Molecular features of the measles virus viral fusion complex that favor infection and spread in the brain [human]

A measles virus (MeV) isolate bearing a single amino acid change in the fusion protein (F) -- L454W -- was identified in two patients who died of MeV central nervous system (CNS) infection. We analyzed whether this mutation confers an advantage over wild type virus in the CNS, thereby 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 specific CNS adaptive mutations in F result in augmented spread of virus ex vivo and that this is associated with an enhanced innate immune response. The spread of virus in 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 the virus more neuropathogenic, allowing it to propagate in the face of the innate immune response. RNAseq of human brain organoids following infection with WT or fusion protein mutant measles virus, or no infection Note from submitter: Please note that raw fastq files have not been included for the human data; the consent of the donors of cells that made the iPSC lines used does not explicitly cover sharing of genomic data, therefore our IRB will not allow us to upload sequence data.