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

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

doi:10.1128/mbio.00799-21

Abstract

ABSTRACTMeasles 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.

Highlights

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
The side chain of N462 hydrogen bonds with the side chain of S352 in an adjacent helix, and N462K would likely disrupt this H-bond interaction. These three mutations occur in the portion of the HRC domain where the head and stalk regions of the prefusion conformation meet. Interactions at this junction are likely to be important for stabilizing the prefusion state, and mutations in this region could lead to decreased stability of the MeV-F prefusion structure [15]
Since the fusion inhibitor was added 24 h after infection, these results indicate that the HRC4 peptides block cell-to-cell spread in three-dimensional CNS-derived organotypic brain cultures (OBC), suggesting that MeV dissemination in brain depends on measles virus fusion glycoprotein (MeV F) protein

Summary

Introduction

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. 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. Measles inclusion body encephalitis (MIBE) occurs in immunocompromised patients weeks to months after infection with wild-type (WT) viruses and, in rare cases, has followed previous versions of the attenuated MeV vaccine that are no longer used [6, 12, 13]. The mechanisms governing MeV infection and spread in the CNS remain poorly understood, CNS invasion seems to require the viral fusion (F) protein and may be inhibited by fusion inhibitors [16,17,18,19]

Methods

Results

Conclusion