Abstract
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. 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.
Highlights
We set out to identify host pathways of cellular resistance to pathogens with pandemic potential, using a transposonmutagenesis forward genetic approach
Susceptible wild-type U2OS cells died after 3-4 days of treatment, whereas surviving cells could be expanded from mutagenized libraries and exhibited stable resistance to re-challenge with Ebola glycoprotein (EboGP)-VSV (Fig. 1B)
U2OS cells are haploid at the NPC1 locus [6] and these transposon insertions are predicted to generate NPC1-null cells, explaining why NPC1 was the only predicted gene-disruption mutant identified as a high-stringency candidate gene
Summary
We set out to identify host pathways of cellular resistance to pathogens with pandemic potential, using a transposonmutagenesis forward genetic approach. These cells showed no cross-resistance to VSV containing the VSV glycoprotein (VSVg-VSV) (Fig. 1C), suggesting that the majority of resistance mechanisms selected in this screen targeted EboGP-mediated entry. First release: 27 August 2020 www.sciencemag.org (Page numbers not final at time of first release) 1 chromosome 16, were upstream of the gene CIITA, and were all oriented in the sense orientation, consistent with activation of expression
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