Analysis of a subacute sclerosing #panencephalitis (SSPE) Genotype B3 virus from the 2009/10 South African #measles #epidemic shows hyperfusogenic F proteins contribute to measles virus infection in the #brain (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Analysis of a subacute sclerosing panencephalitis (SSPE) Genotype B3 virus from the 2009/10 South African measles epidemic shows hyperfusogenic F proteins contribute to measles virus infection in the brain.

Fabrizio Angius, Heidi Smuts, Ksenia Rybkina, Debora Stelitano, Brian Eley, Jo Wilmshurst, Marion Ferren, Alexandre Lalande, Cyrille Mathieu, Anne Moscona, Branka Horvat,Takao Hashiguchi, Matteo Porotto, Diana Hardie

DOI: 10.1128/JVI.01700-18

 

ABSTRACT

During a measles virus (MeV) epidemic in 2009 in South Africa, measles inclusion body encephalitis (MIBE) was identified in several HIV-infected patients. Years later, children are presenting with subacute sclerosing panencephalitis (SSPE). To investigate the features of established MeV neuronal infections, viral sequences were analysed from brain tissue samples of a single SSPE case and compared with MIBE sequences previously obtained from patients infected during the same epidemic. Both the SSPE and the MIBE viruses had amino acid substitutions in the ectodomain of the F protein that confer enhanced fusion properties. Functional analysis of the fusion complexes confirmed that both MIBE and SSPE F protein mutations promoted fusion with less dependence on interaction by the viral receptor-binding protein with known MeV receptors. While the SSPE F required the presence of a homotypic attachment protein MeV H in order to fuse, the MIBE F did not. Both F proteins had decreased thermal stability compared to the corresponding wild-type F protein. Finally, recombinant viruses expressing MIBE or SSPE fusion complexes spread in the absence of known MeV receptors, with MIBE F-bearing viruses causing large syncytia in these cells. Our results suggest that alterations to the MeV fusion complex that promote fusion and cell-to-cell spread in the absence of known MeV receptors is a key property for infection of the brain.

 

IMPORTANCE

Measles virus can invade the central nervous system (CNS) and cause severe neurological complications such as MIBE and SSPE. However, mechanisms by which MeV enters the CNS and triggers the disease remain unclear. We analysed viruses from brain tissue of individuals with MIBE or SSPE, infected during the same epidemic, after the onset of neurological disease. Our findings indicate that the emergence of hyper-fusogenic MeV F proteins may be associated with infection of the brain. We also demonstrate that hyper-fusogenic F proteins permit MeV to enter cells and spread without the need to engage nectin-4 or CD150, known receptors for MeV that are not present on neural cells.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Measles; Subacute Sclerosing Panencephalitis; Measles Inclusion Body Encephalitis; Viral pathogenesis.

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Structures of the #prefusion form of #measles virus fusion #protein in #complex with inhibitors (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Structures of the prefusion form of measles virus fusion protein in complex with inhibitors

Takao Hashiguchi, Yoshinari Fukuda, Rei Matsuoka, Daisuke Kuroda, Marie Kubota, Yuta Shirogane, Shumpei Watanabe, Kouhei Tsumoto, Daisuke Kohda, Richard Karl Plemperand Yusuke Yanagi

PNAS 2018; published ahead of print February 20, 2018, https://doi.org/10.1073/pnas.1718957115

Edited by Robert A. Lamb, HHMI and Northwestern University, Evanston, IL, and approved February 2, 2018 (received for review October 31, 2017)

 

Significance

Measles remains a major cause of childhood morbidity and mortality worldwide, and no licensed therapeutic agents are currently available. Measles virus (MeV) sometimes invades the central nervous system (CNS), causing neurodegenerative diseases several months/years after acute infection. Recently, MeV-induced encephalitis among human immunodeficiency virus (HIV)-infected children has become a great concern in high–HIV-prevalence countries. The tropism of MeV for the CNS is mediated by hyperfusogenic mutations in the MeV fusion (F) protein. Here we show the crystal structures of MeV-F alone and bound to inhibitors. The structures and accompanying cell-based fusion assays with inhibitors provide insight into the molecular mechanism for the inhibition of MeV-mediated fusion, which would help us conquer MeV-induced neurodegenerative diseases.

 

Abstract

Measles virus (MeV), a major cause of childhood morbidity and mortality, is highly immunotropic and one of the most contagious pathogens. MeV may establish, albeit rarely, persistent infection in the central nervous system, causing fatal and intractable neurodegenerative diseases such as subacute sclerosing panencephalitis and measles inclusion body encephalitis. Recent studies have suggested that particular substitutions in the MeV fusion (F) protein are involved in the pathogenesis by destabilizing the F protein and endowing it with hyperfusogenicity. Here we show the crystal structures of the prefusion MeV-F alone and in complex with the small compound AS-48 or a fusion inhibitor peptide. Notably, these independently developed inhibitors bind the same hydrophobic pocket located at the region connecting the head and stalk of MeV-F, where a number of substitutions in MeV isolates from neurodegenerative diseases are also localized. Since these inhibitors could suppress membrane fusion mediated by most of the hyperfusogenic MeV-F mutants, the development of more effective inhibitors based on the structures may be warranted to treat MeV-induced neurodegenerative diseases.

 

Footnotes

1 T.H. and Y.F. contributed equally to this work.

2 To whom correspondence may be addressed. Email: takaoh@virology.med.kyushu-u.ac.jp or yyanagi@virology.med.kyushu-u.ac.jp.

Author contributions: T.H., Y.F., and Y.Y. designed research; T.H., Y.F., R.M., D. Kuroda, Y.S., and S.W. performed research; T.H., Y.F., R.M., D. Kuroda, M.K., K.T., D. Kohda, R.K.P., and Y.Y. analyzed data; and T.H., Y.F., and Y.Y. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

Data deposition: The atomic coordinates for the structures reported in this paper have been deposited in the Protein Data Bank, www.wwpdb.org (MeV-F alone, MeV-F–AS-48, and MeV-F–FIP as PDB ID codes 5YXW, 5YZC, and 5YZD, respectively).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1718957115/-/DCSupplemental.

Published under the PNAS license.

Keywords: Measles; Subacute Sclerosing Panencephalitis.

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