SARS-CoV-2 ORF8 drives osteoclastogenesis in preexisting immune-mediated inflammatory diseases
Ivonne Melano, Tamiris Azamor, Camila C.S. Caetano, Nikki M. Meyer, Chineme Onwubueke, Anabelle Visperas, Débora Familiar-Macedo, Gielenny M. Salem, Brandy-Lee Soos, Cassandra M. Calabrese, Youn Jung Choi, Shuyang Chen, Younho Choi, Xianfang Wu, Zilton Vasconcelos, Suzy A.A. Comhair, Karin Nielsen-Saines, Leonard H. Calabrese, M. Elaine Husni, Jae U. Jung, Nicolas S. Piuzzi, Suan-Sin Foo, Weiqiang Chen
Ivonne Melano, Tamiris Azamor, Camila C.S. Caetano, Nikki M. Meyer, Chineme Onwubueke, Anabelle Visperas, Débora Familiar-Macedo, Gielenny M. Salem, Brandy-Lee Soos, Cassandra M. Calabrese, Youn Jung Choi, Shuyang Chen, Younho Choi, Xianfang Wu, Zilton Vasconcelos, Suzy A.A. Comhair, Karin Nielsen-Saines, Leonard H. Calabrese, M. Elaine Husni, Jae U. Jung, Nicolas S. Piuzzi, Suan-Sin Foo, Weiqiang Chen
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Research Article Inflammation Virology

SARS-CoV-2 ORF8 drives osteoclastogenesis in preexisting immune-mediated inflammatory diseases

Abstract

Patients with immune-mediated inflammatory diseases (IMIDs) like rheumatoid arthritis (RA) are at higher risk for severe COVID-19 and long-term complications in bone health. Emerging clinical evidence demonstrated that SARS-CoV-2 infection reduces bone turnover and promotes bone loss, but the mechanism underlying worsened bone health remains elusive. This study sought to identify specific immune mediators that exacerbated preexisting IMIDs after SARS-CoV-2 exposure. Plasma samples from 4 groups were analyzed: healthy, IMID only, COVID-19 only, and COVID-19 + IMID. Using high-throughput multiplexed proteomics, we profiled 1,500 protein biomarkers and identified 148 unique biomarkers in COVID-19 patients with IMIDs, including elevated inflammatory cytokines (e.g., IL-17F) and bone resorption markers. Long-term circulating SARS-CoV-2 ORF8, a virulence factor for COVID-19, was detected in the COVID + IMID group. RA was one of the most common IMIDs in our study. ORF8 treatment of RA-derived human osteoblasts (RA-hOBs) increased levels of inflammatory (TNF, IL6, CCL2) and bone resorption (RANKL/osteoprotegerin ratio) markers compared with healthy controls. Supernatants from ORF8-treated RA-hOBs drove the differentiation of macrophages into osteoclast-like cells. These findings suggest that SARS-CoV-2 exposure can exacerbate IMIDs through ORF8-driven inflammation and osteoclastogenesis, highlighting potential therapeutic targets for managing COVID-19–induced bone pathologies.

Authors

Ivonne Melano, Tamiris Azamor, Camila C.S. Caetano, Nikki M. Meyer, Chineme Onwubueke, Anabelle Visperas, Débora Familiar-Macedo, Gielenny M. Salem, Brandy-Lee Soos, Cassandra M. Calabrese, Youn Jung Choi, Shuyang Chen, Younho Choi, Xianfang Wu, Zilton Vasconcelos, Suzy A.A. Comhair, Karin Nielsen-Saines, Leonard H. Calabrese, M. Elaine Husni, Jae U. Jung, Nicolas S. Piuzzi, Suan-Sin Foo, Weiqiang Chen

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Figure 4

Plasma levels of SARS-CoV-2 ORF8 in COVID-19 patients with preexisting IMIDs correlate with enhanced inflammation and bone resorption.

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Plasma levels of SARS-CoV-2 ORF8 in COVID-19 patients with preexisting I...
(A) Dot plots showing plasma levels of SARS-CoV-2 ORF8 detected in healthy, IMID, COVID, and COVID + IMID groups. Concentration > 50 ng/mL is considered ORF8 positive. Data are represented as means ± SEM (n = 13–20 per group). Statistical analysis was performed using 1-way ANOVA, Kruskal-Wallis test, and uncorrected Dunn’s posttest. ***P < 0.001 and ****P < 0.0001. (B) Venn diagram comparison of significantly altered (P < 0.05) plasma proteins among ORF8-negative (n = 6 per group) and ORF8-positive (n = 7 per group) COVID + IMID patients compared with healthy controls. (C) Bubble plot of significantly upregulated proteins in patients with ORF8-positive COVID + IMID. (D and E) Dot plots of fold-change (relative to healthy controls) of inflammatory factors CXCL13, CXCL9, FCGR2B, and TNFSF12 (D) and bone-associated factors PTH1R, TPO, TNFRSF11A, FETUB, CLEC11A, and TSHR (E) in patients with COVID + IMID belonging to ORF8-negative or ORF8-positive groups (n = 5–7 per group). (F and G) Biological processes upregulated (F) and downregulated (G) in patients with ORF8-positive COVID + IMID. (H and I) Biological processes upregulated (H) and downregulated (I) in patients with ORF8-negative COVID + IMID. Data are represented as means ± SEM. Statistical analysis was performed using Mann-Whitney U test. Significant results are displayed with asterisks (*P < 0.05).