SARS-CoV-2–encoded ORF8 protein possesses complement inhibitory properties

Kumar, Jitendra; Dhyani, Saurabh; Kumar, Prateek; Sharma, Nisha; Ganguly, Shantanu

doi:10.1016/j.jbc.2023.102930

Cited by 15 publications

(10 citation statements)

References 33 publications

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“…Transcriptomic analysis of ORF8-treated monocytes has also suggested that ORF8 upregulates the expression of key factors involved in these pathways [46]. In support of these proteomic and transcriptomic analyses, SARS-CoV-2 ORF8 was reported to bind the β-chain of complement component C3b and, as a result, inhibit the complement amplification loop [97]. Moreover, an impact on fertility by SARS-CoV-2 has been reported by several groups, suggesting that the virus may cause edema of the testes, impair sperm motility and function, and damage seminiferous tubules [98][99][100].…”

Section: Beyond Immunomodulationmentioning

confidence: 87%

SARS-CoV-2 ORF8: A Rapidly Evolving Immune and Viral Modulator in COVID-19

Arduini

Laprise

Liang

2023

Viruses

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The COVID-19 pandemic has resulted in upwards of 6.8 million deaths over the past three years, and the frequent emergence of variants continues to strain global health. Although vaccines have greatly helped mitigate disease severity, SARS-CoV-2 is likely to remain endemic, making it critical to understand its viral mechanisms contributing to pathogenesis and discover new antiviral therapeutics. To efficiently infect, this virus uses a diverse set of strategies to evade host immunity, accounting for its high pathogenicity and rapid spread throughout the COVID-19 pandemic. Behind some of these critical host evasion strategies is the accessory protein Open Reading Frame 8 (ORF8), which has gained recognition in SARS-CoV-2 pathogenesis due to its hypervariability, secretory property, and unique structure. This review discusses the current knowledge on SARS-CoV-2 ORF8 and proposes actualized functional models describing its pivotal roles in both viral replication and immune evasion. A better understanding of ORF8’s interactions with host and viral factors is expected to reveal essential pathogenic strategies utilized by SARS-CoV-2 and inspire the development of novel therapeutics to improve COVID-19 disease outcomes.

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Section: Beyond Immunomodulationmentioning

confidence: 87%

SARS-CoV-2 ORF8: A Rapidly Evolving Immune and Viral Modulator in COVID-19

Arduini

Laprise

Liang

2023

Viruses

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“…Early in the infection, adequate innate immune responses, including complement activation, contribute to a rapid return to homeostasis. To circumvent timely immune recognition, the SARS-CoV-2 virus uses multiple mechanisms, which includes the inhibition of complement ( 69 ) by its open reading frame 8 (ORF8) protein. Later in the disease course, defective viral clearance induces excessive lung inflammation, which is promoted by complement activation ( 70 ).…”

Section: Discussionmentioning

confidence: 99%

A complement atlas identifies interleukin-6–dependent alternative pathway dysregulation as a key druggable feature of COVID-19

Van Damme,

Hoste,

Declercq

et al. 2023

Sci. Transl. Med.

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Improvements in COVID-19 treatments, especially for the critically ill, require deeper understanding of the mechanisms driving disease pathology. The complement system is not only a crucial component of innate host defense but can also contribute to tissue injury. Although all complement pathways have been implicated in COVID-19 pathogenesis, the upstream drivers and downstream effects on tissue injury remain poorly defined. We demonstrate that complement activation is primarily mediated by the alternative pathway, and we provide a comprehensive atlas of the complement alterations around the time of respiratory deterioration. Proteomic and single-cell sequencing mapping across cell types and tissues reveals a division of labor between lung epithelial, stromal, and myeloid cells in complement production, in addition to liver-derived factors. We identify IL-6 and STAT1/3 signaling as an upstream driver of complement responses, linking complement dysregulation to approved COVID-19 therapies. Furthermore, an exploratory proteomic study indicates that inhibition of complement C5 decreases epithelial damage and markers of disease severity. Collectively, these results support complement dysregulation as a key druggable feature of COVID-19.

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“…Early in the infection, adequate innate immune responses, including complement activation, contribute to a rapid return to homeostasis. To circumvent timely immune recognition, the SARS-CoV-2 virus employs multiple mechanisms, which include the disruption of epigenetic regulation 63 and inhibition of complement 64 by its ORF8 protein. Later in the disease course, defective viral clearance induces excessive lung inflammation, which is promoted by complement activation 65 .…”

Section: Discussionmentioning

confidence: 99%

A Complement Atlas identifies interleukin 6 dependent alternative pathway dysregulation as a key druggable feature of COVID-19

Damme

Hoste

Declercq

et al. 2023

Preprint

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To improve COVID-19 therapy, it is essential to understand the mechanisms driving critical illness. The complement system is an essential part of innate host defense that can also contribute to injury. All complement pathways have been implicated in COVID-19 pathogenesis, however the upstream drivers and downstream consequences on tissue injury remain ill-defined. Here, we demonstrate that complement activation is mediated by the alternative pathway and we provide a comprehensive atlas of the alterations in complement around the time of respiratory deterioration. Proteome and single-cell sequencing mapping across cell types and tissues reveals a division of labor between lung epithelial, stromal and myeloid cells in the production of complement, in addition to liver-derived factors. Upstream, IL-6 drives complement responses, linking complement dysregulation to approved COVID-19 therapies. In an exploratory proteomic study, C5 inhibition improves epithelial damage and markers of disease severity. Collectively, these results identify complement dysregulation as a key druggable feature of COVID-19.

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SARS-CoV-2–encoded ORF8 protein possesses complement inhibitory properties

Cited by 15 publications

References 33 publications

SARS-CoV-2 ORF8: A Rapidly Evolving Immune and Viral Modulator in COVID-19

SARS-CoV-2 ORF8: A Rapidly Evolving Immune and Viral Modulator in COVID-19

A complement atlas identifies interleukin-6–dependent alternative pathway dysregulation as a key druggable feature of COVID-19

A Complement Atlas identifies interleukin 6 dependent alternative pathway dysregulation as a key druggable feature of COVID-19

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