The Tumor-Associated Marker, PVRL4 (Nectin-4), Is the Epithelial Receptor for Morbilliviruses

Delpeut, Sébastien; Noyce, Ryan S.; Richardson, Christopher D.

doi:10.3390/v6062268

Cited by 49 publications

(51 citation statements)

References 118 publications

(176 reference statements)

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“…Alternatively, based on positive immunostaining, we speculate that CDV may also use N4 to breach the ependymal and meningeal barriers, which are, throughout the CNS, in intimate contact with an underlying astroglial cell layer (glia limitans). This view might be consistent with the reported frequent periventricular and subpial localization of CDV-induced demyelinating lesions (20,46,47) with intense infection of the ependymal cells. Once astrocytes are targeted, the infection will further spread deeply in the white matter in a GliaR-dependent manner.…”

Section: Discussionsupporting

confidence: 80%

SLAM- and Nectin-4-Independent Noncytolytic Spread of Canine Distemper Virus in Astrocytes

Alves

Khosravi

Avila

et al. 2015

J Virol

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Measles and canine distemper viruses (MeV and CDV, respectively) first replicate in lymphatic and epithelial tissues by using SLAM and nectin-4 as entry receptors, respectively. The viruses may also invade the brain to establish persistent infections, triggering fatal complications, such as subacute sclerosis pan-encephalitis (SSPE) in MeV infection or chronic, multiple sclerosislike, multifocal demyelinating lesions in the case of CDV infection. In both diseases, persistence is mediated by viral nucleocapsids that do not require packaging into particles for infectivity but are directly transmitted from cell to cell (neurons in SSPE or astrocytes in distemper encephalitis), presumably by relying on restricted microfusion events. Indeed, although morphological evidence of fusion remained undetectable, viral fusion machineries and, thus, a putative cellular receptor, were shown to contribute to persistent infections. Here, we first showed that nectin-4-dependent cell-cell fusion in Vero cells, triggered by a demyelinating CDV strain, remained extremely limited, thereby supporting a potential role of nectin-4 in mediating persistent infections in astrocytes. However, nectin-4 could not be detected in either primary cultured astrocytes or the white matter of tissue sections. In addition, a bioengineered "nectin-4-blind" recombinant CDV retained full cell-to-cell transmission efficacy in primary astrocytes. Combined with our previous report demonstrating the absence of SLAM expression in astrocytes, these findings are suggestive for the existence of a hitherto unrecognized third CDV receptor expressed by glial cells that contributes to the induction of noncytolytic cell-to-cell viral transmission in astrocytes. IMPORTANCE While persistent measles virus (MeV) infection induces SSPE in humans, persistent canine distemper virus (CDV) infectioncauses chronic progressive or relapsing demyelination in carnivores. Common to both central nervous system (CNS) infections is that persistence is based on noncytolytic cell-to-cell spread, which, in the case of CDV, was demonstrated to rely on functional membrane fusion machinery complexes. This inferred a mechanism where nucleocapsids are transmitted through macroscopically invisible microfusion events between infected and target cells. Here, we provide evidence that CDV induces such microfusions in a SLAM-and nectin-4-independent manner, thereby strongly suggesting the existence of a third receptor expressed in glial cells (referred to as GliaR). We propose that GliaR governs intercellular transfer of nucleocapsids and hence contributes to viral persistence in the brain and ensuing demyelinating lesions.

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Section: Discussionsupporting

confidence: 80%

SLAM- and Nectin-4-Independent Noncytolytic Spread of Canine Distemper Virus in Astrocytes

Alves

Khosravi

Avila

et al. 2015

J Virol

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“…Many of the PVR/PVRL family members have been shown to be involved in virus entry. PVR was first identified as the poliovirus receptor (39), followed by PVRL1 and PVRL2 as herpesvirus receptors (40,41), and most recently PVRL4 has been identified as an epithelial receptor for measles virus (42,43) and other morbilliviruses (44,45). This study represents the first report to our knowledge of a pathogen using PVRL3 as a receptor, and also the first instance to our knowledge of a bacterial toxin using a member of this family of proteins as a receptor.…”

Section: Discussionmentioning

confidence: 72%

Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity

LaFrance

Farrow

Chandrasekaran

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

155

152

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Clostridium difficile is the leading cause of hospital-acquired diarrhea in the United States. The two main virulence factors of C. difficile are the large toxins, TcdA and TcdB, which enter colonic epithelial cells and cause fluid secretion, inflammation, and cell death. Using a gene-trap insertional mutagenesis screen, we identified poliovirus receptor-like 3 (PVRL3) as a cellular factor necessary for TcdB-mediated cytotoxicity. Disruption of PVRL3 expression by gene-trap mutagenesis, shRNA, or CRISPR/Cas9 mutagenesis resulted in resistance of cells to TcdB. Complementation of the gene-trap or CRISPR mutants with PVRL3 resulted in restoration of TcdB-mediated cell death. Purified PVRL3 ectodomain bound to TcdB by pull-down. Pretreatment of cells with a monoclonal antibody against PVRL3 or prebinding TcdB to PVRL3 ectodomain also inhibited cytotoxicity in cell culture. The receptor is highly expressed on the surface epithelium of the human colon and was observed to colocalize with TcdB in both an explant model and in tissue from a patient with pseudomembranous colitis. These data suggest PVRL3 is a physiologically relevant binding partner that can serve as a target for the prevention of TcdB-induced cytotoxicity in C. difficile infection.

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“…More recently, nectin-4 was identified as an entry point for measles and other viruses and was proposed as a target for oncolytic viral therapy (21,22). Although several groups reported the detection of nectin-4 expression in breast, ovarian, and lung cancers (23)(24)(25)(26), no comprehensive analysis has been reported to date.…”

Section: Discussionmentioning

confidence: 98%

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

Challita-Eid¹,

Satpayev²,

Yang³

et al. 2016

Cancer Research

411

386

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The identification of optimal target antigens on tumor cells is central to the advancement of new antibody-based cancer therapies. We performed suppression subtractive hybridization and identified nectin-4 (PVRL4), a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules, as a potential target in epithelial cancers. We conducted immunohistochemical analysis of 2,394 patient specimens from bladder, breast, lung, pancreatic, ovarian, head/neck, and esophageal tumors and found that 69% of all specimens stained positive for nectin-4. Moderate to strong staining was especially observed in 60% of bladder and 53% of breast tumor specimens, whereas the expression of nectin-4 in normal tissue was more limited. We generated a novel antibody-drug conjugate (ADC) enfortumab vedotin comprising the human anti-nectin-4 antibody conjugated to the highly potent microtubule-disrupting agent MMAE. Hybridoma (AGS-22M6E) and CHO (ASG-22CE) versions of enfortumab vedotin (also known as ASG-22ME) ADC were able to bind to cell surface-expressed nectin-4 with high affinity and induced cell death in vitro in a dose-dependent manner. Treatment of mouse xenograft models of human breast, bladder, pancreatic, and lung cancers with enfortumab vedotin significantly inhibited the growth of all four tumor types and resulted in tumor regression of breast and bladder xenografts. Overall, these findings validate nectin-4 as an attractive therapeutic target in multiple solid tumors and support further clinical development, investigation, and application of nectin-4-targeting ADCs. Cancer Res; 76(10); 3003-13. Ó2016 AACR.

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The Tumor-Associated Marker, PVRL4 (Nectin-4), Is the Epithelial Receptor for Morbilliviruses

Cited by 49 publications

References 118 publications

SLAM- and Nectin-4-Independent Noncytolytic Spread of Canine Distemper Virus in Astrocytes

SLAM- and Nectin-4-Independent Noncytolytic Spread of Canine Distemper Virus in Astrocytes

Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

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