scholarly journals Bma-LAD-2, an intestinal cell adhesion protein, as a potential therapeutic target for lymphatic filariasis

2021 ◽  
Author(s):  
Alexander F. Flynn ◽  
Rebekah T. Taylor ◽  
Marzena E. Pazgier ◽  
Sasisekhar Bennuru ◽  
Alyssa R. Lindrose ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Lymphatic Filariasis ◽  
Adhesion Molecule ◽  
Intestinal Epithelium ◽  
Cell Adhesion Molecule ◽  
Structural Integrity ◽  
Brugia Malayi ◽  
Immunoglobulin Superfamily ◽  
Intestinal Cell ◽  
Complete Eradication

AbstractLymphatic filariasis (LF) is a debilitating disease that afflicts over 70 million people worldwide. It is caused by the parasitic nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori. While efforts to eliminate LF have seen substantial success, complete eradication will likely require more time and resources than predicted. Identifying new drug and vaccine targets in adult filariae could help elimination efforts.This study’s aim was to evaluate intestinal proteins in adult Brugia malayi worms as possible therapeutic targets. Using siRNA, we successfully inhibited transcripts of four candidate genes: Bma-Serpin, Bma-ShTK, Bma-Reprolysin, and Bma-LAD-2. Of those, Bma-LAD-2, an immunoglobulin superfamily cell adhesion molecule (IgSF CAM), was determined to be essential for adult worm survival. We observed a 70.42% knockdown in Bma-LAD-2 transcript levels 1 day post-siRNA incubation and an 87.02% reduction in protein expression 2 days post-siRNA incubation. This inhibition of Bma-LAD-2 expression resulted in an 80% decrease in worm motility over 6 days, a 93.43% reduction in microfilaria release (Mf) by day 6 post-siRNA incubation, and a significant decrease in MTT reduction. Transmission electron microscopy revealed the loss of microvilli and unraveling of mitochondrial cristae in the intestinal epithelium of Bma-LAD-2 siRNA-treated worms. Strikingly, Bma-LAD-2 siRNA-treated worms exhibited an almost complete loss of pseudocoelomic fluid, suggesting that loss of these tight junctions led to the leakage and subsequent loss of the worm’s structural integrity. Luciferase immunoprecipitation system assay demonstrated that serum from 30 patients with LF did not have detectable IgE antibodies against Bma-LAD-2, indicating that LF exposure does not result in IgE sensitization to this antigen.These results indicate that Bma-LAD-2 is an essential protein for adult Brugia malayi and may be an effective drug or vaccine target. In addition, these findings further validate the strategy of targeting the worm intestine to prevent and treat helminthic infections.Author SummaryBrugia malayi is a parasitic nematode that can cause lymphatic filariasis, a debilitating disease prevalent in tropical and subtropical countries. Significant progress has been made towards eliminating the disease. However, complete eradication may require new therapeutics such as drugs or a vaccine that kill adult filariae. In this study, we identified an immunoglobulin superfamily cell adhesion molecule (Bma-LAD-2) as a potential drug and vaccine candidate. When we knocked down Bma-LAD-2 expression, we observed a decrease in worm motility, fecundity, and metabolism. We also visualized the loss of microvilli, destruction of the mitochondria in the intestinal epithelium, and loss of pseudocoelomic fluid contents after Bma-LAD-2 siRNA treatment. Finally, we demonstrated that serum from filaria-infected patients does not contain preexisting IgE to Bma-LAD-2, which indicates that this antigen would likely be safe to administer as a vaccine in endemic populations.

Axonal cell-adhesion molecule L1 in CNS myelination

2004 ◽  
Vol 1 (1) ◽  
pp. 65-72 ◽  
Author(s):  
G. BARBIN ◽  
M.S. AIGROT ◽  
P. CHARLES ◽  
A. FOUCHER ◽  
M. GRUMET ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Culture Medium ◽  
Immunoglobulin Superfamily ◽  
Map Kinase Pathway ◽  
Cell Adhesion Molecule L1 ◽  
Cns Myelination ◽  
Kinase Pathway

Of the axonal signals influencing myelination, adhesion molecules expressed at the axonal surface are strong candidates to mediate interactions between myelinating cells and axons. The recognition cell-adhesion molecule L1, a member of the immunoglobulin superfamily has been shown to play important roles in neuronal migration and survival, and in PNS myelination. We have investigated the role of axonally expressed L1 in CNS myelination. In co-cultures of myelinating oligodendrocytes and neurons derived from murine brain, we demonstrate that, before myelination, L1 immunoreactivity is confined to neurites. After myelination commences, L1 expression is downregulated on myelinated axons and adjacent, but not yet myelinated, internodes. Interfering with L1 before the onset of myelination, by adding either anti-L1 antibody or L1-Fc fusion proteins to the culture medium, inhibits myelination. In addition, in purified cultures of oligodendrocytes, L1-Fc fusion protein prevents lysophosphatidic acid-induced activation of the mitogen-activated kinase (MAP)-kinase pathway. Together, our data indicate that L1 is involved in the initiation of CNS myelination, and that this effect might involve the dephosphorylation of oligodendroglial phosphoproteins.

scholarly journals Direct and Regulated Interaction of Integrin αEβ7 with E-Cadherin

1998 ◽  
Vol 140 (1) ◽  
pp. 197-210 ◽  
Author(s):  
Jonathan M.G. Higgins ◽  
Didier A. Mandlebrot ◽  
Sunil K. Shaw ◽  
Gary J. Russell ◽  
Elizabeth A. Murphy ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Fusion Protein ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Divalent Cations ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Vital Role ◽  
Immunoglobulin Superfamily ◽  
E Cadherin

The cadherins are a family of homophilic adhesion molecules that play a vital role in the formation of cellular junctions and in tissue morphogenesis. Members of the integrin family are also involved in cell to cell adhesion, but bind heterophilically to immunoglobulin superfamily molecules such as intracellular adhesion molecule (ICAM)–1, vascular cell adhesion molecule (VCAM)–1, or mucosal addressin cell adhesion molecule (MadCAM)–1. Recently, an interaction between epithelial (E-) cadherin and the mucosal lymphocyte integrin, αEβ7, has been proposed. Here, we demonstrate that a human E-cadherin–Fc fusion protein binds directly to soluble recombinant αEβ7, and to αEβ7 solubilized from intraepithelial T lymphocytes. Furthermore, intraepithelial lymphocytes or transfected JY′ cells expressing the αEβ7 integrin adhere strongly to purified E-cadherin–Fc coated on plastic, and the adhesion can be inhibited by antibodies to αEβ7 or E-cadherin. The binding of αEβ7 integrin to cadherins is selective since cell adhesion to P-cadherin–Fc through αEβ7 requires >100-fold more fusion protein than to E-cadherin–Fc. Although the structure of the αE-chain is unique among integrins, the avidity of αEβ7 for E-cadherin can be regulated by divalent cations or phorbol myristate acetate. Cross-linking of the T cell receptor complex on intraepithelial lymphocytes increases the avidity of αEβ7 for E-cadherin, and may provide a mechanism for the adherence and activation of lymphocytes within the epithelium in the presence of specific foreign antigen. Thus, despite its dissimilarity to known integrin ligands, the specific molecular interaction demonstrated here indicates that E-cadherin is a direct counter receptor for the αEβ7 integrin.

Expression of the immunoglobulin superfamily cell adhesion molecule F3 by oligodendrocyte-lineage cells

Glia ◽  
1997 ◽  
Vol 19 (3) ◽  
pp. 199-212 ◽  
Author(s):  
Thomas Koch ◽  
Thomas Brugger ◽  
Alfred Bach ◽  
Gianfranco Gennarini ◽  
Jacqueline Trotter
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Immunoglobulin Superfamily

scholarly journals Evidence for regulated dimerization of cell-cell adhesion molecule (C-CAM) in epithelial cells

1996 ◽  
Vol 320 (3) ◽  
pp. 847-853 ◽  
Author(s):  
Irene HUNTER ◽  
Hiroki SAWA ◽  
Magnus EDLUND ◽  
Björn ÖBRINK
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Plasma Membranes ◽  
Immunoglobulin Superfamily ◽  
Dimer Formation ◽  
Rat Liver Plasma Membranes ◽  
Self Association ◽  
Covalently Linked

C-CAM is a Ca2+-independent cell adhesion molecule (CAM) belonging to the immunoglobulin superfamily. Addition of chemical cross-linkers to isolated rat liver plasma membranes, intact epithelial cells and purified preparations of C-CAM stabilized one major C-CAM-containing product whose apparent molecular mass was approximately twice that of the C-CAM monomer. The failure to detect additional proteins after cleavage of the cross-linked species demonstrated that C-CAM exists as non-covalently linked dimers both in solution and on the cell surface. Dimerization occurred to the same extent in adherent monolayers and in single cell populations, indicating that dimer formation was the result of cis- interactions within the membranes of individual cells. Using isoform-specific anti-peptide antibodies, both C-CAM1 and C-CAM2 were found to be involved in dimerization, forming predominantly homo-dimeric species. Both calmodulin and Ca2+ ionophore modulated the level of dimer formation, suggesting a role for regulated self-association in the functional activity of C-CAM.

scholarly journals The Cell Adhesion Molecule L1 Is Developmentally Regulated in the Renal Epithelium and Is Involved in Kidney Branching Morphogenesis

1998 ◽  
Vol 143 (7) ◽  
pp. 2067-2079 ◽  
Author(s):  
Hanna Debiec ◽  
Erik Ilsø Christensen ◽  
Pierre Marie Ronco
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Collecting Duct ◽  
Neuronal Cell ◽  
Branching Morphogenesis ◽  
Immunoglobulin Superfamily ◽  
Glycosylation Pattern ◽  
Cell Adhesion Molecule L1

We immunopurified a surface antigen specific for the collecting duct (CD) epithelium. Microsequencing of three polypeptides identified the antigen as the neuronal cell adhesion molecule L1, a member of the immunoglobulin superfamily. The kidney isoform showed a deletion of exon 3. L1 was expressed in the mesonephric duct and the metanephros throughout CD development. In the adult CD examined by electron microscopy, L1 was not expressed on intercalated cells but was restricted to CD principal cells and to the papilla tall cells. By contrast, L1 appeared late in the distal portion of the elongating nephron in the mesenchymally derived epithelium and decreased during postnatal development. Immunoblot analysis showed that expression, proteolytic cleavage, and the glycosylation pattern of L1 protein were regulated during renal development. L1 was not detected in epithelia of other organs developing by branching morphogenesis. Addition of anti-L1 antibody to kidney or lung organotypic cultures induced dysmorphogenesis of the ureteric bud epithelium but not of the lung. These results suggest a functional role for L1 in CD development in vitro. We further postulate that L1 may be involved in the guidance of developing distal tubule and in generation and maintenance of specialized cell phenotypes in CD.

scholarly journals Nectin/PRR: An Immunoglobulin-like Cell Adhesion Molecule Recruited to Cadherin-based Adherens Junctions through Interaction with Afadin, a PDZ Domain–containing Protein

1999 ◽  
Vol 145 (3) ◽  
pp. 539-549 ◽  
Author(s):  
Kenichi Takahashi ◽  
Hiroyuki Nakanishi ◽  
Masako Miyahara ◽  
Kenji Mandai ◽  
Keiko Satoh ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cell Lines ◽  
Actin Filament ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Adherens Junctions ◽  
Pdz Domain ◽  
Immunoglobulin Superfamily ◽  
Poliovirus Receptor ◽  
Cell Cell

We have isolated a novel actin filament–binding protein, named afadin, localized at cadherin-based cell–cell adherens junctions (AJs) in various tissues and cell lines. Afadin has one PDZ domain, three proline-rich regions, and one actin filament–binding domain. We found here that afadin directly interacted with a family of the immunoglobulin superfamily, which was isolated originally as the poliovirus receptor–related protein (PRR) family consisting of PRR1 and -2, and has been identified recently to be the alphaherpes virus receptor. PRR has a COOH-terminal consensus motif to which the PDZ domain of afadin binds. PRR and afadin were colocalized at cadherin-based cell–cell AJs in various tissues and cell lines. In E-cadherin–expressing EL cells, PRR was recruited to cadherin-based cell–cell AJs through interaction with afadin. PRR showed Ca2+-independent cell–cell adhesion activity. These results indicate that PRR is a cell–cell adhesion molecule of the immunoglobulin superfamily which is recruited to cadherin-based cell–cell AJs through interaction with afadin. We rename PRR as nectin (taken from the Latin word “necto” meaning “to connect”).

Structure of cell–cell adhesion mediated by the Down syndrome cell adhesion molecule

2021 ◽  
Vol 118 (39) ◽  
pp. e2022442118
Author(s):  
Luqiang Guo ◽  
Yichun Wu ◽  
Haishuang Chang ◽  
Ze Zhang ◽  
Hua Tang ◽  
...  
Keyword(s):  
Neural Network ◽  
Down Syndrome ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Neural Development ◽  
Cell Adhesion Molecule ◽  
Network Formation ◽  
Electron Tomography ◽  
Three Dimensional ◽  
Immunoglobulin Superfamily

The Down syndrome cell adhesion molecule (DSCAM) belongs to the immunoglobulin superfamily (IgSF) and plays important roles in neural development. It has a large ectodomain, including 10 Ig-like domains and 6 fibronectin III (FnIII) domains. Previous data have shown that DSCAM can mediate cell adhesion by forming homophilic dimers between cells and contributes to self-avoidance of neurites or neuronal tiling, which is important for neural network formation. However, the organization and assembly of DSCAM at cell adhesion interfaces has not been fully understood. Here we combine electron microscopy and other biophysical methods to characterize the structure of the DSCAM-mediated cell adhesion and generate three-dimensional views of the adhesion interfaces of DSCAM by electron tomography. The results show that mouse DSCAM forms a regular pattern at the adhesion interfaces. The Ig-like domains contribute to both trans homophilic interactions and cis assembly of the pattern, and the FnIII domains are crucial for the cis pattern formation as well as the interaction with the cell membrane. By contrast, no obvious assembly pattern is observed at the adhesion interfaces mediated by mouse DSCAML1 or Drosophila DSCAMs, suggesting the different structural roles and mechanisms of DSCAMs in mediating cell adhesion and neural network formation.

Endothelial Lu/BCAM glycoproteins are novel ligands for red blood cell α4β1integrin: role in adhesion of sickle red blood cells to endothelial cells

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3544-3551 ◽  
Author(s):  
Wassim El Nemer ◽  
Marie-Paule Wautier ◽  
Cécile Rahuel ◽  
Pierre Gane ◽  
Patricia Hermand ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Adhesion Molecule ◽  
Blood Cells ◽  
Cell Adhesion Molecule ◽  
Red Cells ◽  
Immunoglobulin Superfamily ◽  
Flow Conditions

Abstract The Lutheran (Lu) blood group and basal cell adhesion molecule (BCAM) antigens are both carried by 2 glycoprotein isoforms of the immunoglobulin superfamily representing receptors for the laminin α5 chain. In addition to red blood cells, Lu/BCAM proteins are highly expressed in endothelial cells. Abnormal adhesion of red blood cells to the endothelium could potentially contribute to the vaso-occlusive episodes in sickle cell disease. Considering the presence of integrin consensus-binding sites in Lu/BCAM proteins, we investigated their potential interaction with integrin α4β1, the unique integrin expressed on immature circulating sickle red cells. Using cell adhesion assays under static and flow conditions, we demonstrated that integrin α4β1 expressed on transfected cells bound to chimeric Lu-Fc protein. We showed that epinephrine-stimulated sickle cells, but not control red cells, adhered to Lu-Fc via integrin α4β1 under flow conditions. Antibody-mediated activation of integrin α4β1 induced adhesion of sickle red cells to primary human umbilical vein endothelial cells; this adhesion was inhibited by soluble Lu-Fc and vascular cell adhesion molecule-1 (VCAM-1)–Fc proteins. This novel interaction between integrin α4β1 in sickle red cells and endothelial Lu/BCAM proteins could participate in sickle cell adhesion to endothelium and potentially play a role in vaso-occlusive episodes.

1013 Primary structure of OCAM, a novel cell adhesion molecule of the immunoglobulin superfamily

1997 ◽  
Vol 28 ◽  
pp. S120
Author(s):  
Yoshihiro Yoshihara ◽  
Miwa Kawasaki ◽  
Hideyuki Hayashi ◽  
Hiroyuki Kagamiyama ◽  
Kensaku Mori
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Primary Structure ◽  
Cell Adhesion Molecule ◽  
Immunoglobulin Superfamily
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