PMID- 30728259 OWN - NLM STAT- MEDLINE DCOM- 20200128 LR - 20200309 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 93 IP - 8 DP - 2019 Apr 15 TI - Measles Virus Bearing Measles Inclusion Body Encephalitis-Derived Fusion Protein Is Pathogenic after Infection via the Respiratory Route. LID - 10.1128/JVI.01862-18 [doi] LID - e01862-18 AB - 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 degrees 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. CI - Copyright (c) 2019 American Society for Microbiology. FAU - Mathieu, Cyrille AU - Mathieu C AD - Center for Host-Pathogen Interaction, Columbia University Medical Center, New York, New York, USA cyrille.mathieu@inserm.fr mp3509@cumc.columbia.edu. AD - Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. AD - CIRI, International Center for Infectiology Research, Inserm, U1111, University Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Superieure de Lyon, Lyon, France. FAU - Ferren, Marion AU - Ferren M AD - Center for Host-Pathogen Interaction, Columbia University Medical Center, New York, New York, USA. AD - Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. AD - CIRI, International Center for Infectiology Research, Inserm, U1111, University Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Superieure de Lyon, Lyon, France. FAU - Jurgens, Eric AU - Jurgens E AD - Center for Host-Pathogen Interaction, Columbia University Medical Center, New York, New York, USA. AD - Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. FAU - Dumont, Claire AU - Dumont C AD - CIRI, International Center for Infectiology Research, Inserm, U1111, University Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Superieure de Lyon, Lyon, France. FAU - Rybkina, Ksenia AU - Rybkina K AD - Center for Host-Pathogen Interaction, Columbia University Medical Center, New York, New York, USA. AD - Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. FAU - Harder, Olivia AU - Harder O AD - Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA. FAU - Stelitano, Debora AU - Stelitano D AD - Center for Host-Pathogen Interaction, Columbia University Medical Center, New York, New York, USA. AD - Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. FAU - Madeddu, Silvia AU - Madeddu S AD - Center for Host-Pathogen Interaction, Columbia University Medical Center, New York, New York, USA. AD - Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. AD - Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Cagliari, Italy. FAU - Sanna, Giuseppina AU - Sanna G AD - Center for Host-Pathogen Interaction, Columbia University Medical Center, New York, New York, USA. AD - Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. AD - Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Cagliari, Italy. FAU - Schwartz, Dayna AU - Schwartz D AD - Center for Host-Pathogen Interaction, Columbia University Medical Center, New York, New York, USA. AD - Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. FAU - Biswas, Sudipta AU - Biswas S AD - Center for Host-Pathogen Interaction, Columbia University Medical Center, New York, New York, USA. AD - Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. FAU - Hardie, Diana AU - Hardie D AD - Division of Medical Virology, Department of Clinical Laboratory Sciences, University of Cape Town and National Health Laboratory Service, Cape Town, South Africa. FAU - Hashiguchi, Takao AU - Hashiguchi T AD - Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan. FAU - Moscona, Anne AU - Moscona A AD - Center for Host-Pathogen Interaction, Columbia University Medical Center, New York, New York, USA. AD - Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. AD - Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York, USA. AD - Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, New York, USA. FAU - Horvat, Branka AU - Horvat B AUID- ORCID: 0000-0003-0578-7765 AD - CIRI, International Center for Infectiology Research, Inserm, U1111, University Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Superieure de Lyon, Lyon, France. FAU - Niewiesk, Stefan AU - Niewiesk S AD - Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA. FAU - Porotto, Matteo AU - Porotto M AD - Center for Host-Pathogen Interaction, Columbia University Medical Center, New York, New York, USA cyrille.mathieu@inserm.fr mp3509@cumc.columbia.edu. AD - Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. AD - Department of Experimental Medicine, University of Study of Campania Luigi Vanvitelli, Naples, Italy. LA - eng GR - R01 AI121349/AI/NIAID NIH HHS/United States GR - R01 NS091263/NS/NINDS NIH HHS/United States GR - R01 NS105699/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190403 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Viral Fusion Proteins) SB - IM MH - Amino Acid Substitution MH - Animals MH - Central Nervous System/metabolism/*virology MH - Chlorocebus aethiops MH - Disease Models, Animal MH - *Encephalitis, Viral/genetics/metabolism/transmission MH - Humans MH - *Inclusion Bodies, Viral/genetics/metabolism MH - Lung/metabolism/*virology MH - *Measles/metabolism/transmission MH - Measles virus/*physiology MH - Mice MH - Mice, Transgenic MH - *Mutation, Missense MH - Sigmodontinae MH - Vero Cells MH - *Viral Fusion Proteins/genetics/metabolism MH - *Virus Replication PMC - PMC6450100 OTO - NOTNLM OT - central nervous system infections OT - in vivo infection OT - pathogenesis OT - viral fusion EDAT- 2019/02/08 06:00 MHDA- 2020/01/29 06:00 PMCR- 2019/10/03 CRDT- 2019/02/08 06:00 PHST- 2018/10/29 00:00 [received] PHST- 2019/01/30 00:00 [accepted] PHST- 2019/02/08 06:00 [pubmed] PHST- 2020/01/29 06:00 [medline] PHST- 2019/02/08 06:00 [entrez] PHST- 2019/10/03 00:00 [pmc-release] AID - JVI.01862-18 [pii] AID - 01862-18 [pii] AID - 10.1128/JVI.01862-18 [doi] PST - epublish SO - J Virol. 2019 Apr 3;93(8):e01862-18. doi: 10.1128/JVI.01862-18. Print 2019 Apr 15.