Measles Fusion Machinery Is Dysregulated in Neuropathogenic Variants

ABSTRACT Paramyxoviruses, including the human pathogen measles virus (MV), enter host cells by fusing their viral envelope with the target cell membrane. This fusion process is driven by the concerted actions of the two viral envelope glycoproteins, the receptor binding protein (hemagglutinin [H]) a...

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Autores principales:	Eric M. Jurgens, Cyrille Mathieu, Laura M. Palermo, Diana Hardie, Branka Horvat, Anne Moscona, Matteo Porotto
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c087843cec5947ab9912c02ed44f0245
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spelling	oai:doaj.org-article:c087843cec5947ab9912c02ed44f02452021-11-15T15:41:19ZMeasles Fusion Machinery Is Dysregulated in Neuropathogenic Variants10.1128/mBio.02528-142150-7511https://doaj.org/article/c087843cec5947ab9912c02ed44f02452015-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02528-14https://doaj.org/toc/2150-7511ABSTRACT Paramyxoviruses, including the human pathogen measles virus (MV), enter host cells by fusing their viral envelope with the target cell membrane. This fusion process is driven by the concerted actions of the two viral envelope glycoproteins, the receptor binding protein (hemagglutinin [H]) and the fusion (F) protein. H attaches to specific proteinaceous receptors on host cells; once the receptor engages, H activates F to directly mediate lipid bilayer fusion during entry. In a recent MV outbreak in South Africa, several HIV-positive people died of MV central nervous system (CNS) infection. We analyzed the virus sequences from these patients and found that specific intrahost evolution of the F protein had occurred and resulted in viruses that are “CNS adapted.” A mutation in F of the CNS-adapted virus (a leucine-to-tryptophan change present at position 454) allows it to promote fusion with less dependence on engagement of H by the two known wild-type (wt) MV cellular receptors. This F protein is activated independently of H or the receptor and has reduced thermal stability and increased fusion activity compared to those of the corresponding wt F. These functional effects are the result of the single L454W mutation in F. We hypothesize that in the absence of effective cellular immunity, such as HIV infection, MV variants bearing altered fusion machinery that enabled efficient spread in the CNS underwent positive selection. IMPORTANCE Measles virus has become a concern in the United States and Europe due to recent outbreaks and continues to be a significant global problem. While live immunization is available, there are no effective therapies or prophylactics to combat measles infection in unprotected people. Additionally, vaccination does not adequately protect immunocompromised people, who are vulnerable to the more severe CNS manifestations of disease. We found that strains isolated from patients with measles virus infection of the CNS have fusion properties different from those of strains previously isolated from patients without CNS involvement. Specifically, the viral entry machinery is more active and the virus can spread, even in the absence of H. Our findings are consistent with an intrahost evolution of the fusion machinery that leads to neuropathogenic MV variants.Eric M. JurgensCyrille MathieuLaura M. PalermoDiana HardieBranka HorvatAnne MosconaMatteo PorottoAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 1 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Eric M. Jurgens Cyrille Mathieu Laura M. Palermo Diana Hardie Branka Horvat Anne Moscona Matteo Porotto Measles Fusion Machinery Is Dysregulated in Neuropathogenic Variants
description	ABSTRACT Paramyxoviruses, including the human pathogen measles virus (MV), enter host cells by fusing their viral envelope with the target cell membrane. This fusion process is driven by the concerted actions of the two viral envelope glycoproteins, the receptor binding protein (hemagglutinin [H]) and the fusion (F) protein. H attaches to specific proteinaceous receptors on host cells; once the receptor engages, H activates F to directly mediate lipid bilayer fusion during entry. In a recent MV outbreak in South Africa, several HIV-positive people died of MV central nervous system (CNS) infection. We analyzed the virus sequences from these patients and found that specific intrahost evolution of the F protein had occurred and resulted in viruses that are “CNS adapted.” A mutation in F of the CNS-adapted virus (a leucine-to-tryptophan change present at position 454) allows it to promote fusion with less dependence on engagement of H by the two known wild-type (wt) MV cellular receptors. This F protein is activated independently of H or the receptor and has reduced thermal stability and increased fusion activity compared to those of the corresponding wt F. These functional effects are the result of the single L454W mutation in F. We hypothesize that in the absence of effective cellular immunity, such as HIV infection, MV variants bearing altered fusion machinery that enabled efficient spread in the CNS underwent positive selection. IMPORTANCE Measles virus has become a concern in the United States and Europe due to recent outbreaks and continues to be a significant global problem. While live immunization is available, there are no effective therapies or prophylactics to combat measles infection in unprotected people. Additionally, vaccination does not adequately protect immunocompromised people, who are vulnerable to the more severe CNS manifestations of disease. We found that strains isolated from patients with measles virus infection of the CNS have fusion properties different from those of strains previously isolated from patients without CNS involvement. Specifically, the viral entry machinery is more active and the virus can spread, even in the absence of H. Our findings are consistent with an intrahost evolution of the fusion machinery that leads to neuropathogenic MV variants.
format	article
author	Eric M. Jurgens Cyrille Mathieu Laura M. Palermo Diana Hardie Branka Horvat Anne Moscona Matteo Porotto
author_facet	Eric M. Jurgens Cyrille Mathieu Laura M. Palermo Diana Hardie Branka Horvat Anne Moscona Matteo Porotto
author_sort	Eric M. Jurgens
title	Measles Fusion Machinery Is Dysregulated in Neuropathogenic Variants
title_short	Measles Fusion Machinery Is Dysregulated in Neuropathogenic Variants
title_full	Measles Fusion Machinery Is Dysregulated in Neuropathogenic Variants
title_fullStr	Measles Fusion Machinery Is Dysregulated in Neuropathogenic Variants
title_full_unstemmed	Measles Fusion Machinery Is Dysregulated in Neuropathogenic Variants
title_sort	measles fusion machinery is dysregulated in neuropathogenic variants
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/c087843cec5947ab9912c02ed44f0245
work_keys_str_mv	AT ericmjurgens measlesfusionmachineryisdysregulatedinneuropathogenicvariants AT cyrillemathieu measlesfusionmachineryisdysregulatedinneuropathogenicvariants AT laurampalermo measlesfusionmachineryisdysregulatedinneuropathogenicvariants AT dianahardie measlesfusionmachineryisdysregulatedinneuropathogenicvariants AT brankahorvat measlesfusionmachineryisdysregulatedinneuropathogenicvariants AT annemoscona measlesfusionmachineryisdysregulatedinneuropathogenicvariants AT matteoporotto measlesfusionmachineryisdysregulatedinneuropathogenicvariants
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Measles Fusion Machinery Is Dysregulated in Neuropathogenic Variants

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