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Early Permissiveness of Central Nervous System Cells to Measles Virus Infection Is Determined by Hyperfusogenicity
Marion Ferren1, Alexandre Lalande1, Mathieu Iampietro2
1CIRI, Centre International de Recherche en Infectiologie, Team Neuro-Invasion, TROpism and VIRal Encephalitis, Université de Lyon, Inserm, U1111, CNRS, UMR5308, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, 69007 Lyon, France.
Abstract:
The cessation of measles virus (MeV) vaccination in more than 40 countries as a consequence of the COVID-19 pandemic is expected to significantly increase deaths due to measles. MeV can infect the central nervous system (CNS) and lead to lethal encephalitis. Substantial part of virus sequences recovered from patients' brain were mutated in the matrix and/or the fusion protein (F). Mutations of the heptad repeat domain located in the C terminal (HRC) part of the F protein were often observed and were associated to hyperfusogenicity. These mutations promote brain invasion as a hallmark of neuroadaptation. Wild-type F allows entry into the brain, followed by limited spreading compared with the massive invasion observed for hyperfusogenic MeV. Taking advantage of our ex vivo models of hamster organotypic brain cultures, we investigated how the hyperfusogenic mutations in the F HRC domain modulate virus distribution in CNS cells. In this study, we also identified the dependence of neural cells susceptibility on both their activation state and destabilization of the virus F protein. Type I interferon (IFN-I) impaired mainly astrocytes and microglial cells permissiveness contrarily to neurons, opening a new way of consideration on the development of treatments against viral encephalitis.
Insights
Measles virus (MeV) brain infections can be lethal, especially with mutations enhancing cell fusion. Understanding these mutations is key to developing treatments for MeV encephalitis.
Area of Science:
- Virology
- Neuroscience
- Immunology
Background:
- Measles virus (MeV) vaccination cessation due to COVID-19 may increase measles deaths.
- MeV can cause fatal encephalitis by infecting the central nervous system (CNS).
- Mutations in MeV's fusion (F) protein, particularly in the HRC domain, are linked to hyperfusogenicity and enhanced brain invasion.
Purpose of the Study:
- To investigate how hyperfusogenic mutations in the F protein's HRC domain affect MeV distribution in CNS cells.
- To explore the role of neural cell activation state and F protein destabilization in MeV susceptibility.
- To examine the impact of Type I interferon (IFN-I) on neural cell permissiveness to MeV.
Main Methods:
- Utilized ex vivo models of hamster organotypic brain cultures.
- Analyzed MeV sequences from patients' brains, focusing on matrix and F protein mutations.
- Assessed neural cell susceptibility based on activation state and F protein destabilization.
- Investigated the effect of Type I interferon (IFN-I) on different CNS cell types.
Main Results:
- Hyperfusogenic MeV mutations promote massive brain invasion compared to wild-type MeV.
- Neural cell susceptibility to MeV depends on their activation state and F protein destabilization.
- Type I interferon (IFN-I) primarily reduced permissiveness in astrocytes and microglial cells, but not neurons.
Conclusions:
- Hyperfusogenic mutations in the MeV F protein HRC domain are critical for neuroadaptation and extensive CNS invasion.
- Neural cell permissiveness to MeV is a dynamic process influenced by cell activation and viral factors.
- Targeting IFN-I responses could be a novel therapeutic strategy for MeV encephalitis, sparing neurons.
