MHC class II transactivator CIITA induces
cell resistance to Ebola virus and
Anna Bruchez1*†, Ky Sha1*, Joshua Johnson2‡, Li Chen3, Caroline Stefani1, Hannah McConnell1§,
Lea Gaucherand1¶, Rachel Prins1, Kenneth A. Matreyek4†, Adam J. Hume5,6, Elke Mühlberger5,6,
Emmett V. Schmidt7, Gene G. Olinger2,5,6,8, Lynda M. Stuart1,9, Adam Lacy-Hulbert1,10#
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 SARSCoV-
2. 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
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