Molecular Features of the Measles Virus Viral Fusion Complex That Favor Infection and Spread in the Brain

Mathieu, Cyrille; Bovier, Francesca T.; Ferren, Marion; Lieberman, Nicole A. P.; Predella, Camilla; Lalande, Alexandre; Peddu, Vikas; Lin, Michelle J.; Addetia, Amin; Patel, Achchhe; Outlaw, Victor; Corneo, Barbara; Dorrello, N. Valerio; Briese, Thomas; Hardie, Diana; Horvat, Branka; Moscona, Anne; Greninger, Alexander L.; Porotto, Matteo

Measles virus (MeV) bearing a single amino acid change in the fusion protein (F)—L454W—was isolated from two patients who died of MeV central nervous system (CNS) infection. This mutation in F confers an advantage over wild-type virus in the CNS, contributing to disease in these patients. Using murine ex vivo organotypic brain cultures and human induced pluripotent stem cell-derived brain organoids, we show that CNS adaptive mutations in F enhance the spread of virus ex vivo. The spread of virus in human brain organoids is blocked by an inhibitory peptide that targets F, confirming that dissemination in the brain tissue is attributable to F. A single mutation in MeV F thus alters the fusion complex to render MeV more neuropathogenic.