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

• Published in: mBio 2021-06, Vol.12 (3), p.e0079921-e0079921
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Animals; Brain - cytology; Brain - pathology; Brain - virology; Central Nervous System Diseases - virology; Chlorocebus aethiops; Female; HEK293 Cells; Humans; Induced Pluripotent Stem Cells - pathology; Induced Pluripotent Stem Cells - virology; Life Sciences; Male; Measles - virology; Measles virus - genetics; Measles virus - pathogenicity; Metagenomics; Mice; Microbiology and Parasitology; Neurobiology; Neurons - virology; Neurons and Cognition; Organoids - cytology; Organoids - virology; Research Article; Vero Cells; Viral Fusion Proteins - chemistry; Viral Fusion Proteins - classification; Viral Fusion Proteins - genetics; Viral Fusion Proteins - metabolism; Virology
• ISSN: 2150-7511; 2161-2129; 2150-7511
• DOI: 10.1128/mBio.00799-21

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 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 . 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. Measles virus (MeV) infection can cause serious complications in immunocompromised individuals, including measles inclusion body encephalitis (MIBE). In some cases, MeV persistence and subacute sclerosing panencephalitis (SSPE), another severe central nervous system (CNS) complication, develop even in the face of a systemic immune response. Both MIBE and SSPE are relatively rare but lethal. It is unclear how MeV causes CNS infection. We introduced specific mutations that are found in MIBE or SSPE cases into the MeV fusion protein to test the hypothesis that dysregulation of the viral fusion complex-comprising F and the receptor binding protein, H-allows virus to spread in the CNS. Using metagenomic, structural, and biochemical approaches, we demonstrate that altered fusion properties of the MeV H-F fusion complex permit MeV to spread in brain tissue.