Transplacental SARS-CoV-2 protein ORF8 binds to complement C1q to trigger fetal inflammation
Prenatal SARS-CoV-2 infection is associated with higher rates of pregnancy and birth complications, despite that vertical transmission rates are thought to be low. Here, multi-omics analyses of human placental tissues, cord tissues/plasma, and amniotic fluid from 23 COVID-19 mother-infant pairs revealed robust inflammatory responses in both maternal and fetal compartments. Pronounced expression of complement proteins (C1q, C3, C3b, C4, C5) and inflammatory cytokines (TNF, IL-1α, and IL-17A/E) was detected in the fetal compartment of COVID-19-affected pregnancies. While ~26% of fetal tissues were positive for SARS-CoV-2 RNA, more than 60% of fetal tissues contained SARS-CoV-2 ORF8 proteins, suggesting transplacental transfer of this viral accessory protein. ORF8-positive fetal compartments exhibited increased inflammation and complement activation compared to ORF8-negative COVID-19 pregnancies. In human placental trophoblasts in vitro, exogenous ORF8 exposure resulted in complement activation and inflammatory responses. Co-immunoprecipitation analysis demonstrated that ORF8 binds to C1q specifically by interacting with a 15-peptide region on ORF8 (C37-A51) and the globular domain of C1q subunit A. In conclusion, an ORF8-C1q-dependent complement activation pathway was identified in COVID-19-affected pregnancies, likely contributing to fetal inflammation independently of fetal virus exposure.
Authors
- Charles B. Foster (ORCID: https://orcid.org/0000-0002-0092-8330)
- Tamiris Azamor
- Lu Bian
- Gielenny M. Salem (ORCID: https://orcid.org/0000-0001-6077-1606)
- Edward K. Chien (ORCID: https://orcid.org/0000-0003-3268-0111)
- Suan‐Sin Foo (ORCID: https://orcid.org/0009-0007-8174-0893)
- Ruth M. Farrell (ORCID: https://orcid.org/0000-0002-8258-8842)
- Karin Nielsen‐Saines (ORCID: https://orcid.org/0000-0002-1742-5211)
- Oluwatosin Goje (ORCID: https://orcid.org/0000-0001-7057-6580)
- Xianfang Wu (ORCID: https://orcid.org/0000-0002-2995-935X)
- Débora Familiar-Macedo (ORCID: https://orcid.org/0000-0002-9229-5912)
- Jae U. Jung (ORCID: https://orcid.org/0000-0003-4559-8774)
- Ivonne Melano (ORCID: https://orcid.org/0000-0002-6057-9013)
- Stephen V. Gordon (ORCID: https://orcid.org/0000-0002-4833-5542)
- Zilton Vasconcelos (ORCID: https://orcid.org/0000-0002-2193-2224)
- Hany Aly (ORCID: https://orcid.org/0000-0001-7395-6394)
- Chineme Onwubueke (ORCID: https://orcid.org/0000-0002-3183-8266)
- Feng Lin
- Weiqiang Chen (ORCID: https://orcid.org/0000-0002-8840-1823)
Institutions
- Cleveland Clinic (US)
- University of California, Los Angeles (US)
- Cleveland Clinic Lerner College of Medicine (US)
- Fundação Oswaldo Cruz (BR)
- Case Western Reserve University (US)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-10-10
- DOI
- https://doi.org/10.1038/s44318-024-00260-9
- Citations
- 9
- Primary Topic
- COVID-19 Impact on Reproduction
- Type
- article
- Field-Weighted Citation Impact
- 5.24
Funders
- National Institutes of Health
- National Institute of Dental and Craniofacial Research
- Clinical and Translational Science Center, Weill Cornell Medical College