Robust Virus-Specific Adaptive Immunity in COVID-19 Patients with SARS-CoV-2 Δ382 Variant Infection

Fong, Siew‐Wai; Yeo, Nicholas Kim‐Wah; Chan, Yi‐Hao; Goh, Yun Shan; Amrun, Siti Naqiah; Ang, Nicholas; Rajapakse, Menaka Priyadharsani; Lum, Josephine; Foo, Shihui; Lee, Cheryl Yi‐Pin; Carissimo, Guillaume; Chee, Rhonda Sin‐Ling; Torres‐Ruesta, Anthony; Tay, Matthew Zirui; Chang, Zi Wei; Poh, Chek Meng; Young, Barnaby Edward; Tambyah, Paul A.; Kalimuddin, Shirin; Leo, Yee‐Sin; Lye, David C.; Lee, Bernett; Biswas, Subhra K.; Howland, Shanshan W.; Rénia, Laurent; Ng, Lisa F. P.

doi:10.1007/s10875-021-01142-z

Cited by 15 publications

(17 citation statements)

References 82 publications

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“…39 However, new data from COVID-19 human patients examined a rare 382-nucleotide deletion variation in SARS-CoV-2 found in Singapore that results in the loss of a small portion of ORF7B and the majority of the ORF8 gene. This work found that this SARS-CoV-2 variant is associated with a milder infection in COVID-19 patients and an improved interferon response 40,41 . Our findings in a human iPSC line point toward the loss of Orf8 as a possible cause of these differences and provide a mechanism underlying the role of Orf8 in promoting SARS-CoV-2 virulence within the patient population.…”

Section: Mainmentioning

confidence: 79%

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SARS-CoV-2 ORF8 encoded protein contains a histone mimic, disrupts chromatin regulation, and enhances replication

Thudium

Renner

et al. 2021

Preprint

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SARS-CoV-2 emerged in China at the end of 2019 and caused the global pandemic of COVID-19, a disease with high morbidity and mortality. While our understanding of this new virus is rapidly increasing, gaps remain in our understanding of how SARS-CoV-2 can effectively suppress host cell antiviral responses. Recent work on other viruses has demonstrated a novel mechanism through which viral proteins can mimic critical regions of human histone proteins. Histone proteins are responsible for governing genome accessibility and their precise regulation is critical for a cell’s ability to control transcription and respond to viral threats. Here, we show that the protein encoded by ORF8 (Orf8) in SARS-CoV-2 functions as a histone mimic of the ARKS motif in histone 3. Orf8 is associated with chromatin, binds to numerous histone-associated proteins, and is itself acetylated within the histone mimic site. Orf8 expression in cells disrupts multiple critical histone post-translational modifications (PTMs) including H3K9ac, H3K9me3, and H3K27me3 and promotes chromatin compaction while Orf8 lacking the histone mimic motif does not. Further, SARS-CoV-2 infection in human cell lines and postmortem patient lung tissue cause these same disruptions to chromatin. However, deletion of the Orf8 gene from SARS-CoV-2 largely blocks its ability to disrupt host-cell chromatin indicating that Orf8 is responsible for these effects. Finally, deletion of the ORF8 gene affects the host-cell transcriptional response to SARS-CoV-2 infection in multiple cell types and decreases the replication of SARS-CoV-2 in human induced pluripotent stem cell-derived lung alveolar type 2 (iAT2) pulmonary cells. These findings demonstrate a novel function for the poorly understood ORF8-encoded protein and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Finally, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.

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Section: Mainmentioning

confidence: 79%

“…In addition, these effects are reliant on the ARKSAP histone mimic motif within Orf8 protein. Notably, this work provides a molecular basis for the 2020 discovery that patients infected with a form of SARS-CoV-2 containing a deletion in the gene encoding Orf8 mount a stronger adaptive immune response 41 and improved outcomes 40 .…”

Section: Mainmentioning

confidence: 98%

SARS-CoV-2 ORF8 encoded protein contains a histone mimic, disrupts chromatin regulation, and enhances replication

Thudium

Renner

et al. 2021

Preprint

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“…Despite this early apparition, the expression of CD69 peaks between 18 and 24 h after activation before starting to decrease [ 28 ]. Emerging data suggest that CD4 + and CD8 + T cell responses play key roles in controlling SARS-CoV-2 infection and COVID-19 [ 29 – 31 ].…”

Section: Introductionmentioning

confidence: 99%

Helminth antigens differentially modulate the activation of CD4+ and CD8+ T lymphocytes of convalescent COVID-19 patients in vitro

Adjobimey

Meyer

Terkeš

et al. 2022

BMC Med

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Background The coronavirus disease 2019 (COVID-19) is a respiratory disease caused by SARS-CoV-2, a recently discovered strain of coronavirus. The virus has spread rapidly, causing millions of death worldwide. Contrary to the predictions, prevalence and mortality due to COVID-19 have remained moderate on the African continent. Several factors, including age, genetics, vaccines, and co-infections, might impact the course of the pandemic in Africa. Helminths are highly endemic in Sub-Saharan Africa and are renowned for their ability to evade, skew, and suppress human immune responses through various immune-modulatory mechanisms. Such effects will likely impact SARS-CoV-2 transmission and disease progression. Methods Here, we analyzed in vitro the impact of antigen extracts from three major helminth parasites, including Onchocerca volvulus, Brugia malayi, and Ascaris lumbricoides, on the immune reactivity to SARS-CoV-2 peptides in COVID-19 patients. Activation of CD4+ and CD8+ T cells was investigated using flow cytometry to monitor the expression of CD137 (4-1BB) and CD69. Cytokine expression, including IL-6, IL-10, IFN-γ, and TNFα, was measured by Luminex in cell culture supernatants. Results We observed that helminth antigens significantly reduced the frequency of SARS-CoV-2-reactive CD4+ T helper cells. In contrast, the expression of SARS-CoV-2-reactive CD8+ T cells was not affected and even significantly increased when PBMCs from COVID-19 patients living in Benin, an endemic helminth country, were used. In addition, stimulation with helminth antigens was associated with increased IL-10 and a reduction of IFNγ and TNFα. Conclusions Our data offer a plausible explanation for the moderate incidence of COVID-19 in Africa and support the hypothesis that helper T cell-mediated immune responses to SARS-CoV-2 are mitigated in the presence of helminth antigens, while virus-specific cytotoxic T cell responses are maintained.

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“…Likewise, studies from early in the COVID-19 pandemic observed the variability and rapid evolution of SARS-CoV-2 ORF8 gene (Alkhansa et al, 2021; Velazquez-Salinas et al, 2020). Notably, SARS-CoV-2 isolates with 382nt deletion spanning ORF7b-ORF8 gene region were observed in Singapore (Su et al, 2020), which correlated with robust T cell response and mild clinical outcome (Fong et al, 2022; Young et al, 2020). Mutations in ORF8 gene thus may play a key role in modulating viral pathogenesis and adaptation to the host by regulating MHC-I levels and ISGs.…”

Section: Discussionmentioning

confidence: 99%

“…SARS-CoV-2 ORF8 protein induces autophagic degradation of MHC-I and confers resistance to CTL surveillance (Zhang et al, 2021). Studies from the first 3 months of the pandemic showed the rapid evolution of the SARS-CoV-2 ORF8 gene including isolates with 382nt deletion spanning ORF7b-ORF8 gene region (Su et al, 2020; Velazquez-Salinas et al, 2020), which is associated with robust T cell response and mild clinical outcome (Fong et al, 2022; Young et al, 2020). These findings collectively raised a question of whether VOC and its ORF8 protein have evolved to further enhance the ability to shut down MHC-I, thereby evading from antigen- specific memory CD8 + T cells established by previous infection or vaccination.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Omicron subvariants evolved to promote further escape from MHC-I recognition

Moriyama

Lucas

Monteiro

et al. 2022

Preprint

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SummarySARS-CoV-2 variants of concern (VOCs) possess mutations that confer resistance to neutralizing antibodies within the Spike protein and are associated with breakthrough infection and reinfection. By contrast, less is known about the escape from CD8+ T cell-mediated immunity by VOC. Here, we demonstrated that VOCs retain similar MHC-I downregulation capacity compared to the ancestral virus. However, VOCs exhibit a greater ability to suppress type I IFN than the ancestral virus. Although VOCs possess unique mutations within the ORF8 gene, which suppresses MHC-I expression, none of these mutations enhanced the ability of ORF8 to suppress MHC-I expression. Notably, MHC-I upregulation was strongly inhibited after the ancestral SARS-CoV-2 infection in vivo. Collectively, our data suggest that the ancestral SARS-CoV-2 already possesses an intrinsically potent MHC-I evasion capacity, and that further adaptation by the variants was not observed.

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Robust Virus-Specific Adaptive Immunity in COVID-19 Patients with SARS-CoV-2 Δ382 Variant Infection

Cited by 15 publications

References 82 publications

SARS-CoV-2 ORF8 encoded protein contains a histone mimic, disrupts chromatin regulation, and enhances replication

SARS-CoV-2 ORF8 encoded protein contains a histone mimic, disrupts chromatin regulation, and enhances replication

Helminth antigens differentially modulate the activation of CD4+ and CD8+ T lymphocytes of convalescent COVID-19 patients in vitro

SARS-CoV-2 Omicron subvariants evolved to promote further escape from MHC-I recognition

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