MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Recent outbreaks of Ebola virus (EBOV) and SARS-CoV-2 highlight limitations in antiviral therapies and understanding of host defense mechanisms.
• The cellular pathways that confer resistance to viral infections remain incompletely understood.

Purpose of the Study:

• To identify host factors that provide antiviral defense against EBOV and SARS-CoV-2.
• To elucidate the molecular mechanisms by which host factors inhibit viral entry.

Main Methods:

• A transposon-mediated gene-activation screen was employed in human cells to identify antiviral factors.
• The antiviral activity of identified factors against EBOV and SARS-CoV-2 was validated.
• Mechanistic studies were performed to understand how identified factors inhibit viral entry pathways.

Main Results:

• The major histocompatibility complex (MHC) class II transactivator (CIITA) was identified as a key antiviral factor against EBOV.
• CIITA activates the expression of the p41 isoform of invariant chain CD74.
• CD74 p41 inhibits EBOV entry by blocking cathepsin-mediated processing of the Ebola glycoprotein.
• CD74 p41 also inhibits the endosomal entry pathway utilized by SARS-CoV-2.

Conclusions:

• CIITA and CD74 play significant roles in host defense against a broad spectrum of viruses, including EBOV and SARS-CoV-2.
• These findings reveal a novel antiviral function for CIITA and CD74 beyond their established roles in antigen presentation.
• The study identifies CD74 p41 as a potential therapeutic target for viral infections.