SARS-CoV-2 ORF8 is a viral cytokine regulating immune responses

Kohyama, Masanori; Suzuki, Tatsuya; Nakai, Wataru; Ono, Chikako; Matsuoka, Sumiko; Iwatani, Koichi; Liu, Yafei; Sakai, Yusuke; Nakagawa, Atsushi; Tomii, Keisuke; Ohmura, Koichiro; Okada, Masato; Matsuura, Yoshiharu; Ohshima, Shiro; Maeda, Yusuke; Okamoto, Tomoyoshi; Arase, Hisashi

doi:10.1093/intimm/dxac044

Cited by 19 publications

(19 citation statements)

References 38 publications

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“…These data indicate that the intrinsic pathogenicity has lowered on evolution due to the acquisition of the S:S486P and ORF8 stop mutations. In a previous study, Kohyama et al showed that ORF8 functions as a viral cytokine and that functional loss of ORF8 resulted in impairment of inflammation 30 . As shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Virological characteristics of the SARS-CoV-2 XBB.1.5 variant

Tamura,

Irie,

Deguchi

et al. 2023

Preprint

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Circulation of SARS-CoV-2 Omicron XBB has resulted in the emergence of XBB.1.5, a new Variant of Interest. Our phylogenetic analysis suggests that XBB.1.5 evolved from XBB.1 by acquiring the F486P spike (S) mutation, subsequent to the acquisition of a nonsense mutation in ORF8. Neutralization assays showed similar abilities of immune escape between XBB.1.5 and XBB.1. We determined the structural basis for the interaction between human ACE2 and the S protein of XBB.1.5, showing similar overall structures between the S proteins of XBB.1 and XBB.1.5. The intrinsic pathogenicity of XBB.1.5 in hamsters is lower than that of XBB.1. Importantly, we found that the ORF8 nonsense mutation of XBB.1.5 resulted in impairment of MHC expression. In vivo experiments using recombinant viruses revealed that the XBB.1.5 mutations are involved with reduced virulence of XBB.1.5. Together, these data suggest that the mutations in ORF8 and S could enhance spreading of XBB.1.5 in humans.

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Section: Discussionmentioning

confidence: 99%

Virological characteristics of the SARS-CoV-2 XBB.1.5 variant

Tamura,

Irie,

Deguchi

et al. 2023

Preprint

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“…For instance, several groups have revealed that ∆ORF8 SARS-CoV-2 had reduced replication capabilities in immune-competent human pulmonary cells, particularly in angiotensinconverting enzyme 2 (ACE2)-expressing A549 (hACE2-A549) cells and in induced human pluripotent stem cell-derived lung alveolar type II (iAT2) cells, and it generated fewer and less infectious viral particles than wild-type SARS-CoV-2 in viral plaque assays [58][59][60]. Consistent with findings in COVID-19 patients, Syrian hamsters infected with ∆ORF8 SARS-CoV-2 experienced milder disease, with reduced immune infiltration, lung damage, and inflammatory cytokine production compared to wild-type, despite no significant effect on viral titer [61]. Detailed studies in K18-human ACE2 transgenic mice did not show a significant impact of ORF8-deletions on SARS-CoV-2 morbidity, mortality, viral lung titers, inflammation, and tissue damage [58,60].…”

Section: Orf8 Evolution During the Covid-19 Pandemicmentioning

confidence: 59%

“…ORF8 interaction with IL-17RA is implicated in ORF8 binding to monocytes in human blood, as well as to both THP1 and U937 monocytic cell lines [35,36,41,46,61]. Concordantly with the fact that monocytes are major drivers of the atypical cytokine storm contributing to severe COVID-19, ORF8-treatment of either CD14+/CD16+ monocytes or THP1 cells also results in pro-inflammatory cytokine overexpression (Figure 3) [35,36,46,61,91,92]. Ongoing work reveals that ORF8-monocyte interactions may not influence the differentiation of these cells into dendritic cells (DCs), but rather promote DC maturation and resulting cytokine storm [41].…”

Section: Orf8 As a Virokinementioning

confidence: 99%

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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“…Recently, several groups have independently reported that ORF8 is a secretory protein [ 34 , 52 – 55 ]; however, some of the results seem inconsistent with the others. For example, we found that the unglycosylated form of ORF8 was relatively low in Matsuoka’s system [ 52 ], while in our system 34.5~46.1% of ORF8 ( Fig 3B ) was unglycosylated.…”

Section: Discussionmentioning

confidence: 99%

Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection

Lin

Xiong

et al. 2023

PLoS Pathog

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Coronavirus disease 2019 is a respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence on the pathogenesis of SARS-CoV-2 is accumulating rapidly. In addition to structural proteins such as Spike and Envelope, the functional roles of non-structural and accessory proteins in regulating viral life cycle and host immune responses remain to be understood. Here, we show that open reading frame 8 (ORF8) acts as messenger for inter-cellular communication between alveolar epithelial cells and macrophages during SARS-CoV-2 infection. Mechanistically, ORF8 is a secretory protein that can be secreted by infected epithelial cells via both conventional and unconventional secretory pathways. Conventionally secreted ORF8 is glycosylated and loses the ability to recognize interleukin 17 receptor A of macrophages, possibly due to the steric hindrance imposed by N-glycosylation at Asn78. However, unconventionally secreted ORF8 does not undergo glycosylation without experiencing the ER-Golgi trafficking, thereby activating the downstream NF-κB signaling pathway and facilitating a burst of cytokine release. Furthermore, we show that ORF8 deletion in SARS-CoV-2 attenuates inflammation and yields less lung lesions in hamsters. Our data collectively highlights a role of ORF8 protein in the development of cytokine storms during SARS-CoV-2 infection.

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SARS-CoV-2 ORF8 is a viral cytokine regulating immune responses

Cited by 19 publications

References 38 publications

Virological characteristics of the SARS-CoV-2 XBB.1.5 variant

Virological characteristics of the SARS-CoV-2 XBB.1.5 variant

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

Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection

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