Measles virus bearing measles inclusion body encephalitis-derived fusion protein is pathogenic after infection via the respiratory route

Cyrille Mathieu, Marion Ferren, Eric Jurgens, Claire Dumont, Ksenia Rybkina, Olivia Harder, Debora Stelitano, Silvia Madeddu, Giuseppina Sanna, Dayna Schwartz, Sudipta Biswas, Diana Hardie, Takao Hashiguchi, Anne Moscona, Branka Horvat, Stefan Niewiesk, Matteo Porotto

Research output: Contribution to journalArticle

Abstract

A clinical isolate of measles virus (MeV) bearing a single amino acid alteration in the viral fusion protein (F; L454W) was previously identified in two patients with lethal sequelae of MeV central nervous system (CNS) infection. The mutation dysregulated the viral fusion machinery so that the mutated F protein mediated cell fusion in the absence of known MeV cellular receptors. While this virus could feasibly have arisen via intrahost evolution of the wild-type (wt) virus, it was recently shown that the same mutation emerged under the selective pressure of small-molecule antiviral treatment. Under these conditions, a potentially neuropathogenic variant emerged outside the CNS. While CNS adaptation of MeV was thought to generate viruses that are less fit for interhost spread, we show that two animal models can be readily infected with CNS-adapted MeV via the respiratory route. Despite bearing a fusion protein that is less stable at 37°C than the wt MeV F, this virus infects and replicates in cotton rat lung tissue more efficiently than the wt virus and is lethal in a suckling mouse model of MeV encephalitis even with a lower inoculum. Thus, either during lethal MeV CNS infection or during antiviral treatment in vitro, neuropathogenic MeV can emerge, can infect new hosts via the respiratory route, and is more pathogenic (at least in these animal models) than wt MeV. IMPORTANCE Measles virus (MeV) infection can be severe in immunocompromised individuals and lead to complications, including measles inclusion body encephalitis (MIBE). In some cases, MeV persistence and subacute sclerosing panencephalitis (SSPE) occur even in the face of an intact immune response. While they are relatively rare complications of MeV infection, MIBE and SSPE are lethal. This work addresses the hypothesis that despite a dysregulated viral fusion complex, central nervous system (CNS)-adapted measles virus can spread outside the CNS within an infected host.

Original languageEnglish
Article numberY
JournalJournal of virology
Volume93
Issue number8
DOIs
Publication statusPublished - Jan 1 2019

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Measles virus
Subacute Sclerosing Panencephalitis
inclusion bodies
encephalitis
Respiratory Tract Infections
infection
central nervous system
Proteins
proteins
lethal genes
Central Nervous System
Viruses
viruses
Central Nervous System Infections
animal models
Virus Diseases
Antiviral Agents
Sigmodon
viral fusion proteins
Animal Models

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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Measles virus bearing measles inclusion body encephalitis-derived fusion protein is pathogenic after infection via the respiratory route. / Mathieu, Cyrille; Ferren, Marion; Jurgens, Eric; Dumont, Claire; Rybkina, Ksenia; Harder, Olivia; Stelitano, Debora; Madeddu, Silvia; Sanna, Giuseppina; Schwartz, Dayna; Biswas, Sudipta; Hardie, Diana; Hashiguchi, Takao; Moscona, Anne; Horvat, Branka; Niewiesk, Stefan; Porotto, Matteo.

In: Journal of virology, Vol. 93, No. 8, Y, 01.01.2019.

Research output: Contribution to journalArticle

Mathieu, C, Ferren, M, Jurgens, E, Dumont, C, Rybkina, K, Harder, O, Stelitano, D, Madeddu, S, Sanna, G, Schwartz, D, Biswas, S, Hardie, D, Hashiguchi, T, Moscona, A, Horvat, B, Niewiesk, S & Porotto, M 2019, 'Measles virus bearing measles inclusion body encephalitis-derived fusion protein is pathogenic after infection via the respiratory route', Journal of virology, vol. 93, no. 8, Y. https://doi.org/10.1128/JVI.01862-18
Mathieu, Cyrille ; Ferren, Marion ; Jurgens, Eric ; Dumont, Claire ; Rybkina, Ksenia ; Harder, Olivia ; Stelitano, Debora ; Madeddu, Silvia ; Sanna, Giuseppina ; Schwartz, Dayna ; Biswas, Sudipta ; Hardie, Diana ; Hashiguchi, Takao ; Moscona, Anne ; Horvat, Branka ; Niewiesk, Stefan ; Porotto, Matteo. / Measles virus bearing measles inclusion body encephalitis-derived fusion protein is pathogenic after infection via the respiratory route. In: Journal of virology. 2019 ; Vol. 93, No. 8.
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abstract = "A clinical isolate of measles virus (MeV) bearing a single amino acid alteration in the viral fusion protein (F; L454W) was previously identified in two patients with lethal sequelae of MeV central nervous system (CNS) infection. The mutation dysregulated the viral fusion machinery so that the mutated F protein mediated cell fusion in the absence of known MeV cellular receptors. While this virus could feasibly have arisen via intrahost evolution of the wild-type (wt) virus, it was recently shown that the same mutation emerged under the selective pressure of small-molecule antiviral treatment. Under these conditions, a potentially neuropathogenic variant emerged outside the CNS. While CNS adaptation of MeV was thought to generate viruses that are less fit for interhost spread, we show that two animal models can be readily infected with CNS-adapted MeV via the respiratory route. Despite bearing a fusion protein that is less stable at 37°C than the wt MeV F, this virus infects and replicates in cotton rat lung tissue more efficiently than the wt virus and is lethal in a suckling mouse model of MeV encephalitis even with a lower inoculum. Thus, either during lethal MeV CNS infection or during antiviral treatment in vitro, neuropathogenic MeV can emerge, can infect new hosts via the respiratory route, and is more pathogenic (at least in these animal models) than wt MeV. IMPORTANCE Measles virus (MeV) infection can be severe in immunocompromised individuals and lead to complications, including measles inclusion body encephalitis (MIBE). In some cases, MeV persistence and subacute sclerosing panencephalitis (SSPE) occur even in the face of an intact immune response. While they are relatively rare complications of MeV infection, MIBE and SSPE are lethal. This work addresses the hypothesis that despite a dysregulated viral fusion complex, central nervous system (CNS)-adapted measles virus can spread outside the CNS within an infected host.",
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AU - Harder, Olivia

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AU - Biswas, Sudipta

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