Transposon Mediated Forward Genetic Screens Identify Cell Intrinsic Resistance to Emerging Viral Pathogens

Recent outbreaks of Ebola virus (EBOV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have exposed our limited therapeutic options for such diseases and our poor understanding of the cellular mechanisms that block viral infections. Using a transposon-mediated gene-activation screen in human cells, we identify that the major histocompatibility complex (MHC) class II transactivator (CIITA) has antiviral activity against EBOV. CIITA induces resistance by activating expression of the p41 isoform of invariant chain CD74, which inhibits viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein. We further show that CD74 p41 can block the endosomal entry pathway of coronaviruses, including SARS-CoV-2. However, coronavirus entry mediated by cell surface proteases like TMPRSS2 bypasses inhibition by CD74 p41. These data therefore implicate CIITA and CD74 in host defense against a range of viruses, and they identify an additional function of these proteins beyond their canonical roles in antigen presentation.

Learning Objectives:

1. Analyze about transposon activation tagging and its potential use to rapidly identify virus/host interactions for emerging viral pathogens.

2. Clarify how upregulation of the master regulator of MHC class II (CIITA) and the invariant chain (CD74) leads to cellular restriction of Ebola and SARS-CoV-2 viral entry independent of their role in adaptive immunity.

3. Classify the similarities and differences in the entry pathways of Ebola and SARS-CoV-2.