Recent outbreaks of Ebola virus (EBOV) and SARS-CoV-2 have exposed our limited therapeutic options and poor understanding of cellular mechanisms that block viral infections. Using a transposon-mediated gene-activation screen in human cells, we identify that the 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 (EboGP). 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 identify an additional function of these proteins beyond their canonical roles in antigen presentation.
Recent and ongoing outbreaks of Ebola virus (EBOV) in Africa (1) and the SARS-CoV-2 pandemic highlight the need to identify additional treatment strategies for viral infections, including approaches that might complement traditional antivirals. Of particular interest is the identification of host-directed therapies that target common vulnerabilities and may be potentially efficacious against multiple viruses, including those that may emerge in the future.
We set out to identify host pathways of cellular resistance to pathogens with pandemic potential, using a transposon-mutagenesis forward genetic approach. We used a modified PiggyBac (PB) transposon, which stimulates or disrupts expression of neighboring genes, allowing an interrogation of both gene activation and inactivation in a single screen (2). Transposon-mutagenized libraries were treated with Ebola glycoprotein (EboGP)-expressing recombinant vesicular stomatitis virus (referred to as EboGP-VSV). Susceptible wild-type (wt) 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 EboGP-VSV. These cells showed no cross-resistance to VSV containing the VSV glycoprotein (VSVg-VSV), suggesting that the majority of resistance mechanisms selected in this screen targeted EboGP-mediated entry.
Reference & Source information: https://science.sciencemag.org/
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