), C-reactive protein (P = 0.004), 25-hydroxyvitamin D (P < 0.001), erythrocyte sedimentation rate (P < 0.001), and real-time PCR Ct values (P < 0.001) were linked with increased COVID-19 death rates. In conclusion, IFITM3 rs34481144 gene polymorphism was linked to the mortality of COVID-19, with the rs34481144-T allele being especially important for mortality. Further studies are needed to confirm the results of this study.

Interferon production by Viral, Bacterial & Yeast system: A comparative overview in 2023.

Interferons play a critical role in the innate immune response against several infections and play a key role in the control of a variety of viral and bacterial infectious diseases such as hepatitis, covid-19, cancer, and multiple sclerosis. Therefore, natural or synthetic IFN production is important and had three common methods, including bacterial fermentation, animal cell culture, and recombinant nucleic acid technology. However, the safety, purity, and accuracy of the most preferred INF production systems have not been extensively studied. This study provides a comprehensive comparative overview of interferon production in various systems that include viral, bacterial, yeast, and mammalian. We aim to determine the most efficient, safe, and accurate interferon production system available in the year 2023. The mechanisms of artificial interferon production were reviewed in various organisms, and the types and subtypes of interferons produced by each system were compared. Our analysis provides a comprehensive overview of the similarities and differences in interferon production and highlights the potential for developing new therapeutic strategies to combat infectious diseases. This review article offers the diverse strategies used by different organisms in producing and utilizing interferons, providing a framework for future research into the evolution and function of this critical immune response pathway.

Mechanisms of impairment of interferon production by SARS-CoV-2.

Interferons (IFNs) are crucial components of the cellular innate immune response to viral infections. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a remarkable capacity to suppress the host IFN production to benefit viral replication and spread. Thus far, of the 28 known virus-encoded proteins, 16 have been found to impair the host's innate immune system at various levels ranging from detection and signaling to transcriptional and post-transcriptional regulation of expression of the components of the cellular antiviral response. Additionally, there is evidence that the viral genome encodes non-protein-coding microRNA-like elements that could also target IFN-stimulated genes. In this brief review, we summarise the current state of knowledge regarding the factors and mechanisms by which SARS-CoV-2 impairs the production of IFNs and thereby dampens the host's innate antiviral immune response.

SARS-CoV-2 omicron sub-lineages differentially modulate interferon response in human lung epithelial cells.

Although most of the attention was focused on the characterization of changes in the Spike protein among variants of SARS-CoV-2 virus, mutations outside the Spike region are likely to contribute to virus pathogenesis, virus adaptation and escape to the immune system. Phylogenetic analysis of SARS-CoV-2 Omicron strains reveals that several virus sub-lineages could be distinguished, from BA.1 up to BA.5. Regarding BA.1, BA.2 and BA.5, several mutations concern viral proteins with antagonistic activity to the innate immune system, such as NSP1 (S135R), which is involved in mRNAs translation, exhibiting a general shutdown in cellular protein synthesis. Additionally, mutations and/or deletions in the ORF6 protein (D61L) and in the nucleoprotein N (P13L, D31-33ERS, P151S, R203K, G204R and S413R) have been reported, although the impact of such mutations on protein function has not been further studied. The aim of this study was to better investigate the innate immunity modulation by different Omicron sub-lineages, in the attempt to identify viral proteins that may affect virus fitness and pathogenicity. Our data demonstrated that, in agreement with a reduced Omicron replication in Calu-3 human lung epithelial cells compared to the Wuhan-1 strain, a lower secretion of interferon beta (IFN-ß) from cells was observed in all sub-lineages, except for BA.2. This evidence might be correlated with the presence of a mutation within the ORF6 protein (D61L), which is strikingly associated to the antagonistic function of the viral protein, since additional mutations in viral proteins acting as interferon antagonist were not detected or did not show significant influence. Indeed, the recombinant mutated ORF6 protein failed to inhibit IFN-ß production in vitro. Furthermore, we found an induction of IFN-ß transcription in BA.1 infected cells, that was not correlated with the cytokine release at 72 h post-infection, suggesting that post-transcriptional events can be involved in controlling the innate immunity.

Interferon regulatory factor 3 mediates effective antiviral responses to human coronavirus 229E and OC43 infection.

Interferon regulatory factors (IRFs) are key elements of antiviral innate responses that regulate the transcription of interferons (IFNs) and IFN-stimulated genes (ISGs). While the sensitivity of human coronaviruses to IFNs has been characterized, antiviral roles of IRFs during human coronavirus infection are not fully understood. Type I or II IFN treatment protected MRC5 cells from human coronavirus 229E infection, but not OC43. Cells infected with 229E or OC43 upregulated ISGs, indicating that antiviral transcription is not suppressed. Antiviral IRFs, IRF1, IRF3 and IRF7, were activated in cells infected with 229E, OC43 or severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2). RNAi knockdown and overexpression of IRFs demonstrated that IRF1 and IRF3 have antiviral properties against OC43, while IRF3 and IRF7 are effective in restricting 229E infection. IRF3 activation effectively promotes transcription of antiviral genes during OC43 or 229E infection. Our study suggests that IRFs may be effective antiviral regulators against human coronavirus infection.

Autoantibodies against type I interferons in COVID-19 infection: A systematic review and meta-analysis.

OBJECTIVES: In this study, we aimed to study the rate of autoantibodies against type I interferons (IFNs) in patients with COVID-19 and analyze its dependence on severity of infection and some other variables. METHODS: A systemic review with the search terms: "COVID-19" or "SARS-CoV-2" and "autoantibodies" or "autoantibody" and "IFN" or "interferon" for the period 20 December 2019 to 15 August 2022 was carried out using PubMed, Embase, Cochrane, and Web of Science. R 4.2.1 software was used for meta-analysis of the published results. Pooled risk ratios and 95% confidence intervals (CIs) were calculated. RESULTS: We identified eight studies involving 7729 patients, of whom 5097 (66%) had severe COVID-19 and 2632 (34%) had mild or moderate symptoms. The positive rate of anti-type-I-IFN-autoantibodies in the total dataset was 5% (95% CI, 3-8%), but reached 10% (95% CI, 7-14%) in those with severe infection. The most common subtypes were anti-IFN-α (89%) and anti-IFN-ω (77%). The overall prevalence in male patients was 5% (95% CI, 4-6%), and in female patients 2% (95% CI, 1-3%). CONCLUSION: Severe COVID-19 is associated with high rates of autoantibodies against type-I-IFN and more so in male than female patients.

Interferon lambda as a potential treatment for COVID-19.

INTRODUCTION: Pegylated interferon lambda substantially reduced the risk of COVID-19-related hospitalizations or emergency room visits in a recent phase 3, multi-center, randomized, double-blind, placebo-controlled study of high-risk, non-hospitalized adult patients with SARS-CoV-2 infection compared to treatment with placebo. AREAS COVERED: Interferons are a family of signaling molecules produced as part of the innate immune response to viral infections. The administration of exogenous interferon may limit disease progression in patients with COVID-19. EXPERT OPINION: Interferons have been used to treat viral infections, including hepatitis B and hepatitis C, and malignancies such as non-Hodgkin's lymphoma, as well as the autoimmune condition multiple sclerosis. This manuscript examines what is known about the role of interferon lambda in the treatment of COVID-19, including potential limitations, and explores how this approach may be used in the future.

IFI44 is an immune evasion biomarker for SARS-CoV-2 and Staphylococcus aureus infection in patients with RA.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of severe coronavirus disease 2019 (COVID-19). Staphylococcus aureus is one of the most common pathogenic bacteria in humans, rheumatoid arthritis (RA) is among the most prevalent autoimmune conditions. RA is a significant risk factor for SARS-CoV-2 and S. aureus infections, although the mechanism of RA and SARS-CoV-2 infection in conjunction with S. aureus infection has not been elucidated. The purpose of this study is to investigate the biomarkers and disease targets between RA and SARS-CoV-2 and S. aureus infections using bioinformatics analysis, to search for the molecular mechanisms of SARS-CoV-2 and S. aureus immune escape and potential drug targets in the RA population, and to provide new directions for further analysis and targeted development of clinical treatments. Methods: The RA dataset (GSE93272) and the S. aureus bacteremia (SAB) dataset (GSE33341) were used to obtain differentially expressed gene sets, respectively, and the common differentially expressed genes (DEGs) were determined through the intersection. Functional enrichment analysis utilizing GO, KEGG, and ClueGO methods. The PPI network was created utilizing the STRING database, and the top 10 hub genes were identified and further examined for functional enrichment using Metascape and GeneMANIA. The top 10 hub genes were intersected with the SARS-CoV-2 gene pool to identify five hub genes shared by RA, COVID-19, and SAB, and functional enrichment analysis was conducted using Metascape and GeneMANIA. Using the NetworkAnalyst platform, TF-hub gene and miRNA-hub gene networks were built for these five hub genes. The hub gene was verified utilizing GSE17755, GSE55235, and GSE13670, and its effectiveness was assessed utilizing ROC curves. CIBERSORT was applied to examine immune cell infiltration and the link between the hub gene and immune cells. Results: A total of 199 DEGs were extracted from the GSE93272 and GSE33341 datasets. KEGG analysis of enrichment pathways were NLR signaling pathway, cell membrane DNA sensing pathway, oxidative phosphorylation, and viral infection. Positive/negative regulation of the immune system, regulation of the interferon-I (IFN-I; IFN-α/ß) pathway, and associated pathways of the immunological response to viruses were enriched in GO and ClueGO analyses. PPI network and Cytoscape platform identified the top 10 hub genes: RSAD2, IFIT3, GBP1, RTP4, IFI44, OAS1, IFI44L, ISG15, HERC5, and IFIT5. The pathways are mainly enriched in response to viral and bacterial infection, IFN signaling, and 1,25-dihydroxy vitamin D3. IFI44, OAS1, IFI44L, ISG15, and HERC5 are the five hub genes shared by RA, COVID-19, and SAB. The pathways are primarily enriched for response to viral and bacterial infections. The TF-hub gene network and miRNA-hub gene network identified YY1 as a key TF and hsa-mir-1-3p and hsa-mir-146a-5p as two important miRNAs related to IFI44. IFI44 was identified as a hub gene by validating GSE17755, GSE55235, and GSE13670. Immune cell infiltration analysis showed a strong positive correlation between activated dendritic cells and IFI44 expression. Conclusions: IFI144 was discovered as a shared biomarker and disease target for RA, COVID-19, and SAB by this study. IFI44 negatively regulates the IFN signaling pathway to promote viral replication and bacterial proliferation and is an important molecular target for SARS-CoV-2 and S. aureus immune escape in RA. Dendritic cells play an important role in this process. 1,25-Dihydroxy vitamin D3 may be an important therapeutic agent in treating RA with SARS-CoV-2 and S. aureus infections.

Interferon resistance of emerging SARS-CoV-2 variants.

The emergence of SARS-CoV-2 variants with enhanced transmissibility, pathogenesis, and resistance to vaccines presents urgent challenges for curbing the COVID-19 pandemic. While Spike mutations that enhance virus infectivity or neutralizing antibody evasion may drive the emergence of these novel variants, studies documenting a critical role for interferon responses in the early control of SARS-CoV-2 infection, combined with the presence of viral genes that limit these responses, suggest that interferons may also influence SARS-CoV-2 evolution. Here, we compared the potency of 17 different human interferons against multiple viral lineages sampled during the course of the global outbreak, including ancestral and five major variants of concern that include the B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), B.1.617.2 (delta), and B.1.1.529 (omicron) lineages. Our data reveal that relative to ancestral isolates, SARS-CoV-2 variants of concern exhibited increased interferon resistance, suggesting that evasion of innate immunity may be a significant, ongoing driving force for SARS-CoV-2 evolution. These findings have implications for the increased transmissibility and/or lethality of emerging variants and highlight the interferon subtypes that may be most successful in the treatment of early infections.

Sex affects immune response capacity against COVID-19 infection.

The genetic variability of each individual may lead to the identification of completely different genetic polymorphisms which are associated with a different sensitivity to infectious diseases in humans. Such genetic variability allows the immune system to respond differently to viral agents, therefore only a fraction of humans develop severe symptoms, as happened with SARS-CoV-2. Such knowledge is critical to enable the development of appropriate pharmacological solutions to prevent the consequences of insufficient immunity in dealing with serious viral diseases such as SARS-CoV-2. For instance, global epidemiological data show that male sex is a risk factor for the severe evolution of SARS-CoV-2 disease. Men, due to higher production of Testosterone (TLT), are more vulnerable than females. Women, due to greater expression of the TLR7 gene found on the X chromosome, a key innate immunity gene that encodes Toll-like proteins, are able to synthesise more antiviral proteins and interferons in dendritic cells, resulting in a more robust immune system capable of preventing severe SARS-CoV-2 viral disease. This manuscript highlights how human genetic variability can lead to severe infectious symptoms in some individuals who must take appropriate prophylactic actions, such as vaccination, to prevent this.

[In vitro activity of human recombinant interferon gamma against SARS-CoV-2 virus].

INTRODUCTION: The development of drugs against SARS-CoV-2 continues to be crucial for reducing the spread of infection and associated mortality. The aim of the work is to study the neutralization of the SARS-CoV-2 virus with interferon gamma preparations in vitro. MATERIALS AND METHODS: The activity of recombinant human interferon gamma for intramuscular and subcutaneous administration of 500,000 IU and for intranasal administration of 100,000 IU against the SARS-CoV-2 virus in vitro was studied. The methodological approach of this study is based on the phenomenon of a decrease in the number of plaques formed under the action of a potential antiviral drug. RESULTS: The antiviral activity of recombinant interferon gamma has been experimentally confirmed, both in preventive and therapeutic application schemes. The smallest number of plaques was observed with the preventive scheme of application of the tested object at concentrations of 1000 and 333 IU/ml. The semi-maximal effective concentration (EC50) with the prophylactic regimen was 24 IU/ml. DISCUSSION: The preventive scheme of application of the tested object turned out to be more effective than therapeutic one, which is probably explained by the launch of the expression of various interferon-stimulated genes that affect to a greater extent the steps of virus entry into the cell and its reproduction. CONCLUSION: Further study of the effect of drugs based on recombinant interferon gamma on the reproduction of the SARS-CoV-2 virus for clinical use for prevention and treatment is highly relevant.

Interferons and Resistance Mechanisms in Tumors and Pathogen-Driven Diseases-Focus on the Major Histocompatibility Complex (MHC) Antigen Processing Pathway.

Interferons (IFNs), divided into type I, type II, and type III IFNs represent proteins that are secreted from cells in response to various stimuli and provide important information for understanding the evolution, structure, and function of the immune system, as well as the signaling pathways of other cytokines and their receptors. They exert comparable, but also distinct physiologic and pathophysiologic activities accompanied by pleiotropic effects, such as the modulation of host responses against bacterial and viral infections, tumor surveillance, innate and adaptive immune responses. IFNs were the first cytokines used for the treatment of tumor patients including hairy leukemia, renal cell carcinoma, and melanoma. However, tumor cells often develop a transient or permanent resistance to IFNs, which has been linked to the escape of tumor cells and unresponsiveness to immunotherapies. In addition, loss-of-function mutations in IFN signaling components have been associated with susceptibility to infectious diseases, such as COVID-19 and mycobacterial infections. In this review, we summarize general features of the three IFN families and their function, the expression and activity of the different IFN signal transduction pathways, and their role in tumor immune evasion and pathogen clearance, with links to alterations in the major histocompatibility complex (MHC) class I and II antigen processing machinery (APM). In addition, we discuss insights regarding the clinical applications of IFNs alone or in combination with other therapeutic options including immunotherapies as well as strategies reversing the deficient IFN signaling. Therefore, this review provides an overview on the function and clinical relevance of the different IFN family members, with a specific focus on the MHC pathways in cancers and infections and their contribution to immune escape of tumors.

Interfering with Interferons: A Critical Mechanism for Critical COVID-19 Pneumonia.

Infection with SARS-CoV-2 results in clinical outcomes ranging from silent or benign infection in most individuals to critical pneumonia and death in a few. Genetic studies in patients have established that critical cases can result from inborn errors of TLR3- or TLR7-dependent type I interferon immunity, or from preexisting autoantibodies neutralizing primarily IFN-α and/or IFN-ω. These findings are consistent with virological studies showing that multiple SARS-CoV-2 proteins interfere with pathways of induction of, or response to, type I interferons. They are also congruent with cellular studies and mouse models that found that type I interferons can limit SARS-CoV-2 replication in vitro and in vivo, while their absence or diminution unleashes viral growth. Collectively, these findings point to insufficient type I interferon during the first days of infection as a general mechanism underlying critical COVID-19 pneumonia, with implications for treatment and directions for future research.

Autoantibodies targeting type I interferons: Prevalence, mechanisms of induction, and association with viral disease susceptibility.

The type I IFN (IFN-I) system is essential to limit severe viral disease in humans. Thus, IFN-I deficiencies are associated with serious life-threatening infections. Remarkably, some rare individuals with chronic autoimmune diseases develop neutralizing autoantibodies (autoAbs) against IFN-Is thereby compromising their own innate antiviral defenses. Furthermore, the prevalence of anti-IFN-I autoAbs in apparently healthy individuals increases with age, such that ∼4% of those over 70 years old are affected. Here, I review the literature on factors that may predispose individuals to develop anti-IFN-I autoAbs, such as reduced self-tolerance caused by defects in the genes AIRE, NFKB2, and FOXP3 (among others), or by generally impaired thymus function, including thymic involution in the elderly. In addition, I discuss the hypothesis that predisposed individuals develop anti-IFN-I autoAbs following "autoimmunization" with IFN-Is generated during some acute viral infections, systemic inflammatory events, or chronic IFN-I exposure. Finally, I highlight the enhanced susceptibility that individuals with anti-IFN-I autoAbs appear to have towards viral diseases such as severe COVID-19, influenza, or herpes (e.g., varicella-zoster virus, herpes simplex virus, cytomegalovirus), as well as adverse reactions to live-attenuated vaccines. Understanding the mechanisms underlying development and consequences of anti-IFN-I autoAbs will be key to implementing effective prophylactic and therapeutic measures.

The Anti-Viral Activity of Stem Cells: A Rational Explanation for their Use in Clinical Application.

It is well established the importance of stem cells (SCs) in tissue growth, regeneration and repair, given their ability to self-renew and differentiate into mature cells. Stem cells are present in all individuals and are potentially active to the end of life. However, less is known about their unique function within the immune system as immune regulators and their important task in viral protection. Antiviral resistance is a common mechanism in all cells though stem cells utilize an antiviral RNA interference (RNAi) mechanism, while adult cells react by using the interferondependent repression pathway via interferon-associated protein-based response to induce an antiviral response. Therefore, the idea behind this review is to highlight the mechanisms of viral evasion of host defense, which would then allow us to highlight the rationale use of autologous stem cells and their biochemical and immunological ability to reset the subverted immune responses. Recently, scientists have highlighted their use in the field of immune-therapy, establishing the possibilities of using them outside the conventional protocol with the advancement in manipulating these cells in such a way that specific body activity can be restored. This paper describes the remarkable SCs profile and discusses some ideas regarding their promising use in vivo.