A Study of the Measles Virus-Induced Proteins Incorporated into the Cell Membrane

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.

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Characterization of octyl glucoside-solubilized cell membrane receptors for binding measles virus

Virology ◽

10.1016/0042-6822(89)90147-5 ◽

1989 ◽

Vol 172 (1) ◽

pp. 386-390 ◽

Cited By ~ 9

Author(s):

David L. Krah

Keyword(s):

Cell Membrane ◽

Measles Virus ◽

Membrane Receptors ◽

Octyl Glucoside

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Moesin: A Cell Membrane Protein Linked with Susceptibility to Measles Virus Infection

Virology ◽

10.1006/viro.1994.1029 ◽

1994 ◽

Vol 198 (1) ◽

pp. 265-274 ◽

Cited By ~ 38

Author(s):

Lee M. Dunster ◽

Jürgen Schneider-Schaulies ◽

Sieglinde Lüffler ◽

Wolfgang Lankes ◽

Reinhard Schwartz-Albiez ◽

...

Keyword(s):

Virus Infection ◽

Cell Membrane ◽

Membrane Protein ◽

Measles Virus ◽

A Cell ◽

Cell Membrane Protein

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Structural changes in the membrane of vero cells infected with a paramyxovirus.

The Journal of Cell Biology ◽

10.1083/jcb.67.3.551 ◽

1975 ◽

Vol 67 (3) ◽

pp. 551-565 ◽

Cited By ~ 29

Author(s):

M Dubois-Dalcq ◽

T S Reese

Keyword(s):

Cell Membrane ◽

Measles Virus ◽

Structural Changes ◽

Vero Cells ◽

Small Particles ◽

Freeze Fracturing ◽

Viral Antigens ◽

Viral Budding ◽

Membrane Surfaces ◽

Viral Maturation

Vero cells productively infected with the Halle strain of measles virus have been studied by means of surface replication, freeze-fracturing, and surface labeling with horseradish peroxidase-measles antibody conjugate in order to examine changes in the structure of the cell membrane during viral maturation. Early in infection, the surfaces of infected cells are embossed by scattered groups of twisted strands, and diffuse patches of label for viral antigens cover regions marked by these strands. At later stages, when numerous nucleocapsids become aligned under the plasmalemmal strands, the strands increase in number and width and become more convoluted. At this stage, label for viral antigens on the surface of the cell membrane is organized into stripes lying on the crests of strands. Finally, regions of the membrane displaying twisted strands protrude to form ridges or bulges, and the freeze-fractured membrane surrounding these protrusions is characterized by an abundance of particles small than those found on the rest of the cell membrane. The fractured membranes of viral buds are continuous sheets of these small particles, and the spacing between both nucleocapsids and stripes of surface antigen in buds is less than in the surrounding cell membrane. Detached virus is covered with a continuous layer of viral antigen, has unusually large but no small particles on its membrane surfaces exposed by freeze-fracturing, and no longer has nucleocapsids aligned under its surface. Thus, surface antigens, membrane particles, and nucleocapsids attached to the cell membrane are mobile within the plane of the membrane during viral maturation. All three move simutaneously in preparation for viral budding.

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The Distal Short Consensus Repeats 1 and 2 of the Membrane Cofactor Protein CD46 and Their Distance from the Cell Membrane Determine Productive Entry of Species B Adenovirus Serotype 35

Journal of Virology ◽

10.1128/jvi.79.15.10013-10022.2005 ◽

2005 ◽

Vol 79 (15) ◽

pp. 10013-10022 ◽

Cited By ~ 39

Author(s):

Christoph Fleischli ◽

Sandra Verhaagh ◽

Menzo Havenga ◽

Dominique Sirena ◽

Walter Schaffner ◽

...

Keyword(s):

Cell Membrane ◽

Measles Virus ◽

Transgene Expression ◽

Membrane Cofactor Protein ◽

Virus Binding ◽

Short Consensus Repeats ◽

As Species ◽

Binding Surface ◽

Short Consensus Repeat ◽

Type 3

ABSTRACT The human regulator of complement activation membrane cofactor protein (CD46) has recently been identified as an attachment receptor for most species B adenoviruses (Ads), including Ad type 3 (Ad3), Ad11, and Ad35, as well as species D Ad37. To characterize the interaction between Ad35 and CD46, hybrid receptors composed of different CD46 short consensus repeat (SCR) domains fused to immunoglobulin-like domains of CD4 and a set of 36 CD46 mutants containing semiconservative changes of single amino acids within SCR domains I and II were tested in binding and in Ad35-mediated luciferase transduction assays. In addition, anti-CD46 antibodies and soluble polypeptides constituting various CD46 domains were used in binding inhibition studies. Our data indicate that (i) CD46 SCR I or SCR II alone confers low but significant Ad35 binding; (ii) the presence of SCR I and II is required for optimal binding and transgene expression; (iii) transduction efficiencies equivalent to that of full-length CD46 are obtained if SCR I and II are at an appropriate distance from the cell membrane; (iv) ablation of the N-glycan attached to SCR I has no influence on receptor function, whereas ablation of the SCR II N-glycan results in about a two- to threefold reduction of binding and transgene expression; (v) most putative Ad35 binding residues are located on the same solvent-exposed face of the SCR I or SCR II domain, which are twisted by about 90°; and (vi) the putative Ad35 binding sites partly overlap with the measles virus binding surface.

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In Vivo Efficacy of Measles Virus Fusion Protein-Derived Peptides Is Modulated by the Properties of Self-Assembly and Membrane Residence

Journal of Virology ◽

10.1128/jvi.01554-16 ◽

2016 ◽

Vol 91 (1) ◽

Cited By ~ 19

Author(s):

T. N. Figueira ◽

L. M. Palermo ◽

A. S. Veiga ◽

D. Huey ◽

C. A. Alabi ◽

...

Keyword(s):

Cell Membrane ◽

Target Cell ◽

Self Assembly ◽

Measles Virus ◽

Structural Transition ◽

Target Cells ◽

Fusion Inhibitor ◽

Inhibitory Peptides ◽

Target Cell Membrane

ABSTRACT Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV hemagglutinin (H) and fusion (F) envelope glycoproteins; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad repeat (HR) regions of F can inhibit MV infection at the entry stage. In previous work, we have generated potent MV fusion inhibitors by dimerizing the F-derived peptides and conjugating them to cholesterol. We have shown that prophylactic intranasal administration of our lead fusion inhibitor efficiently protects from MV infection in vivo. We show here that peptides tagged with lipophilic moieties self-assemble into nanoparticles until they reach the target cells, where they are integrated into cell membranes. The self-assembly feature enhances biodistribution and the half-life of the peptides, while integration into the target cell membrane increases fusion inhibitor potency. These factors together modulate in vivo efficacy. The results suggest a new framework for developing effective fusion inhibitory peptides. IMPORTANCE Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS) and severe neurological disease. No specific treatment is available. We have shown that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. We show here that specific biophysical properties regulate the in vivo efficacy of MV F-derived peptides.

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

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100054376 ◽

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.

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Sarcolemmal permeability changes during early myocardial anoxia

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100084089 ◽

1978 ◽

Vol 36 (2) ◽

pp. 642-643

Author(s):

M. Ashraf ◽

L. Landa ◽

L. Nimmo ◽

C. M. Bloor

Keyword(s):

Cell Membrane ◽

Membrane Permeability ◽

Coronary Artery Occlusion ◽

Artery Occlusion ◽

Cell Membrane Permeability ◽

Enzyme Release ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Sarcolemmal Permeability ◽

Membrane Changes

Following coronary artery occlusion, the myocardial cells lose intracellular enzymes that appear in the serum 3 hrs later. By this time the cells in the ischemic zone have already undergone irreversible changes, and the cell membrane permeability is variably altered in the ischemic cells. At certain stages or intervals the cell membrane changes, allowing release of cytoplasmic enzymes. To correlate the changes in cell membrane permeability with the enzyme release, we used colloidal lanthanum (La+++) as a histological permeability marker in the isolated perfused hearts. The hearts removed from sprague-Dawley rats were perfused with standard Krebs-Henseleit medium gassed with 95% O2 + 5% CO2. The hypoxic medium contained mannitol instead of dextrose and was bubbled with 95% N2 + 5% CO2. The final osmolarity of the medium was 295 M osmol, pH 7. 4.

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

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100077591 ◽

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.

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