1. Transplacental SARS-CoV-2 protein ORF8 binds to complement C1q to trigger fetal inflammation.
- Author
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Azamor T, Familiar-Macedo D, Salem GM, Onwubueke C, Melano I, Bian L, Vasconcelos Z, Nielsen-Saines K, Wu X, Jung JU, Lin F, Goje O, Chien E, Gordon S, Foster CB, Aly H, Farrell RM, Chen W, and Foo SS
- Subjects
- Humans, Pregnancy, Female, Viral Proteins metabolism, Viral Proteins genetics, Fetus virology, Fetus metabolism, Fetus immunology, Complement Activation, Adult, Protein Binding, Trophoblasts metabolism, Trophoblasts virology, Cytokines metabolism, Complement C1q metabolism, Complement C1q genetics, COVID-19 virology, COVID-19 metabolism, COVID-19 immunology, SARS-CoV-2 metabolism, SARS-CoV-2 immunology, Placenta metabolism, Placenta virology, Pregnancy Complications, Infectious virology, Pregnancy Complications, Infectious metabolism, Inflammation metabolism
- Abstract
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., Competing Interests: Disclosure and competing interests statement The authors declare no competing interests., (© 2024. The Author(s).)
- Published
- 2024
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