ORF8 contributes to cytokine storm during SARS-CoV-2 infection by activating IL-17 pathway

Lin, Xiaoyuan; Fu, Binying; Yin, Shutao; Li, Zhifeng; Liu, Huawen; Zhang, Haiwei; Xing, Na; Wang, Yu; Xue, Weiwei; Xiong, Yan; Zhang, Shanfu; Zhao, Qingting; Xu, Shiyao; Zhang, Jing; Wang, Pei‐Hui; Nian, Weiqi; Xingsheng, Wang; Wu, Haibo

doi:10.1016/j.isci.2021.102293

Cited by 116 publications

(132 citation statements)

References 42 publications

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“…ORF8 has also been suggested to facilitate immune evasion by directly interacting with and downregulating MHC-I molecules in various cell types [32]. Conversely, it has been suggested to contribute to "cytokine storms" through an interaction with the IL-17 receptor [33]. Here, we confirm SP-dependent secretion of SARS-CoV-2 ORF8 and show that the secreted form is predominantly a disulphide-linked dimer glycosylated at position 78.…”

Section: Introductionsupporting

confidence: 73%

Secreted SARS-CoV-2 ORF8 modulates the cytokine expression profile of human macrophages

Kriplani

Clohisey

Fonseca

et al. 2021

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still adapting to its new human host. Attention has focussed on the viral spike protein, but substantial variation has been seen in the ORF8 gene. Here, we show that SARS-CoV-2 ORF8 protein undergoes signal peptide-mediated processing through the endoplasmic reticulum and is secreted as a glycosylated, disulphide-linked dimer. The secreted protein from the prototype SARS-CoV-2 virus had no major effect on viability of a variety of cell types, or on IFN or NF-κB; signalling. However, it modulated cytokine expression from primary CSF1-derived human macrophages, most notably by decreasing IL-6 and IL-8 secretion. Furthermore, a sequence polymorphism L84S that appeared early in the pandemic associated with the Clade S lineage of virus, showed a markedly different effect, of increasing IL-6 production. We conclude that ORF8 sequence polymorphisms can potentially affect SARS-CoV-2 virulence and should therefore be monitored in sequencing-based surveillance.

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Section: Introductionsupporting

confidence: 73%

Secreted SARS-CoV-2 ORF8 modulates the cytokine expression profile of human macrophages

Kriplani

Clohisey

Fonseca

et al. 2021

Preprint

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“…On the other side, SARS-CoV-2 ORF8 is a type I IFN antagonist, which exerts its function by targeting the PRRs-mediated pathway of IFN-β promoter and the downstream signal transduction that induces the interaction between IFN-β and IFNAR of INF stimulated genes ( 58 ). Also, ORF8 could activate IL-17 signaling pathway and promote proinflammatory factors expression by interacting with host IL17RA, thus contributing to SARS-CoV-2 cytokine storm during infection ( 59 ).…”

Section: Accessory Proteins Of Sars-cov-2mentioning

confidence: 99%

SARS-CoV-2 Accessory Proteins in Viral Pathogenesis: Knowns and Unknowns

et al. 2021

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There are still many unanswered questions concerning viral SARS-CoV-2 pathogenesis in COVID-19. Accessory proteins in SARS-CoV-2 consist of eleven viral proteins whose roles during infection are still not completely understood. Here, a review on the current knowledge of SARS-CoV-2 accessory proteins is summarized updating new research that could be critical in understanding SARS-CoV-2 interaction with the host. Some accessory proteins such as ORF3b, ORF6, ORF7a and ORF8 have been shown to be important IFN-I antagonists inducing an impairment in the host immune response. In addition, ORF3a is involved in apoptosis whereas others like ORF9b and ORF9c interact with cellular organelles leading to suppression of the antiviral response in infected cells. However, possible roles of ORF7b and ORF10 are still awaiting to be described. Also, ORF3d has been reassigned. Relevant information on the knowns and the unknowns in these proteins is analyzed, which could be crucial for further understanding of SARS-CoV-2 pathogenesis and to design strategies counteracting their actions evading immune responses in COVID-19.

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“…IL-17 signaling is important for the clearance of bacterial and fungal infections but its role in viral infection remains poorly defined (Lin et al 2021 , Xue et al 2021 ). In COVID-19, lymphocytes isolated from these cases were demonstrated to secret more IL-17 (De Biasi et al 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic analyses suggest augmented interleukin-17 signaling as the mechanism of COVID-19-associated herpes zoster

Chan

et al. 2021

Environ Sci Pollut Res

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Herpes zoster results from latent varicella zoster virus reactivation in the dorsal root ganglia, causing blistering rash along the dermatomal distribution and post-herpetic neuralgia. Increasing studies indicated that there may be a correlation between herpes zoster and COVID-19. Nevertheless, the detailed pathophysiological mechanism is still unclear. We used bioinformatic analyses to study the potential genetic crosstalk between herpes zoster and COVID-19. COVID-19 and herpes zoster were associated with a similar subset of genes involved in “cytokine-cytokine receptor interaction,” “Jak-STAT signaling pathway,” and “IL-17 signaling pathway,” including TNF , IL10 , ESR1 , INFG , HLA-A , CRP , STAT3 , IL6 , IL7 , and IL17A . Protein-protein interaction network assay showed that the combined gene set indicated a raised connectivity as compared to herpes zoster or COVID-19 alone, particularly the potentiated interactions with APOE , ARSA , CCR2 , CCR5 , CXCL13 , EGFR , GAL , GP2 , HLA-B , HLA-DRB1 , IL5 , TECTA , and THBS1 , and these genes are related to “cytokine-cytokine receptor interaction”. Augmented Th17 cell differentiation and the resulting enhanced IL-17 signaling were identified in both COVID-19 and herpes zoster. Our data suggested aberrant interleukin-17 signaling as one possible mechanism through which COVID-19 could raise the risk of herpes zoster.

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ORF8 contributes to cytokine storm during SARS-CoV-2 infection by activating IL-17 pathway

Cited by 116 publications

References 42 publications

Secreted SARS-CoV-2 ORF8 modulates the cytokine expression profile of human macrophages

Secreted SARS-CoV-2 ORF8 modulates the cytokine expression profile of human macrophages

SARS-CoV-2 Accessory Proteins in Viral Pathogenesis: Knowns and Unknowns

Bioinformatic analyses suggest augmented interleukin-17 signaling as the mechanism of COVID-19-associated herpes zoster

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