Secreted ORF8 is a pathogenic cause of severe COVID-19 and is potentially targetable with select NLRP3 inhibitors

Wu, Xiaosheng; Manske, Michelle K.; Ruan, Gordon; Nowakowski, Kevin E.; Abeykoon, Jithma P.; Tang, Xinyi; Yu, Yue; Witter, Taylor L.; Taupin, Vanessa; Paludo, Jonas; Ansell, Stephen M.; Badley, Andrew D.; Schellenberg, M.J.; Witzig, Thomas E.

doi:10.1101/2021.12.02.470978

Cited by 16 publications

(26 citation statements)

References 44 publications

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“…We first produced soluble ORF8 in culture media by transfecting HEK293T cells with ORF8 DNA. In agreement with previous data showing ORF8 secretion (8, 9), we also observed ORF8 secretion and supernatant accumulation (Fig. 2A).…”

Section: Textsupporting

confidence: 93%

“…Notably, ORF8 was shown to directly interact with major histocompatibility complex class I molecules (MHC-I) and mediate their downregulation by targeting them to lysosomal degradation via autophagy rendering infected cells more resistant to lysis by cytotoxic T cells (7). Interestingly, a recent study has shown that ORF8 is secreted from infected cells, can be detected in the plasma of acutely-infected individuals, and is negatively associated with survival (8). Whether this association is linked to its capacity to induce a cytokine storm remains to be determined (9).…”

Section: Textmentioning

confidence: 99%

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SARS-CoV-2 accessory protein ORF8 decreases antibody-dependent cellular cytotoxicity

Beaudoin-Bussières

Arduini

Bourassa³

et al. 2022

Preprint

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SARS-CoV-2 Spike glycoprotein is the major target of host neutralizing antibodies and the most changing viral protein in the continuously emerging SARS-CoV-2 variants as a result of frequent viral evasion from host antibody responses. In addition, SARS-CoV-2 encodes multiple accessory proteins that modulate host antiviral immunity by different mechanisms. Among all SARS-CoV-2 accessory proteins, ORF8 is rapidly evolving and a deletion in this protein has been linked to milder disease. Here, we studied the effect of ORF8 on peripheral blood mononuclear cells (PBMC). Specifically, we found that ORF8 can bind monocytes as well as NK cells. Strikingly, ORF8 binds CD16a (FcGRIIIA) with nanomolar affinity and decreases the overall level of CD16 at the surface of monocytes and, to a lesser extent, NK cells. Strikingly, this decrease significantly reduces the capacity of PBMCs and particularly monocytes to mediate antibody-dependent cellular cytotoxicity (ADCC). Overall, our data identifies a new immune-evasion activity used by SARS-CoV-2 to escape humoral responses.

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Section: Textsupporting

confidence: 93%

Section: Textmentioning

confidence: 99%

SARS-CoV-2 accessory protein ORF8 decreases antibody-dependent cellular cytotoxicity

Beaudoin-Bussières

Arduini

Bourassa³

et al. 2022

Preprint

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“…Additionally, they have recently been found to act as viral modulators, regulating viral infection and host defense [51, 52]. Glycoprotein metabolic processes are expected to be relevant to Orf8, as induction of proinflammatory cytokine production by secreted Orf8 is glycosylation dependent [53]. RNA export from the nucleus is also relevant, as SARS-CoV-2-infected cells have an increased level of nuclear mRNA accumulation.…”

Section: Resultsmentioning

confidence: 99%

Open modification searching of SARS-CoV-2–human protein interaction data reveals novel viral modification sites

Adams

Boonen

Laukens

et al. 2022

Preprint

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The outbreak of the SARS-CoV-2 coronavirus, the causative agent of the COVID-19 disease, has led to an ongoing global pandemic since 2019. Mass spectrometry can be used to understand the molecular mechanisms of viral infection by SARS-CoV-2, for example, by determining virus-host protein-protein interactions (PPIs) through which SARS-CoV-2 hijacks its human hosts during infection, and to study the role of post-translational modifications (PTMs). We have reanalyzed public affinity purification mass spectrometry data using open modification searching to investigate the presence of PTMs in the context of the SARS-CoV-2 virus-host PPI network. Based on an over two-fold increase in identified spectra, our detected protein interactions show a high overlap with independent mass spectrometry-based SARS-CoV-2 studies and virus-host interactions for alternative viruses, as well as previously unknown protein interactions. Additionally, we identified several novel modification sites on SARS-CoV-2 proteins that we investigated in relation to their interactions with host proteins. A detailed analysis of relevant modifications, including phosphorylation, ubiquitination, and S-nitrosylation, provides important hypotheses about the functional role of these modifications during viral infection by SARS-CoV-2.

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“…ORF8 induces proinflammatory cytokines through activation of NLRP3-mediated inflammasome pathways. [13] Dysregulation of the interferon response is a strategy employed by viruses to evade host immunity. Previous investigations of the host response to SARS-CoV and MERS-CoV infection suggest that multiple coronaviruses employ this strategy [14][15][16][17][18].…”

Section: Discussionmentioning

confidence: 99%

Mutational analysis of SARS-CoV-2. ORF8 and the evolution of the Delta and Omicron variants

Trieu¹,

Trieu²

2021

Preprint

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SARS-CoV-2 the virus responsible for the current pandemic. This virus is continually evolving, adapting to both innate and acquired immune responses and therapeutic drugs. Therefore, it is important to understand how the virus evolving to design the appropriate therapeutic and vaccine in preparation for future variants. Here, we used the online SARS-CoV-2 databases, Nextstrain and Ourworld, to map the evolution and epidemiology of the virus. We identified 30 high entropy residues which underwent a progressive evolution to arrive at the current dominant variant - Delta variant. The virus underwent mutational waves with the first wave made up of structural proteins important in its infectivity and the second wave made up of the ORFs important for its contagion. The most important driver of the second wave is ORF8 mutations at residue 119 and 120. Further mutations of these two residues are creating new clades that are offshoots from the Delta backbone. More importantly the further expansion of the S protein in the Omicron variant is now followed with the acquisition of ORF8 mutations 119 and 120. These findings demonstrate how SARS-CoV-2 mutates and points to two evolutionary paths; 1) Mutational expansion on the Delta backbone among the ORFs and 2) Mutational expansion of the S protein on other backbone follow with mutational wave among the ORFs. Both are happening at the same time right now with the Omicron variant early in the first wave to follow with a more aggressive second wave of mutations.

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Secreted ORF8 is a pathogenic cause of severe COVID-19 and is potentially targetable with select NLRP3 inhibitors

Cited by 16 publications

References 44 publications

SARS-CoV-2 accessory protein ORF8 decreases antibody-dependent cellular cytotoxicity

SARS-CoV-2 accessory protein ORF8 decreases antibody-dependent cellular cytotoxicity

Open modification searching of SARS-CoV-2–human protein interaction data reveals novel viral modification sites

Mutational analysis of SARS-CoV-2. ORF8 and the evolution of the Delta and Omicron variants

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