Transplacental SARS-CoV-2 protein ORF8 binds to complement C1q to trigger fetal inflammation

Area of Science:

• Immunology
• Virology
• Obstetrics

Background:

• Prenatal SARS-CoV-2 infection links to adverse pregnancy and birth outcomes.
• Vertical transmission is considered low, but fetal inflammation is observed.

Purpose of the Study:

• Investigate mechanisms of fetal inflammation in pregnancies with prenatal SARS-CoV-2 infection.
• Identify specific viral proteins and host factors involved in placental and fetal inflammation.

Main Methods:

• Multi-omics analysis of placental, cord, and amniotic fluid samples from 23 COVID-19 mother-infant pairs.
• Detection of SARS-CoV-2 RNA and proteins (ORF8) in fetal tissues.
• In vitro studies using human placental trophoblasts exposed to ORF8.
• Co-immunoprecipitation to identify protein interactions.

Main Results:

• Robust inflammatory responses and complement protein expression (C1q, C3, C4, C5) in fetal compartments.
• SARS-CoV-2 ORF8 protein detected in over 60% of fetal tissues, correlating with increased inflammation and complement activation.
• Exogenous ORF8 exposure induced complement activation and inflammation in placental cells.
• ORF8 directly binds to complement C1q via a specific peptide region.

Conclusions:

• A novel ORF8-C1q-dependent complement activation pathway contributes to fetal inflammation in prenatal COVID-19.
• This pathway may mediate fetal inflammation independently of direct fetal SARS-CoV-2 infection.