Mutations in SARS-CoV-2 ORF8 Altered the Bonding Network With Interferon Regulatory Factor 3 to Evade Host Immune System.
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ABSTRACT:
SUBMITTER: Rashid F
PROVIDER: S-EPMC8322779 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Prenatal SARS-CoV-2 infection is associated with higher rates of pregnancy and birth complications, despite that vertical transmission rates are thought to be low. Here, multi-omics analyses of human placental tissues, cord tissues/plasma, and amniotic fluid from 23 COVID-19 mother-infant pairs revealed robust inflammatory responses in both maternal and fetal compartments. Pronounced expression of complement proteins (C1q, C3, C3b, C4, C5) and inflammatory cytokines (TNF, IL-1α, and IL-17A/E) was detected in the fetal compartment of COVID-19-affected pregnancies. While approximately 26% of fetal tissues were positive for SARS-CoV-2 RNA, more than 60% of fetal tissues contained SARS-CoV-2 ORF8 proteins, suggesting transplacental transfer of this viral accessory protein. ORF8-positive fetal compartments exhibited increased inflammation and complement activation compared to ORF8-negative COVID-19 pregnancies. In human placental trophoblasts in vitro, exogenous ORF8 exposure resulted in complement activation and inflammatory responses. Co-immunoprecipitation analysis demonstrated that ORF8 binds to C1q specifically by interacting with a 15-peptide region on ORF8 (C37-A51) and the globular domain of C1q subunit A. In conclusion, an ORF8-C1q-dependent complement activation pathway was identified in COVID-19-affected pregnancies, likely contributing to fetal inflammation independently of fetal virus exposure.
| S-SCDT-10_1038-S44318-024-00260-9 | biostudies-other
Project description:As the world continues to fight the coronavirus pandemic caused by SARS‐CoV‐2, we are gaining valuable insights by comparing this virus to other human coronaviruses such as SARS‐CoV and MERS‐CoV that have also caused outbreaks. Coronaviruses infect many animal species, but disease severity varies between strains. Viral accessory proteins are generally implicated in increased infectivity, pathogenicity, and virulence. The accessory protein open reading frame 8 (ORF8), although not essential for viral replication, appears to play a critical role in disease severity by inhibiting multiple pathways of the immune response. Furthermore, the ORF8 gene is found within a highly variable portion of the genome, increasing the possibility of dangerous mutant forms arising. Structure‐based design of therapeutics holds great promise for effective targeting of such rapidly evolving threats. Thus, we designed physical models and computer representations of ORF8, based on the published structure 7JTL, to better evaluate the structural features responsible for viral pathogenicity. ORF8 exists as a homodimer held together by amino acid residues that interact through hydrophobic interactions, hydrogen bonding, a salt bridge, and a disulfide bond. These interactions occur in a region referred to as the covalent interface. Another interface, referred to as the noncovalent interface, exists between separate homodimers and results in oligomerization. The homodimers in the oligomer are held together by an intermolecular beta sheet that is stabilized by an extensive hydrophobic surface. These two dimerization interfaces are unique to SARS‐CoV‐2 and have been proposed to be involved in the protein's ability to evade and suppress the host immune response. The computer and physical representations allow for better visualization of the ORF8 structure to evaluate the role of the multimeric structure. ORF8 has been found to interact with various host proteins, including Interleukin‐17 Receptor A (IL17RA), a pro‐inflammatory cytokine. To further corroborate the existence of this interaction and to better understand the role oligomerization might play in pathogenicity, we assessed the possible interactions of ORF8 (7JTL) and IL17RA (5N9B) through theoretical modeling using available tools such as HDOCK. A better understanding of these inter‐subunit interactions may improve our understanding of the unique mechanism the virus uses to evade the immune system and may be instrumental in the development of effective therapeutics.
| S-EPMC8239924 | biostudies-literature
Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus causing the pandemic of severe pneumonia (Coronavirus Disease 2019, COVID-19). SARS-CoV-2 is highly pathogenic in human, having posed immeasurable public health challenges to the world. Innate immune response is critical for the host defense against viral infection and the dysregulation of the host innate immune responses probably aggravates SARS-CoV-2 infection, contributing to the high morbidity and lethality of COVID-19. It has been reported that some coronavirus proteins play an important role in modulating innate immunity of the host, but few studies have been conducted on SARS-CoV-2. In this study, we screened the viral proteins of SARS-CoV-2 and found that the viral ORF6, ORF8 and nucleocapsid proteins were potential inhibitors of type I interferon signaling pathway, a key component for antiviral response of host innate immune. All the three proteins showed strong inhibition on type I interferon (IFN-β) and NF-κB-responsive promoter, further examination revealed that these proteins were able to inhibit the interferon-stimulated response element (ISRE) after infection with Sendai virus, while only ORF6 and ORF8 proteins were able to inhibit the ISRE after treatment with interferon beta. These findings would be helpful for the further study of the detailed signaling pathway and unveil the key molecular player that may be targeted.
| S-EPMC7309931 | biostudies-literature
Project description:The COVID-19 pandemic, in the first seven months, has led to more than 15 million confirmed infected cases and 600,000 deaths. SARS-CoV-2, the causative agent for COVID-19, has proved to be a great challenge for its ability to spread in asymptomatic stages and the diverse disease spectrum it has generated. This has created a challenge of unimaginable magnitude, not only affecting human health and life but also potentially generating a long-lasting socioeconomic impact. Both medical sciences and biomedical research have also been challenged, consequently leading to a large number of clinical trials and vaccine initiatives. While known proteins of pathobiological importance are targets for these therapeutic approaches, it is imperative to explore other factors of viral significance. Accessory proteins are one such trait that have diverse roles in coronavirus pathobiology. Here, we analyze certain genomic characteristics of SARS-CoV-2 accessory protein ORF8 and predict its protein features. We have further reviewed current available literature regarding its function and comparatively evaluated these and other features of ORF8 and ORF8ab, its homolog from SARS-CoV. Because coronaviruses have been infecting humans repeatedly and might continue to do so, we therefore expect this study to aid in the development of holistic understanding of these proteins. Despite low nucleotide and protein identity and differentiating genome level characteristics, there appears to be significant structural integrity and functional proximity between these proteins pointing towards their high significance. There is further need for comprehensive genomics and structural-functional studies to lead towards definitive conclusions regarding their criticality and that can eventually define their relevance to therapeutics development.
| S-EPMC7558349 | biostudies-literature
Project description:AimsTo study effects on cellular innate immune responses to ORF8, ORF10, and Membrane protein (M protein) from the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, in combination with cannabidiol (CBD).Main methodsHEK293 cells transfected with plasmids expressing control vector, ORF8, ORF10, or M protein were assayed for cell number and markers of apoptosis at 24 h, and interferon and interferon-stimulated gene expression at 14 h, with or without CBD. Cells transfected with polyinosinic:polycytidylic acid (Poly (I:C)) were also studied as a general model of RNA-type viral infection.Key findingsReduced cell number and increased early and late apoptosis were found when expression of viral genes was combined with 1-2 μM CBD treatment, but not in control-transfected cells treated with CBD, or in cells expressing viral genes but treated only with vehicle. In cells expressing viral genes, CBD augmented expression of IFNγ, IFNλ1 and IFNλ2/3, as well as the 2'-5'-oligoadenylate synthetase (OAS) family members OAS1, OAS2, OAS3, and OASL. CBD also augmented expression of these genes in control cells not expressing viral genes, but without enhancing apoptosis. CBD similarly enhanced the cellular anti-viral response to Poly (I:C).SignificanceOur results demonstrate a poor ability of HEK293 cells to respond to SARS-CoV-2 genes alone, but an augmented innate anti-viral response to these genes in the presence of CBD. Thus, CBD may prime components of the innate immune system, increasing readiness to respond to RNA-type viral infection without activating apoptosis, and could be studied for potential in prophylaxis.
| S-EPMC9091075 | biostudies-literature
Project description:SARS-CoV-2 infection triggers cytokine-mediated inflammation, leading to a myriad of clinical presentations in COVID19. The SARS-CoV-2 ORF8 is a secreted and rapidly evolving glycoprotein. Patients infected with SARS-CoV-2 ORF8-deleted variants are associated with mild disease outcomes, but the molecular mechanism this behind is unknown. Here, we report that SARS-CoV-2 ORF8 is a viral cytokine that is similar but distinct from interleukin 17A (IL-17A) as it induces stronger and broader human IL-17 receptor (hIL-17R) signaling than IL-17A. ORF8 primarily targeted blood monocytes and induced the heterodimerization of hIL-17RA and hIL-17RC, triggering robust inflammatory response. Transcriptome analysis revealed that besides its activation of the hIL-17R pathway, ORF8 upregulated gene expressions for fibrosis signaling and coagulation dysregulation. A naturally occurring ORF8 L84S variant that highly associated with mild COVID-19 showed reduced hIL-17RA binding and attenuated inflammatory responses. This study discovers SARS-CoV-2 ORF8 as a viral mimicry of IL-17 cytokine to contribute COVID-19 severe inflammation.
2022-03-11 | GSE196455 | GEO
Project description:CD8+ T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8+ T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8+ T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8+ T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8+ T cell surveillance through point mutations in MHC-I-restricted viral epitopes.
| S-EPMC8224398 | biostudies-literature
Project description:The new SARS-CoV-2 poses a significant threat to human health but many aspects of its basic biology remain unknown. Its genome encodes accessory genes that differ significantly within coronaviruses and contribute to the virus pathogenicity. Among accessory genes, open reading frame 8 (ORF8) stands out by being highly variable and showing structural changes suspected to be related with the virus ability to spread. However, the function of ORF8 remains to be elucidated, making it less studied than other SARS-CoV-2 genes. Here I show that ORF8 is poorly conserved among related coronaviruses. The ORF8 phylogeny built using 11,113 SARS-CoV-2 sequences revealed traces of a typical expanding population with a small number of highly frequent lineages. Interestingly, I detected several nonsense mutations and three main deletions in the ORF8 gene that either remove or significantly change the ORF8 protein. These findings suggest that SARS-CoV-2 can persist without a functional ORF8 protein. Deletion breakpoints were found located in predicted hairpins suggesting a possible involvement of these elements in the rearrangement process. Although the function of ORF8 remains to be elucidated, its structural plasticity and high diversity suggest an important role in SARS-CoV-2 pathogenicity.
| S-EPMC7467077 | biostudies-literature
Project description:Hyperactivation of the complement system, a major component of innate immunity, has been recognized as one of the core clinical features in severe covid-19 patients. However, how the virus escapes the targeted elimination by the network of activated complement pathways still remains an enigma. Here, we identified SARS-CoV-2-encoded ORF8 protein as one of the major binding partners of human complement C3/C3b components and their metabolites. Our results demonstrated that preincubation of ORF8 with C3/C3b in the fluid phase has two immediate functional consequences in the alternative pathway; this preincubation inhibits factor I-mediated proteolysis and blocks factor B zymogen activation into active Bb. ORF8 binding results in the occlusion of both factor H and factor B from C3b, rendering the complexes resistant to factor I-mediated proteolysis and inhibition of pro-C3-convertase (C3bB) formation, respectively. We also confirmed the complement inhibitory activity of ORF8 in our hemolysis-based assay, where ORF8 prevented human serum-induced lysis of rabbit erythrocytes with an IC50 value of about 2.3 μM. This inhibitory characteristic of ORF8 was also supported by in-silico protein-protein docking analysis, as it appeared to establish primary interactions with the β-chain of C3b, orienting itself near the C3b CUB (C1r/C1s, Uegf, Bmp1) domain like a peptidomimetic compound, sterically hindering the binding of essential cofactors required for complement amplification. Thus, ORF8 has characteristics to act as an inhibitor of critical regulatory steps in the alternative pathway, converging to hasten the decay of C3-convertase and thereby, attenuating the complement amplification loop.
| S-EPMC9851726 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-07-21 | GSE186628 | GEO