Researchers working in human cells have identified a new pathway that targets a common vulnerability in several different pandemic viruses. This pathway can protect cells from infection by Ebola virus and from coronaviruses like SARS-CoV-2, they say. Their new findings, uncovered by an innovative screening approach, may inform future therapies against a broad range of viruses. Recent and ongoing outbreaks of Ebola virus in Africa and the SARS-CoV-2 pandemic globally highlight the need to identify additional treatment strategies for viral infections. Therapies that focus on host pathways of cellular resistance to viruses, and that target common vulnerabilities across multiple viruses, are of particular interest, but finding these pathways has been difficult using conventional genetic screens. Here, Anna Bruchez and colleagues used a novel screening approach based on activation of chromosomal segments called transposons to look for new genes that can prevent infection by Ebola virus. This screening strategy uncovered that the gene MHC class II transactivator (CIITA) induces resistance to Ebola virus in human cell lines by activating the expression of a second gene, CD74. One isoform of CD74, known as p41, disrupts the processing of proteins on the coat of the Ebola virus protein by cellular proteases called cathepsins. This prevents entry of the virus into the cell and subsequent infection. In further research using human cell lines, Bruchez and colleagues showed that CD74 p41 also blocked the cathepsin-dependent entry pathway of coronaviruses, including SARS-CoV-2. The results reveal a new role for the two genes identified, which likely came before their better-known role in antigen processing, the authors say. "We anticipate that the application of this transposon screening approach to other models of infection will reveal other mechanisms that have eluded conventional screening strategies," they write.