scholarly journals CADM1 and CADM2 triggers neuropathogenic measles virus-mediated membrane fusion by acting in cis

2021 ◽  
Author(s):  
Yuta Shirogane ◽  
Ryuichi Takemoto ◽  
Tateki Suzuki ◽  
Tomonori Kameda ◽  
Kinichi Nakashima ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Measles Virus ◽  
Cell Adhesion Molecule ◽  
Rna Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Attachment Protein ◽  
Enveloped Virus ◽  
Childhood Morbidity ◽  
Cell Adhesion Molecule 1 ◽  
The Brain

Measles virus (MeV), an enveloped RNA virus in the family Paramyxoviridae, is still an important cause of childhood morbidity and mortality worldwide. MeV usually causes acute febrile illness with skin rash, but in rare cases persists in the brain, causing a progressive neurological disorder, subacute sclerosing panencephalitis (SSPE). The disease is fatal, and no effective therapy is currently available. Although trans-synaptic cell-to-cell transmission is thought to account for MeV propagation in the brain, neurons do not express the known receptors for MeV. Recent studies have shown that hyperfusogenic changes in the MeV fusion (F) protein play a key role in MeV propagation in the brain. However, how such mutant viruses spread in neurons remains unexplained. Here we show that cell adhesion molecule 1 (CADM1, also known as IGSF4A, Necl-2, SynCAM1) and CADM2 (also known as IGSF4D, Necl-3, SynCAM2) are host factors which enable MeV to cause membrane fusion in cells lacking the known receptors and to spread between neurons. During enveloped virus entry, a cellular receptor generally interacts in trans with the attachment protein on the envelope. However, CADM1 and CADM2 interact in cis with the MeV attachment protein on the same cell membrane, causing the fusion protein triggering and membrane fusion. Knockdown of CADM1 and CADM2 inhibits syncytium formation and virus transmission between neurons that are both mediated by hyperfusogenic F proteins. Thus, our results unravel the molecular mechanism (receptor-mimicking cis-acting fusion triggering) by which MeV spreads trans-synaptically between neurons, thereby causing SSPE. Importance Measles virus (MeV), an enveloped RNA virus, is the causative agent of measles, which is still an important cause of childhood morbidity and mortality worldwide. Persistent MeV infection in the brain causes a fatal progressive neurological disorder, subacute sclerosing panencephalitis (SSPE), several years after acute infection. However, how MeV spreads in neurons, which are mainly affected in SSPE, remains largely unknown. In this study, we demonstrate that cell adhesion molecule 1 (CADM1) and CADM2 are host factors enabling MeV spread between neurons. During enveloped virus entry, a cellular receptor generally interacts in trans with the attachment protein on the viral membrane (envelope). Remarkably, CADM1 and CADM2 interact in cis with the MeV attachment protein on the same membrane, triggering the fusion protein and causing membrane fusion, as viral receptors usually do in trans. Careful screening may lead to more examples of such “receptor mimicking cis-acting fusion triggering” in other viruses.

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

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Yuta Shirogane ◽  
Takao Hashiguchi ◽  
Yusuke Yanagi
Keyword(s):  
Membrane Fusion ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Target Cells ◽  
Wild Type ◽  
F Protein ◽  
The Brain ◽  
H Protein ◽  
In Cells ◽  
Cell Cell

ABSTRACT 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.

Use of Protein a Conjugated to Peroxidase to Localize Immunoglobulin G in SSPE Ferret Brain

1982 ◽  
Vol 40 ◽  
pp. 350-351
Author(s):  
Hannah R. Brown ◽  
Anthony F. Nostro ◽  
Halldor Thormar
Keyword(s):  
Immunoglobulin G ◽  
Human Disease ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Protein A ◽  
Inflammatory Lesions ◽  
Sspe Virus ◽  
Specific Immunoglobulin ◽  
Antibody Titers ◽  
The Brain

Subacute sclerosing panencephalitis (SSPE) is a slowly progressing disease of the CNS in children which is caused by measles virus. Ferrets immunized with measles virus prior to inoculation with the cell associated, syncytiogenic D.R. strain of SSPE virus exhibit characteristics very similar to the human disease. Measles virus nucleocapsids are present, high measles antibody titers are found in the sera and inflammatory lesions are prominent in the brains. Measles virus specific immunoglobulin G (IgG) is present in the brain,and IgG/ albumin ratios indicate that the antibodies are synthesized within the CNS.

Presence of antibody in virus-infected brain cells of SSPE ferrets

1983 ◽  
Vol 41 ◽  
pp. 804-805
Author(s):  
Hannah R. Brown ◽  
Tammy L. Donato ◽  
Halldor Thormar
Keyword(s):  
Measles Virus ◽  
Plasma Cells ◽  
Subacute Sclerosing Panencephalitis ◽  
Protein A ◽  
Neutralizing Antibody ◽  
Brain Cells ◽  
Antibody Titers ◽  
A Cell ◽  
The Central Nervous System ◽  
The Brain

Measles virus specific immunoglobulin G (IgG) has been found in the brains of patients with subacute sclerosing panencephalitis (SSPE), a slowly progressing disease of the central nervous system (CNS) in children. IgG/albumin ratios indicate that the antibodies are synthesized within the CNS. Using the ferret as an animal model to study the disease, we have been attempting to localize the Ig's in the brains of animals inoculated with a cell associated strain of SSPE. In an earlier report, preliminary results using Protein A conjugated to horseradish peroxidase (PrAPx) (Dynatech Diagnostics Inc., South Windham, ME.) to detect antibodies revealed the presence of immunoglobulin mainly in antibody-producing plasma cells in inflammatory lesions and not in infected brain cells.In the present experiment we studied the brain of an SSPE ferret with neutralizing antibody titers of 1:1024 in serum and 1:512 in CSF at time of sacrifice 7 months after i.c. inoculation with SSPE measles virus-infected cells. The animal was perfused with saline and portions of the brain and spinal cord were immersed in periodate-lysine-paraformaldehyde (P-L-P) fixative. The ferret was not perfused with fixative because parts of the brain were used for virus isolation.

scholarly journals Antiviral Screen against Canine Distemper Virus-Induced Membrane Fusion Activity

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 128
Author(s):  
Neeta Shrestha ◽  
Flavio M. Gall ◽  
Jonathan Vesin ◽  
Marc Chambon ◽  
Gerardo Turcatti ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Small Molecule ◽  
High Throughput Screening ◽  
Measles Virus ◽  
Canine Distemper Virus ◽  
Rna Virus ◽  
Preventive Measure ◽  
Close Relative ◽  
Fusion Activity ◽  
Canine Distemper

Canine distemper virus (CDV), a close relative of the human pathogen measles virus (MeV), is an enveloped, negative sense RNA virus that belongs to the genus Morbillivirus and causes severe diseases in dogs and other carnivores. Although the vaccination is available as a preventive measure against the disease, the occasional vaccination failure highlights the importance of therapeutic alternatives such as antivirals against CDV. The morbilliviral cell entry system relies on two interacting envelope glycoproteins: the attachment (H) and fusion (F) proteins. Here, to potentially discover novel entry inhibitors targeting CDV H, F and/or the cognate receptor: signaling lymphocyte activation molecule (SLAM) proteins, we designed a quantitative cell-based fusion assay that matched high-throughput screening (HTS) settings. By screening two libraries of small molecule compounds, we successfully identified two membrane fusion inhibitors (F2736-3056 and F2261-0043). Although both inhibitors exhibited similarities in structure and potency with the small molecule compound 3G (an AS-48 class morbilliviral F-protein inhibitor), F2736-3056 displayed improved efficacy in blocking fusion activity when a 3G-escape variant was employed. Altogether, we present a cell-based fusion assay that can be utilized not only to discover antiviral agents against CDV but also to dissect the mechanism of morbilliviral-mediated cell-binding and cell-to-cell fusion activity.

Short-stalk isoforms of CADM1 and CADM2 trigger neuropathogenic measles virus-mediated membrane fusion by interacting with the viral hemagglutinin

2021 ◽  
Author(s):  
Ryuichi Takemoto ◽  
Tateki Suzuki ◽  
Takao Hashiguchi ◽  
Yusuke Yanagi ◽  
Yuta Shirogane
Keyword(s):  
Cell Membrane ◽  
Membrane Fusion ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Febrile Illness ◽  
Host Factors ◽  
F Protein ◽  
Short Stalk ◽  
Head Domain ◽  
H Protein

Measles virus (MeV), an enveloped RNA virus in the family Paramyxoviridae , usually causes acute febrile illness with skin rash, but in rare cases persists in the brain, causing a progressive neurological disorder, subacute sclerosing panencephalitis (SSPE). MeV bears two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins. The H protein possesses a head domain that initially mediates receptor binding and a stalk domain that subsequently transmits the fusion-triggering signal to the F protein. We have recently shown that cell adhesion molecule 1 (CADM1, also known as IGSF4A, Necl-2, SynCAM1) and CADM2 (also known as IGSF4D, Necl-3, SynCAM2) are host factors enabling cell-cell membrane fusion mediated by hyperfusogenic F proteins of neuropathogenic MeVs as well as MeV spread between neurons lacking the known receptors. CADM1 and CADM2 interact in cis with the H protein on the same cell membrane, triggering hyperfusogenic F protein-mediated membrane fusion. Multiple isoforms of CADM1 and CADM2 containing various lengths of their stalk regions are generated by alternative splicing. Here we show that only short-stalk isoforms of CADM1 and CADM2 predominantly expressed in the brain induce hyperfusogenic F protein-mediated membrane fusion. While the known receptors interact in trans with the H protein through its head domain, these isoforms can interact in cis even with the H protein lacking the head domain and trigger membrane fusion, presumably through its stalk domain. Thus, our results unveil a new mechanism of viral fusion triggering by host factors. Importance Measles, an acute febrile illness with skin rash, is still an important cause of childhood morbidity and mortality worldwide. Measles virus (MeV), the causative agent of measles, may also cause a progressive neurological disorder, subacute sclerosing panencephalitis (SSPE), several years after acute infection. The disease is fatal, and no effective therapy is available. Recently, we have reported that cell adhesion molecule 1 (CADM1) and CADM2 are host factors enabling MeV cell-to-cell spread in neurons. These molecules interact in cis with the MeV attachment protein on the same cell membrane, triggering the fusion protein and causing membrane fusion. CADM1 and CADM2 are known to exist in multiple splice isoforms. In this study, we report that their short-stalk isoforms can induce membrane fusion by interacting in cis with the viral attachment protein independently of its receptor-binding head domain. This finding may have important implications for cis -acting fusion triggering by host factors.

scholarly journals Canine Distemper Virus Fusion Activation: Critical Role of Residue E123 of CD150/SLAM

2015 ◽  
Vol 90 (3) ◽  
pp. 1622-1637 ◽  
Author(s):  
Mojtaba Khosravi ◽  
Fanny Bringolf ◽  
Silvan Röthlisberger ◽  
Maria Bieringer ◽  
Jürgen Schneider-Schaulies ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Binding Site ◽  
Measles Virus ◽  
Canine Distemper Virus ◽  
Cell Entry ◽  
Physical Interaction ◽  
Canine Distemper ◽  
Attachment Protein ◽  
Binding Interfaces

ABSTRACTMeasles virus (MeV) and canine distemper virus (CDV) possess tetrameric attachment proteins (H) and trimeric fusion proteins, which cooperate with either SLAM or nectin 4 receptors to trigger membrane fusion for cell entry. While the MeV H-SLAM cocrystal structure revealed the binding interface, two distinct oligomeric H assemblies were also determined. In one of the conformations, two SLAM units were sandwiched between two discrete H head domains, thus spotlighting two binding interfaces (“front” and “back”). Here, we investigated the functional relevance of both interfaces in activating the CDV membrane fusion machinery. While alanine-scanning mutagenesis identified five critical regulatory residues in the front H-binding site of SLAM, the replacement of a conserved glutamate residue (E at position 123, replaced with A [E123A]) led to the most pronounced impact on fusion promotion. Intriguingly, while determination of the interaction of H with the receptor using soluble constructs revealed reduced binding for the identified SLAM mutants, no effect was recorded when physical interaction was investigated with the full-length counterparts of both molecules. Conversely, although mutagenesis of three strategically selected residues within the back H-binding site of SLAM did not substantially affect fusion triggering, nevertheless, the mutants weakened the H-SLAM interaction recorded with the membrane-anchored protein constructs. Collectively, our findings support a mode of binding between the attachment protein and the V domain of SLAM that is common to all morbilliviruses and suggest a major role of the SLAM residue E123, located at the front H-binding site, in triggering the fusion machinery. However, our data additionally support the hypothesis that other microdomain(s) of both glycoproteins (including the back H-binding site) might be required to achieve fully productive H-SLAM interactions.IMPORTANCEA complete understanding of the measles virus and canine distemper virus (CDV) cell entry molecular framework is still lacking, thus impeding the rational design of antivirals. Both viruses share many biological features that partially rely on the use of analogous Ig-like host cell receptors, namely, SLAM and nectin 4, for entering immune and epithelial cells, respectively. Here, we provide evidence that the mode of binding between the membrane-distal V domain of SLAM and the attachment protein (H) of morbilliviruses is very likely conserved. Moreover, although structural information revealed two discrete conformational states of H, one of the structures displayed two H-SLAM binding interfaces (“front” and “back”). Our data not only spotlight the front H-binding site of SLAM as the main determinant of membrane fusion promotion but suggest that the triggering efficiency of the viral entry machinery may rely on a local conformational change within the front H-SLAM interactive site rather than the binding affinity.

Recurrent Drop Attacks as Presenting Manifestation of Subacute Sclerosing Panencephalitis: An Atypical Presentation

2017 ◽  
Vol 16 (01) ◽  
pp. 021-024
Author(s):  
Aniruddha More ◽  
Rajesh Verma
Keyword(s):  
Cognitive Abilities ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Atypical Presentation ◽  
Progressive Decline ◽  
Drop Attacks ◽  
Atypical Manifestations ◽  
Dreaded Disease ◽  
High Index Of Suspicion ◽  
The Brain

AbstractSubacute sclerosing panencephalitis (SSPE) is a potentially fatal progressive complication of measles virus infection of the brain occurring in children and adolescents. It typically presents with a progressive decline in cognitive abilities along with periodic myoclonic jerks. We report a case of SSPE with atypical presentation. Our patient presented with intermittent drop attacks without any obvious myoclonic jerks or cognitive decline making his diagnosis difficult. Atypical manifestations of SSPE occur in 10% of patients, and a high index of suspicion is necessary for early diagnosis and management of this dreaded disease.

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