Analysis of a Subacute Sclerosing Panencephalitis Genotype B3 Virus from the 2009-2010 South African Measles Epidemic Shows That Hyperfusogenic F Proteins Contribute to Measles Virus Infection in the Brain

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

doi:10.1128/jvi.01700-18

Cited by 34 publications

(45 citation statements)

References 40 publications

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“…The hyperfusogenic properties facilitate the virus for cell‐cell fusion with SLAM and nectin‐4 deficient neuronal cells. H protein and its interaction with a specific neuronal receptor is also important for viral spread between neurons . F protein–mediated transmission of the virus across synapse to another neuronal cell can potentially be inhibited by a fusion inhibitor peptide and antibodies against the measles virus H protein.…”

Section: Transneuronal Spread In the Brainmentioning

confidence: 99%

Subacute sclerosing panencephalitis

Garg

Mahadevan

Malhotra

et al. 2019

Reviews in Medical Virology

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Summary Subacute sclerosing panencephalitis (SSPE) is a slowly progressive brain disorder caused by mutant measles virus. SSPE affects younger age groups. SSPE incidence is proportional to that of measles. High‐income countries have seen substantial decline in SSPE incidence following universal vaccination against measles. SSPE virus differs from wild measles virus. Measles virus genome recovered from the autopsied brain tissues demonstrates clustered mutations in virus genome particularly in the M gene. These mutations destroy the structure and functioning of the encoded proteins. Complete infectious virus particle has rarely been recovered from the brain. Human neurons lack required receptor for entry of measles virus inside the neurons. Recent in vitro studies suggest that mutations in F protein confer hyperfusogenic properties to measles virus facilitating transneuronal viral spread. The inflammatory response in the brain leads to extensive tissue damage. Clinically, SSPE is characterized by florid panencephalitis. Clinically, SSPE is characterized by cognitive decline, periodic myoclonus, gait abnormalities, vision loss, and ultimately to a vegetative state. Chorioretinitis is a common ocular abnormality. Electroencephalography (EEG) shows characteristic periodic discharges. Neuroimaging demonstrates periventricular white matter signal abnormalities. In advanced stages, there is marked cerebral atrophy. Definitive diagnosis requires demonstration of elevated measles antibody titers in cerebrospinal fluid (CSF). Many drugs have been used to stabilize the course of the disease but without evidence from randomized clinical trials. Six percent of patients may experience prolonged spontaneous remission. Fusion inhibitor peptide may, in the future, be exploited to treat SSPE. A universal vaccination against measles is the only proven way to tackle this menace currently.

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Section: Transneuronal Spread In the Brainmentioning

confidence: 99%

Subacute sclerosing panencephalitis

Garg

Mahadevan

Malhotra

et al. 2019

Reviews in Medical Virology

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“…To observe the next step in viral entry, the temperature was warmed to allow activation of F to occur, while progress towards fusion was blocked using VIKI-PEG 4 -chol, a peptide that corresponds to the C-terminal heptad repeat (HRC) region of F protein [85,[104][105][106][107][108][109] and binds to the extended intermediate states of F [41,110] (Fig 4, S4 and S5 Figs, S3 Movie). To capture the transient intermediate fusion state just after HN activates F, receptor-bearing target erythrocyte fragment membranes were exposed to virus on grids at 37˚C, in the presence of the fusion inhibitory peptide VIKI-PEG 4 -chol [33].…”

Section: Capture Of the Transient Intermediate State Of F Extended Amentioning

confidence: 99%

Human parainfluenza virus fusion complex glycoproteins imaged in action on authentic viral surfaces

et al. 2020

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Infection by human parainfluenza viruses (HPIVs) causes widespread lower respiratory diseases, including croup, bronchiolitis, and pneumonia, and there are no vaccines or effective treatments for these viruses. HPIV3 is a member of the Respirovirus species of the Paramyxoviridae family. These viruses are pleomorphic, enveloped viruses with genomes composed of single-stranded negative-sense RNA. During viral entry, the first step of infection, the viral fusion complex, comprised of the receptor-binding glycoprotein hemagglutininneuraminidase (HN) and the fusion glycoprotein (F), mediates fusion upon receptor binding. The HPIV3 transmembrane protein HN, like the receptor-binding proteins of other related viruses that enter host cells using membrane fusion, binds to a receptor molecule on the host cell plasma membrane, which triggers the F glycoprotein to undergo major conformational rearrangements, promoting viral entry. Subsequent fusion of the viral and host membranes allows delivery of the viral genetic material into the host cell. The intermediate states in viral entry are transient and thermodynamically unstable, making it impossible to understand these transitions using standard methods, yet understanding these transition states is important for expanding our knowledge of the viral entry process. In this study, we use cryoelectron tomography (cryo-ET) to dissect the stepwise process by which the receptor-binding protein triggers F-mediated fusion, when forming a complex with receptor-bearing membranes. Using an on-grid antibody capture method that facilitates examination of fresh, biologically active strains of virus directly from supernatant fluids and a series of biological tools that permit the capture of intermediate states in the fusion process, we visualize the series of events that occur when a pristine, authentic viral particle interacts with target receptors and proceeds from the viral entry steps of receptor engagement to membrane fusion.

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“…Since these hyperfusogenic F proteins still require the H protein to induce membrane fusion and anti-H protein monoclonal antibodies inhibit membrane fusion mediated by hyperfusogenic F proteins, there must be a specific neuron receptor(s) interacting with the H protein (14). Furthermore, these hyperfusogenic F proteins are structurally unstable and more readily triggered for the conformational changes (13,(21)(22)(23)25).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have demonstrated that specific substitutions in the ectodomain of the F protein are critical for neuropathogenicity of MeV, conferring on the virus the ability to spread in primary human neurons in vitro as well as in the brains of experimentally infected mice and hamsters (6,(12)(13)(14)(21)(22)(23)(24)(25)(26). These substitutions were shown to destabilize the prefusion form of the F protein, rendering it hyperfusogenic.…”

mentioning

confidence: 99%

Weak cis and trans Interactions of the Hemagglutinin with Receptors Trigger Fusion Proteins of Neuropathogenic Measles Virus Isolates

Shirogane

Hanabusa

Yanagi

2020

J Virol

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Measles virus (MeV) is an enveloped RNA virus bearing two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins. Upon receptor binding, the H protein triggers conformational changes of the F protein, causing membrane fusion and subsequent virus entry. MeV may persist in the brain, infecting neurons and causing fatal subacute sclerosing panencephalitis (SSPE). Since neurons do not express either of the MeV receptors, signaling lymphocytic activation molecule (SLAM; also called CD150) and nectin-4, how MeV propagates in neurons is unknown. Recent studies have shown that specific substitutions in the F protein found in MeV isolates from SSPE patients are critical for MeV neuropathogenicity by rendering the protein unstable and hyperfusogenic. Recombinant MeVs possessing the F proteins with such substitutions can spread in primary human neurons and in the brains of mice and hamsters and induce cell-cell fusion in cells lacking SLAM and nectin-4. Here, we show that receptor-blind mutant H proteins that have decreased binding affinities to receptors can support membrane fusion mediated by hyperfusogenic mutant F proteins, but not the wild-type F protein, in cells expressing the corresponding receptors. The results suggest that weak interactions of the H protein with certain molecules (putative neuron receptors) trigger hyperfusogenic F proteins in SSPE patients. Notably, where cell-cell contacts are ensured, the weak cis interaction of the H protein with SLAM on the same cell surface also could trigger hyperfusogenic F proteins. Some enveloped viruses may exploit such cis interactions with receptors to infect target cells, especially in cell-to-cell transmission. IMPORTANCE Measles virus (MeV) may persist in the brain, causing incurable subacute sclerosing panencephalitis (SSPE). Because neurons, the main target in SSPE, do not express receptors for wild-type (WT) MeV, how MeV propagates in the brain is a key question for the disease. Recent studies have demonstrated that specific substitutions in the MeV fusion (F) protein are critical for neuropathogenicity. Here, we show that weak cis and trans interactions of the MeV attachment protein with receptors that are not sufficient to trigger the WT MeV F protein can trigger the mutant F proteins from neuropathogenic MeV isolates. Our study not only provides an important clue to understand MeV neuropathogenicity but also reveals a novel viral strategy to expand cell tropism.

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Analysis of a Subacute Sclerosing Panencephalitis Genotype B3 Virus from the 2009-2010 South African Measles Epidemic Shows That Hyperfusogenic F Proteins Contribute to Measles Virus Infection in the Brain

Cited by 34 publications

References 40 publications

Subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis

Human parainfluenza virus fusion complex glycoproteins imaged in action on authentic viral surfaces

Weak cis and trans Interactions of the Hemagglutinin with Receptors Trigger Fusion Proteins of Neuropathogenic Measles Virus Isolates

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