Next Article in Journal / Special Issue
Peste Des Petits Ruminants Virus Infection of Small Ruminants: A Comprehensive Review
Previous Article in Journal
Clustering of Giant Virus-DNA Based on Variations in Local Entropy
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

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

1
The Department of Microbiology and Immunology, Dalhousie University, Halifax, B3H 1X5 NS, Canada
2
IWK Health Centre, Canadian Center for Vaccinology, Goldbloom Pavilion, Halifax, B3H 1X5 NS, Canada
3
The Department of Pediatrics, Dalhousie University, Halifax, B3K 6R8 NS, Canada
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Viruses 2014, 6(6), 2268-2286; https://doi.org/10.3390/v6062268
Submission received: 19 March 2014 / Revised: 14 May 2014 / Accepted: 15 May 2014 / Published: 2 June 2014
(This article belongs to the Special Issue Morbillivirus Infections)

Abstract

:
PVRL4 (nectin-4) was recently identified as the epithelial receptor for members of the Morbillivirus genus, including measles virus, canine distemper virus and peste des petits ruminants virus. Here, we describe the role of PVRL4 in morbillivirus pathogenesis and its promising use in cancer therapies. This discovery establishes a new paradigm for the spread of virus from lymphocytes to airway epithelial cells and its subsequent release into the environment. Measles virus vaccine strains have emerged as a promising oncolytic platform for cancer therapy in the last ten years. Given that PVRL4 is a well-known tumor-associated marker for several adenocarcinoma (lung, breast and ovary), the measles virus could potentially be used to specifically target, infect and destroy cancers expressing PVRL4.

1. Introduction

Morbilliviruses, which include measles virus (MeV), canine distemper virus (CDV) and peste des petits ruminants virus (PPRV), are among the most widespread and highly contagious pathogens in their respective hosts. Lapses in vaccination have produced frequent outbreaks of measles in recent years. Although measles virus infects human and non-human primates, humans are the only reservoir for MeV [1]. On the other hand, CDV, isolated from dogs, infects a wide range of wild carnivore species [2,3,4], while PPRV primarily infects small ruminants, such as sheep and goats [5]. The role of wildlife as reservoir hosts for PPRV remains unclear [5]. The genus, Morbillivirus, belongs to the Paramyxoviridae family in the order, Mononegavirales. The genome is a negative-sense, non-segmented, single-stranded RNA, and its structure is conserved with the nucleocapsid (N), phosphoprotein (P), matrix (M), fusion (F), attachment (H) and large (L) genes present in all morbilliviruses [6]. MeV, CDV and PPRV are not only genetically related, but also induce similar symptoms in their hosts, such as fever, respiratory and gastrointestinal signs, often complicated by secondary bacterial infections, due to morbillivirus-induced immunosuppression [7,8,9,10]. Interestingly, neurological disease caused by MeV is rare, whereas with CDV, it is more frequent. Central nervous system complications are not associated with PPRV infection [11]. As well as producing an enormous health burden on human, livestock and wildlife health by causing mild to severe or fatal diseases, the economic impact of these human and animal viruses is considerable [3, 12,13,14,15,16,17].
This review highlights recent advances on the role of PVRL4 (nectin-4) during morbillivirus infections. Specifically, the function of PVRL4 during morbillivirus entry and exit, and, in particular, the role the variable (V) domain of PVRL4 plays in the recognition of morbillivirus attachment receptors, is discussed. Finally, the oncolytic potential of morbilliviruses in targeting PVRL4 as a tumor marker on adenocarcinomas is proposed.

2. Routes of Morbillivirus Entry

Most morbilliviruses have established lymphotropism and epitheliotropism that are receptor-dependent (Figure 1) [18,19,20,21,22,23,24,25]. Interestingly, vaccine and laboratory-adapted strains of MeV can use the human membrane cofactor protein, CD46/MCP, as an additional receptor, resulting from the adaptation of MeV to growth in cell culture [26, 27]. However, CD46/MCP is not a natural receptor involved in wtMeV pathogenesis and is not used by other morbillivirus species. Specific interactions between cellular receptors and the viral hemagglutinin protein (H) facilitate virus entry into host cells [18,19,20,21,22,23,24,25] by inducing virus-cell and cell-cell membrane fusion in cooperation with the fusion protein (F) [28,29,30,31]. Importantly, morbilliviruses are highly lymphotropic viruses that use the signaling lymphocyte activation molecule (SLAM/CD150) as an immune cell entry receptor that is expressed on the surface of activated T- and B-lymphocytes, macrophages and dendritic cells [23,24,25, 32,33,34]. During infection, tissue resident dendritic cells and macrophages initially become infected and migrate to the lymph nodes, where the virus has access to a large pool of activated T- and B-lymphocytes [6, 35, 36]. These lymphocytes disseminate the virus throughout the lymphatic system. The appearance of clinical signs coincides with viral spread to epithelial cells [1, 33, 37]. Finally, infected cells and virus subsequently shed in respiratory secretions, urine and feces [38,39,40,41,42,43]. Ruminants, carnivores or primates can become infected through close contact with or eating sick prey [40, 44,45,46,47] (Figure 2). While SLAM is not expressed in epithelial tissues, PVRL4 (nectin-4) was recently identified as the epithelial receptor for MeV, CDV and PPRV [18,19,20,21,22].
Figure 1. Structure of Morbillivirus receptors. (A) CD46/MCP structure consists of four short consensus repeats (SCRs I, II, III and IV), a serine/threonine/proline region (STPs A, B and C), a sequence of unknown significance (U), a transmembrane sequence and a cytoplasmic domain. Only vaccine or laboratory adapted strains of measles virus (MeV) use CD46 as a receptor. (B) CD150/SLAM contains a variable (V) domain and a constant (C2) Ig-like repeat in its extracellular domain. SLAM is the universal immune receptor for all morbilliviruses. (C) The PVRL4/nectin-4 extracellular domain is composed of a variable domain and two C2 domains. To date, PVRL4 was shown to serve as an epithelial receptor for measles virus, canine distemper virus and peste des petits ruminants virus.
Figure 1. Structure of Morbillivirus receptors. (A) CD46/MCP structure consists of four short consensus repeats (SCRs I, II, III and IV), a serine/threonine/proline region (STPs A, B and C), a sequence of unknown significance (U), a transmembrane sequence and a cytoplasmic domain. Only vaccine or laboratory adapted strains of measles virus (MeV) use CD46 as a receptor. (B) CD150/SLAM contains a variable (V) domain and a constant (C2) Ig-like repeat in its extracellular domain. SLAM is the universal immune receptor for all morbilliviruses. (C) The PVRL4/nectin-4 extracellular domain is composed of a variable domain and two C2 domains. To date, PVRL4 was shown to serve as an epithelial receptor for measles virus, canine distemper virus and peste des petits ruminants virus.
Viruses 06 02268 g001
Figure 2. The entry and release of measles virus in human bronchial epithelium. MeV infects the basolateral surface of well-differentiated human airway epithelia via infected immune cells, which migrate to and interact with the adherens junction molecule, PVRL4. The infection subsequently spreads to adjacent cells via PVRL4. Later, measles virus is released from the apical surface of ciliated cells into the airway lumen.
Figure 2. The entry and release of measles virus in human bronchial epithelium. MeV infects the basolateral surface of well-differentiated human airway epithelia via infected immune cells, which migrate to and interact with the adherens junction molecule, PVRL4. The infection subsequently spreads to adjacent cells via PVRL4. Later, measles virus is released from the apical surface of ciliated cells into the airway lumen.
Viruses 06 02268 g002

2.1. PVRL4 Expression and Distribution

Expression and distribution of cellular morbillivirus receptors in a host is particularly important, because the interaction of a virus with its cellular receptor links virus tropism and pathogenesis [48]. High levels of ovine PVRL4 transcripts are found in epithelial tissues, including the mouth, the upper respiratory tract and the stomach [19], while human PVRL4 is abundantly expressed in placental trophoblasts, gastric glandular cells and adenocarcinomas of the lung, breast and ovary [49]. In the human respiratory tract, PVRL4 expression is a prerequisite for MeV infection of both well-differentiated human airway epithelial cells [22] and primary human small airway epithelial cells grown in the presence of serum [21]. Interestingly, PVRL4 is expressed on both the apical and basolateral surfaces of a number of polarized adenocarcinoma cells, where MeV infection is more efficient via the apical route [21]. Direct virus binding and entry via the apical surface of normal airway epithelial cells does not appear to occur during initial virus exposure. Indeed, it was previously reported that ciliated epithelial cells are refractory to MeV infection from the apical side, preventing them from being the primary target cells [50, 51]. In contrast, MeV preferentially infects differentiated primary epithelial cells via the basolateral route, which is consistent with polarized expression of PVRL4 along the basolateral surface of pseudostratified ciliated epithelial cells in the trachea and nasal concha [51,52,53,54]. PVRL4 actually plays a key role in virus spread from immune to epithelial cells [54,55,56]. A study with monkeys highlights the fact that MeV preferentially infects the basolateral surface of well-differentiated human airway epithelia via the migration of CD150-expressing myeloid cells into the tracheal epithelium [55]. These findings were corroborated by another study showing that MeV infection of epithelial cells in the macaque upper respiratory tract is mediated by subepithelial CD150 positive B-lymphocytes [54]. Once MeV gains entry into the respiratory tract, the spread of the virus is primarily mediated by PVRL4. Although wtMeV spreads efficiently to the epithelium in tracheal infections compared to PVRL4-blind MeV infection in monkeys [55], the lack of an epithelial infection by PVRL4-blind MeV could result from the more rapid clearance of this virus in vivo [55]. Moreover, MeV is released from the apical membrane of polarized epithelia [55, 57,58,59,60]. Rhesus macaques infected with epithelial receptor-blind MeV developed clinical symptoms similar to monkeys infected with wild-type MeV, but the virus was unable to cross the airway epithelium to be shed in the airways [52]. Similarly, the epithelial receptor-blind CDV was not detected in epithelial tissues from infected ferrets [37]. Taken together, these data suggest a novel model for the spread of morbilliviruses through the respiratory tract epithelia, which requires PVRL4 as an exit receptor.
Nevertheless, morbillivirus pathogenesis cannot be explained by the presence of SLAM and PVRL4 alone. Small ruminants infected with PPRV often exhibit lesions in the intestine that express relatively low levels of SLAM and PVRL4 [19, 61, 62]. In contrast, higher levels of cytoplasmic PVRL4 expression in the stomach epithelial cells [49] does not correlate with the gastric pathology associated with PPRV infection [19, 61, 62]. As a consequence of these observations, the relevance of PVRL4 accessibility and localization within different epithelial cells should also be considered, as this might influence virus spread beyond just PVRL4 expression levels. Additional unidentified cellular receptors may also play a key role in morbillivirus-induced pathogenesis within the central nervous system, as complications associated with MeV and CDV infections can arise here at late stages of the disease. Finally, virus replication might also be blocked by a restriction factor in cells permissive to morbillivirus entry [63].

3. Structural Insights into the Interaction of Morbilliviruses with PVRL4

The characterization of virus-receptor interactions is particularly important to better understand virus entry and offers new opportunities for developing antiviral therapies. PVRL4 is a member of the nectin family of adhesion molecules, which belongs to the immunoglobulin (Ig) superfamily, comprised of nectin-1, -2, -3, -4 and the prototypic poliovirus receptor (PVR) [64,65,66]. PVR mediates the entry for poliovirus [67], while PVRL1 and 2 serve as a receptor for herpes simplex viruses [68]. Nectins are normally localized to the adherens junctions and are components of the cell-cell adhesion system, where they play a key role in limiting cell movement, facilitating intercellular communication and regulating proliferation [64,65,66]. PVRL4 is a type I transmembrane glycoprotein with three Ig-like ectodomains (V and two C2 domains), a transmembrane region and a cytoplasmic tail [65, 69]. V domains are involved in homotypic or heterotypic interactions with nectin-1, while C2 domains enhance the affinity of these interactions [66, 69, 70]. PVRL4 initially interacts with other PVRL4 molecules in cis-, followed by trans-interactions with PVRL4 on adjacent cells, while PVRL4-PVRL1 interactions only appear in trans on adjacent cells [69, 71,72,73]. As a consequence of other binding partners for PVRL4, it will be of interest to determine if such PVRL protein interactions might influence morbillivirus entry.

3.1. The V Domain of PVRL4 is Essential for Morbillivirus Entry

PVRL4 was biochemically shown to support binding to MeV H through its V domain, leading to virus entry [22]. This is similar to the scenario where the V domain of SLAM also interacts with MeV H [74]. Interestingly PVRL4-MeV H interactions are stronger than MeV H binding to SLAM, although PVRL4-MeV-induced syncytia formation is less extensive compared to SLAM [22]. In cell culture, the PVRL4 V domain was shown to be essential for CDV infection using whole chimeric nectins, where the V domains of PVRL4 and PVRL1 were exchanged [75]. A crystallographic structure of the ligand-binding domains between PVRL4 and MeV H has identified three binding interfaces [76]. Sites II and III are respectively located in the B-C and C’-C’’ loops of the PVRL4 V domain and contribute to receptor-ligand interactions [76]. In contrast, the F-G loop containing Site I interacts with two hydrophobic patches in MeV H, conferring strong stabilizing forces [76]. Importantly, mutations F101S, P102S, A103S and G104Y in Site I of the PVRL4 V domain almost completely abolished MeV H recognition in vitro [76]. This FPAG motif (F101, P102, A103 and G104) within the V domain of PVRL4 is conserved in the related PVRL4 V domains from ovine and dog species [18,19,76] (Figure 3) and is critical for CDV entry and virus spread [75]. Although FPxG is a consensus amino acid sequence located in all human nectin V domains [76, 77], PVRL1, PVRL2 and PVRL3 are not used as a receptor by MeV [21, 22]. Taken together, these studies demonstrate that morbillivirus epithelial cell infections are highly conserved, since both MeV and CDV H proteins share key PVRL4 binding residues [37, 52, 75].
Figure 3. Amino acid sequence alignment of the V domains from human PVRL1 to PVRL4, human PVR, dog PVRL4 and ovine PVRL4. Residues having similarity are shaded (dark shading represents identical amino acid residues; dark grey shading represents residues with 80%–100% identity, light grey shading represents residues with 60%–80% identity, no shading represents residues with less than 60% identity). The consensus FPxG amino acid sequence is boxed in red. The Geneious sequence alignment software was used to perform pairwise protein alignments [78].
Figure 3. Amino acid sequence alignment of the V domains from human PVRL1 to PVRL4, human PVR, dog PVRL4 and ovine PVRL4. Residues having similarity are shaded (dark shading represents identical amino acid residues; dark grey shading represents residues with 80%–100% identity, light grey shading represents residues with 60%–80% identity, no shading represents residues with less than 60% identity). The consensus FPxG amino acid sequence is boxed in red. The Geneious sequence alignment software was used to perform pairwise protein alignments [78].
Viruses 06 02268 g003

3.2. High Similarity between the PVRL4 Receptors from Different Origins Might Weaken the Species Barrier for Morbillivirus

In contrast to MeV and PPRV, canine distemper virus infects a wide range of hosts, highlighting its ability to jump across species. Interestingly, PVRL4 sequences from human and dog origin are almost identical at the amino acid level, and both V domains contain the FPAG motif [18, 19]. Due to these similarities, CDV has the intrinsic ability to use both human and dog PVRL4 as an epithelial receptor, without a requirement for adaptive mutations in H [79, 80]. Thus, CDV can replicate in human epithelial cells after blocking the host innate immune response [81]. Although a single mutation in the hemagglutinin gene is still required for CDV to use the human SLAM entry receptor [79, 80], canine distemper virus has the potential to emerge as a novel human pathogen [80]. Indeed, natural infections with CDV have already been reported in non-human primates [46, 47], including an outbreak of CDV in rhesus monkeys at a breeding farm in China [45]. However, a recent study suggests that additional mutations are likely necessary to achieve full virulence in non-natural hosts [82]. On the other hand, the chance of CDV adapting to humans is low, due to the presence of cross-reactive cellular and humoral immunity against pre-existing MeV antigens induced by the MMR vaccine or childhood infection [83,84,85]. A study performed with monkeys proved that measles vaccination can prevent CDV from crossing species barriers to infect primates [82]. Importantly, these studies imply that measles eradication and lapses in MMR vaccination could allow CDV to emerge and infect humans.

4. The Oncolytic Potential of Measles Virus

During the past decade, measles virus vaccine strains have emerged as a promising oncolytic platform that may not be compromised by pre-existing MeV immunity [86,87,88,89,90,91]. Preclinical virotherapeutic studies have been primarily performed using MeV vaccine strains over wild-type strains, due to the exceptional genetic stability and safety record of the vaccine strains [92]. The development of oncolytic virotherapy provides a new approach to cancer therapy by selectively targeting tumor cells using previously identified tumor markers on the tumor surface [93].

4.1. MeV Receptor Expression in Cancer Cells

Numerous studies have reported SLAM, CD46 and PVRL4 as being tumor cell markers. A number of previous clinical case studies documenting “spontaneous” tumor regression in patients with Hodgkin’s disease and Burkitt’s lymphoma were reported after concurrent measles virus infections [94, 95]. These tumors are known to express elevated levels of SLAM on their surface [96], suggesting that MeV infection may have been responsible for the apparent tumor regression. The oncolytic efficacy of MeV in T-cell lymphomas has also been observed [97, 98]. Secondly, CD46 is expressed at low levels on all nucleated cells [99] and is upregulated in numerous cancers (breast, cervical, colorectal, gastrointestinal, lung, leukemias and multiple myelomas) [100,101,102,103,104,105,106]. Attenuated vaccine strains of MeV can preferentially infect cancer cells expressing higher densities of CD46 molecules on their surface [107, 108]. Finally, PVRL4 is upregulated on the tumor surface of breast [109], lung [110], ovary [111] and colon [21]. During the process of tumorigenesis, expression of PVRL4 promotes the anchorage independence and cell-cell clustering in epithelial cells by engaging PVRL1 on juxtaposed cells [112]. Given the restricted PVRL4 distribution to most human body tissues compared to the ubiquitous CD46 expression and the presence of SLAM on activated lymphocytes and dendritic cells, PVRL4 is a promising tumor-associated marker for cancer therapy. MeV can successfully infect PVRL4-positive adenocarcinoma cells derived from lung, breast and colons tumors (Figure 4) [21].
Figure 4. PVRL4 expression in breast ((MD M.D. Anderson (MDA)-231 + PVRL4, MDA-468), lung (National Cancer Institute (NCI-H358)) and colon ((D.L. Dexter (DLD-1) carcinoma cells correlates with wtMeV infection [21]. Adenocarcinoma cells were infected with wtMeV-GFP (Ichinose-323 strain, Roberto Cattaneo, Mayo Clinic) at a multiplicity of infection (MOI) of 0.1, and virus replication was monitored by microscopy at 72 h post infection. Cell lines were monitored for PVRL4 expression by flow cytometry using specific rabbit polyclonal antibodies. PVRL4-positive cells were susceptible to wtMeV infection.
Figure 4. PVRL4 expression in breast ((MD M.D. Anderson (MDA)-231 + PVRL4, MDA-468), lung (National Cancer Institute (NCI-H358)) and colon ((D.L. Dexter (DLD-1) carcinoma cells correlates with wtMeV infection [21]. Adenocarcinoma cells were infected with wtMeV-GFP (Ichinose-323 strain, Roberto Cattaneo, Mayo Clinic) at a multiplicity of infection (MOI) of 0.1, and virus replication was monitored by microscopy at 72 h post infection. Cell lines were monitored for PVRL4 expression by flow cytometry using specific rabbit polyclonal antibodies. PVRL4-positive cells were susceptible to wtMeV infection.
Viruses 06 02268 g004

4.2. Enhancing MeV Oncolytic Activity and Anti-Tumor Immunity

Genetic engineering is widely used to enhance MeV oncolytic activity and selectively target tumors [88]. A recombinant MeV that was unable to use SLAM (SLAM blind) targeted PVRL4 on human breast cancer xenografts in immunodeficient mice and showed oncolytic activity [113]. In addition to targeting tumor markers, other strategies increase oncolytic activity by arming oncolytic viruses with therapeutic genes [114,115,116] or using vesicular stomatitis virus (VSV)/MeV hybrid viruses as an oncolytic platform [117]. This hybrid incorporates the powerful replication machinery of VSV and encodes both MeV H and F instead of the VSV-G attachment protein [118]. The VSV/MeV hybrid virus is capable of enhanced spread and a cytopathic effect in cancer cell lines compared to MeV alone [118]. Unfortunately, the tumor fighting ability of such hybrid viruses is restricted by the high sensitivity of VSV to the type I IFN response [119, 120]. However, preliminary studies indicate that recombinant viruses incorporating the PVRL4 binding properties of MeV H could be useful in targeting and destroying PVRL4 positive tumors.
A major concern with oncolytic virotherapy, however, is how to continue tumor regression once the virus is cleared from the host. Inducing anti-tumor immunity may be one strategy to continue ongoing tumor destruction once the virus has been cleared (Figure 5). Other oncolytic viruses, like VSV, can induce anti-tumor immunity in models expressing exogenous antigens [121]. Several studies have investigated the role of anti-tumor immunity after MeV virotherapy. For example, activated neutrophils were found to be important for tumor regression following MeV oncolytic therapy. Infection of human lymphoma xenografts in mice with MeV that expressed the granulocyte macrophage colony stimulating factor (GMCSF) recruited neutrophils to the tumor site, resulting in enhanced tumor regression [122]. In addition, Guillerme et al. [123] observed that MeV-infected melanoma cell lines are efficiently internalized by plasmacytoid DCs, leading to the presentation of tumor-associated antigens to CD8+ T-lymphocytes and sustained tumor regression. Although intravenous administration of oncolytic viruses is the preferred method of delivery, the likelihood that virus particles will encounter neutralizing antibodies is increased [124]. A number of strategies are being developed, such as receptor switching, the use of cell carriers or immunosuppressive drugs, to overcome this potential hurdle [125].
Finding the right balance between tumor destruction by MeV and eliciting host anti-tumor immunity will be key considerations in eradicating tumors using oncolytic measles virotherapy.
Figure 5. Oncolytic MeV induces both virus-mediated tumor cell lysis and immune cell recruitment to the tumor site. Intravenous (IV) delivery of oncolytic MeV crosses the endothelial cell layer and infects PVRL4 positive tumors. Infected cells (orange cells) are lysed and release tumor-associated antigens, which are recognized by immune cells, including dendritic cells (DC) and neutrophils. DCs present tumor peptides to T-cells (CD8+), which induces an anti-tumor immune response, leading to enhanced tumor cell killing (grey tumor cells) by the host immune system.
Figure 5. Oncolytic MeV induces both virus-mediated tumor cell lysis and immune cell recruitment to the tumor site. Intravenous (IV) delivery of oncolytic MeV crosses the endothelial cell layer and infects PVRL4 positive tumors. Infected cells (orange cells) are lysed and release tumor-associated antigens, which are recognized by immune cells, including dendritic cells (DC) and neutrophils. DCs present tumor peptides to T-cells (CD8+), which induces an anti-tumor immune response, leading to enhanced tumor cell killing (grey tumor cells) by the host immune system.
Viruses 06 02268 g005

5. Conclusions

Identification of PVRL4 as an epithelial cell receptor for MeV, CDV and PPRV is a major advance in the morbillivirus field. Indeed, this discovery provides a better understanding of morbillivirus pathogenicity and establishes a new paradigm for the spread of virus from lymphocytes to airway epithelial cells and virus shedding into the lumen of the lungs. Identification of inhibitors that block membrane fusion and entry by measles virus have been previously reported in the literature. However, the identification of important amino acid residues within the V domain structures of SLAM and PVRL4 could lead to the development of prophylactic antiviral agents that block virus attachment during the early (lymphocyte) and late (epithelial cell) stages of infections. Finally, many adenocarcinomas express PVRL4 on their cell surfaces, making them obvious targets for oncolytic and immune therapy based upon recombinant morbilliviruses.

Acknowledgments

This work was supported by grants from the Canadian Institute for Health Research, the Nova Scotia Health Research Foundation and the Canadian Breast Cancer Foundation-Atlantic Region. Christopher D. Richardson is a Canada Research Chair (Tier I) in Vaccinology and Viral Therapeutics and received an equipment grant from the Canadian Foundation for Innovation. Ryan S. Noyce was supported by a CIHR (Canadian Institutes of Health Research) Banting Postdoctoral Fellowship.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. McChesney, M.B.; Miller, C.J.; Rota, P.A.; Zhu, Y.D.; Antipa, L.; Lerche, N.W.; Ahmed, R.; Bellini, W.J. Experimental measles. I. Pathogenesis in the normal and the immunized host. Virology 1997, 233, 74–84. [Google Scholar] [CrossRef]
  2. Appel, M.J. Distemper pathogenesis in dogs. J. Am. Vet. Med. Assoc. 1970, 156, 1681–1684. [Google Scholar]
  3. Barrett, T. Morbillivirus infections, with special emphasis on morbilliviruses of carnivores. Vet. Microbiol. 1999, 69, 3–13. [Google Scholar] [CrossRef]
  4. Deem, S.L.; Spelman, L.H.; Yates, R.A.; Montali, R.J. Canine distemper in terrestrial carnivores: A review. J. Zoo Wildl. Med. 2000, 31, 441–451. [Google Scholar]
  5. Banyard, A.C.; Parida, S.; Batten, C.; Oura, C.; Kwiatek, O.; Libeau, G. Global distribution of peste des petits ruminants virus and prospects for improved diagnosis and control. J. Gen. Virol. 2010, 91, 2885–2897. [Google Scholar] [CrossRef] [Green Version]
  6. Griffin, D.E.; Knipe, D.M.; Lamb, R.A.; Martin, M.A.; Roizman, B.; Straus, S.E. Measles Virus. In fields Virology, 5th ed.; Lippincott Williams & Wilkins: Philadelphia, PA, USA, 2007; pp. 1551–1586. [Google Scholar]
  7. Beineke, A.; Puff, C.; Seehusen, F.; Baumgartner, W. Pathogenesis and immunopathology of systemic and nervous canine distemper. Vet. Immunol. Immunopathol. 2009, 127, 1–18. [Google Scholar] [CrossRef]
  8. De Vries, R.D.; Mesman, A.W.; Geijtenbeek, T.B.; Duprex, W.P.; de Swart, R.L. The pathogenesis of measles. Curr. Opin. Virol. 2012, 2, 248–255. [Google Scholar] [CrossRef]
  9. Avota, E.; Gassert, E.; Schneider-Schaulies, S. Measles virus-induced immunosuppression: From effectors to mechanisms. Med. Microbiol. Immunol. 2010, 199, 227–237. [Google Scholar] [CrossRef]
  10. Beckford, A.P.; Kaschula, R.O.; Stephen, C. Factors associated with fatal cases of measles. A retrospective autopsy study. S Afr. Med. J. 1985, 68, 858–863. [Google Scholar]
  11. Cosby, S.L.; Duprex, W.P.; Hamill, L.A.; Ludlow, M.; McQuaid, S. Approaches in the understanding of morbillivirus neurovirulence. J. Neurovirol. 2002, 8 (Suppl. 2), 85–90. [Google Scholar] [CrossRef]
  12. Wichmann, O.; Siedler, A.; Sagebiel, D.; Hellenbrand, W.; Santibanez, S.; Mankertz, A.; Vogt, G.; Treeck, U.; Krause, G. Further efforts needed to achieve measles elimination in Germany: results of an outbreak investigation. Bull. World Health Organ. 2009, 87, 108–115. [Google Scholar] [CrossRef]
  13. Carabin, H.; Edmunds, W.J.; Kou, U.; van den Hof, S.; Nguyen, V.H. The average cost of measles cases and adverse events following vaccination in industrialised countries. BMC Public Health 2002, 2. [Google Scholar] [CrossRef] [Green Version]
  14. Filia, A.; Tavilla, A.; Bella, A.; Magurano, F.; Ansaldi, F.; Chironna, M.; Nicoletti, L.; Palu, G.; Iannazzo, S.; Declich, S.; et al. Measles in Italy, July 2009 to September 2010. Euro. Surveill. 2011, 16, pii: 19925. [Google Scholar]
  15. Abubakar, M.; Munir, M. Peste des Petits Ruminants Virus: An Emerging Threat to Goat Farming in Pakistan. Transbound. Emerg. Dis. 2014. [Google Scholar] [CrossRef]
  16. Libeau, G.; Diallo, A.; Parida, S. Evolutionary genetics underlying the spread of peste des petits ruminants virus. Animal Frontiers 2014, 4, 14–20. [Google Scholar] [CrossRef] [Green Version]
  17. Ortega-Sanchez, I.R.; Vijayaraghavan, M.; Barskey, A.E.; Wallace, G.S. The economic burden of sixteen measles outbreaks on United States public health departments in 2011. Vaccine 2014, 32, 1311–1317. [Google Scholar] [CrossRef]
  18. Noyce, R.S.; Delpeut, S.; Richardson, C.D. Dog nectin-4 is an epithelial cell receptor for canine distemper virus that facilitates virus entry and syncytia formation. Virology 2013, 436, 210–220. [Google Scholar]
  19. Birch, J.; Juleff, N.; Heaton, M.P.; Kalbfleisch, T.; Kijas, J.; Bailey, D. Characterization of ovine Nectin-4, a novel peste des petits ruminants virus receptor. J. Virol. 2013, 87, 4756–4761. [Google Scholar]
  20. Pratakpiriya, W.; Seki, F.; Otsuki, N.; Sakai, K.; Fukuhara, H.; Katamoto, H.; Hirai, T.; Maenaka, K.; Techangamsuwan, S.; Lan, N.T.; et al. Nectin4 is an epithelial cell receptor for canine distemper virus and involved in neurovirulence. J. Virol. 2012, 86, 10207–10210. [Google Scholar] [CrossRef]
  21. Noyce, R.S.; Bondre, D.G.; Ha, M.N.; Lin, L.T.; Sisson, G.; Tsao, M.S.; Richardson, C.D. Tumor cell marker PVRL4 (nectin 4) is an epithelial cell receptor for measles virus. PLoS Pathog. 2011, 7, e1002240. [Google Scholar] [CrossRef]
  22. Muhlebach, M.D.; Mateo, M.; Sinn, P.L.; Prufer, S.; Uhlig, K.M.; Leonard, V.H.; Navaratnarajah, C.K.; Frenzke, M.; Wong, X.X.; Sawatsky, B.; et al. Adherens junction protein nectin-4 is the epithelial receptor for measles virus. Nature 2011, 480, 530–533. [Google Scholar]
  23. Tatsuo, H.; Ono, N.; Yanagi, Y. Morbilliviruses use signaling lymphocyte activation molecules (CD150) as cellular receptors. J. Virol. 2001, 75, 5842–5850. [Google Scholar] [CrossRef]
  24. Hsu, E.C.; Iorio, C.; Sarangi, F.; Khine, A.A.; Richardson, C.D. CDw150(SLAM) is a receptor for a lymphotropic strain of measles virus and may account for the immunosuppressive properties of this virus. Virology 2001, 279, 9–21. [Google Scholar] [CrossRef]
  25. Tatsuo, H.; Ono, N.; Tanaka, K.; Yanagi, Y. SLAM (CDw150) is a cellular receptor for measles virus. Nature 2000, 406, 893–897. [Google Scholar] [CrossRef]
  26. Dorig, R.E.; Marcil, A.; Chopra, A.; Richardson, C.D. The human CD46 molecule is a receptor for measles virus (Edmonston strain). Cell 1993, 75, 295–305. [Google Scholar] [CrossRef]
  27. Naniche, D.; Varior-Krishnan, G.; Cervoni, F.; Wild, T.F.; Rossi, B.; Rabourdin-Combe, C.; Gerlier, D. Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus. J. Virol. 1993, 67, 6025–6032. [Google Scholar]
  28. Baker, K.A.; Dutch, R.E.; Lamb, R.A.; Jardetzky, T.S. Structural basis for paramyxovirus-mediated membrane fusion. Mol. Cell 1999, 3, 309–319. [Google Scholar] [CrossRef]
  29. Colman, P.M.; Lawrence, M.C. The structural biology of type I viral membrane fusion. Nat. Rev. Mol. Cell. Biol. 2003, 4, 309–319. [Google Scholar] [CrossRef]
  30. Hernandez, L.D.; Hoffman, L.R.; Wolfsberg, T.G.; White, J.M. Virus-cell and cell-cell fusion. Annu Rev. Cell Dev. Biol. 1996, 12, 627–661. [Google Scholar] [CrossRef]
  31. Takimoto, T.; Taylor, G.L.; Connaris, H.C.; Crennell, S.J.; Portner, A. Role of the hemagglutinin-neuraminidase protein in the mechanism of paramyxovirus-cell membrane fusion. J. Virol. 2002, 76, 13028–13033. [Google Scholar] [CrossRef]
  32. Cocks, B.G.; Chang, C.C.; Carballido, J.M.; Yssel, H.; de Vries, J.E.; Aversa, G. A novel receptor involved in T-cell activation. Nature 1995, 376, 260–263. [Google Scholar] [CrossRef]
  33. Sidorenko, S.P.; Clark, E.A. Characterization of a cell surface glycoprotein IPO-3, expressed on activated human B and T lymphocytes. J. Immunol 1993, 151, 4614–4624. [Google Scholar]
  34. Von Messling, V.; Milosevic, D.; Cattaneo, R. Tropism illuminated: lymphocyte-based pathways blazed by lethal morbillivirus through the host immune system. Proc. Natl Acad Sci USA 2004, 101, 14216–14221. [Google Scholar] [CrossRef]
  35. Lemon, K.; de Vries, R.D.; Mesman, A.W.; McQuaid, S.; van Amerongen, G.; Yuksel, S.; Ludlow, M.; Rennick, L.J.; Kuiken, T.; Rima, B.K.; et al. Early target cells of measles virus after aerosol infection of non-human primates. PLoS Pathog. 2011, 7, e1001263. [Google Scholar] [CrossRef]
  36. De Swart, R.L.; Ludlow, M.; de Witte, L.; Yanagi, Y.; van Amerongen, G.; McQuaid, S.; Yuksel, S.; Geijtenbeek, T.B.; Duprex, W.P.; Osterhaus, A.D. Predominant infection of CD150+ lymphocytes and dendritic cells during measles virus infection of macaques. PLoS Pathog. 2007, 3, e178. [Google Scholar] [CrossRef]
  37. Sawatsky, B.; Wong, X.X.; Hinkelmann, S.; Cattaneo, R.; von Messling, V. Canine distemper virus epithelial cell infection is required for clinical disease but not for immunosuppression. J. Virol. 2012, 86, 3658–3666. [Google Scholar] [CrossRef]
  38. Fischer, C.D.; Ikuta, N.; Canal, C.W.; Makiejczuk, A.; Allgayer Mda, C.; Cardoso, C.H.; Lehmann, F.K.; Fonseca, A.S.; Lunge, V.R. Detection and differentiation of field and vaccine strains of canine distemper virus using reverse transcription followed by nested real time PCR (RT-nqPCR) and RFLP analysis. J. Virol. Methods 2013, 194, 39–45. [Google Scholar] [CrossRef]
  39. Kim, D.; Jeoung, S.Y.; Ahn, S.J.; Lee, J.H.; Pak, S.I.; Kwon, H.M. Comparison of tissue and fluid samples for the early detection of canine distemper virus in experimentally infected dogs. J. Vet. Med. Sci. 2006, 68, 877–879. [Google Scholar] [CrossRef]
  40. Liu, W.; Wu, X.; Wang, Z.; Bao, J.; Li, L.; Zhao, Y.; Li, J. Virus excretion and antibody dynamics in goats inoculated with a field isolate of peste des petits ruminants virus. Transbound. Emerg. Dis. 2013, 60 (Suppl. 2), 63–68. [Google Scholar]
  41. Rota, P.A.; Khan, A.S.; Durigon, E.; Yuran, T.; Villamarzo, Y.S.; Bellini, W.J. Detection of measles virus RNA in urine specimens from vaccine recipients. J. Clin. Microbiol. 1995, 33, 2485–2488. [Google Scholar]
  42. Saito, T.B.; Alfieri, A.A.; Wosiacki, S.R.; Negrao, F.J.; Morais, H.S.; Alfieri, A.F. Detection of canine distemper virus by reverse transcriptase-polymerase chain reaction in the urine of dogs with clinical signs of distemper encephalitis. Res. Vet. Sci. 2006, 80, 116–119. [Google Scholar] [CrossRef]
  43. Scheifele, D.W.; Forbes, C.E. Prolonged giant cell excretion in severe African measles. Pediatrics 1972, 50, 867–873. [Google Scholar]
  44. Cleaveland, S.; Appel, M.G.; Chalmers, W.S.; Chillingworth, C.; Kaare, M.; Dye, C. Serological and demographic evidence for domestic dogs as a source of canine distemper virus infection for Serengeti wildlife. Vet. Microbiol. 2000, 72, 217–227. [Google Scholar] [CrossRef]
  45. Qiu, W.; Zheng, Y.; Zhang, S.; Fan, Q.; Liu, H.; Zhang, F.; Wang, W.; Liao, G.; Hu, R. Canine distemper outbreak in rhesus monkeys, China. Emerg. Infect. Dis. 2011, 17, 1541–1543. [Google Scholar]
  46. Sun, Z.; Li, A.; Ye, H.; Shi, Y.; Hu, Z.; Zeng, L. Natural infection with canine distemper virus in hand-feeding Rhesus monkeys in China. Vet. Microbiol. 2010, 141, 374–378. [Google Scholar] [CrossRef]
  47. Yoshikawa, Y.; Ochikubo, F.; Matsubara, Y.; Tsuruoka, H.; Ishii, M.; Shirota, K.; Nomura, Y.; Sugiyama, M.; Yamanouchi, K. Natural infection with canine distemper virus in a Japanese monkey (Macaca fuscata). Vet. Microbiol. 1989, 20, 193–205. [Google Scholar] [CrossRef]
  48. Schneider-Schaulies, J. Cellular receptors for viruses: links to tropism and pathogenesis. J. Gen. Virol. 2000, 81, 1413–1429. [Google Scholar]
  49. Uhlen, M.; Oksvold, P.; Fagerberg, L.; Lundberg, E.; Jonasson, K.; Forsberg, M.; Zwahlen, M.; Kampf, C.; Wester, K.; Hober, S.; Wernerus, H.; Bjorling, L.; Ponten, F. Towards a knowledge-based Human Protein Atlas. Nat. Biotechnol. 2010, 28, pp. 1248–1250. Available online: http://www.proteinatlas.org (accessed on 12 May 2013).
  50. Tahara, M.; Takeda, M.; Shirogane, Y.; Hashiguchi, T.; Ohno, S.; Yanagi, Y. Measles virus infects both polarized epithelial and immune cells by using distinctive receptor-binding sites on its hemagglutinin. J. Virol 2008, 82, 4630–4637. [Google Scholar] [CrossRef]
  51. Ludlow, M.; Rennick, L.J.; Sarlang, S.; Skibinski, G.; McQuaid, S.; Moore, T.; de Swart, R.L.; Duprex, W.P. Wild-type measles virus infection of primary epithelial cells occurs via the basolateral surface without syncytium formation or release of infectious virus. J. Gen. Virol. 2010, 91, 971–979. [Google Scholar] [CrossRef]
  52. Leonard, V.H.; Sinn, P.L.; Hodge, G.; Miest, T.; Devaux, P.; Oezguen, N.; Braun, W.; McCray, P.B., Jr.; McChesney, M.B.; Cattaneo, R. Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed. J. Clin. Invest. 2008, 118, 2448–2458. [Google Scholar]
  53. Sinn, P.L.; Williams, G.; Vongpunsawad, S.; Cattaneo, R.; McCray, P.B., Jr. Measles virus preferentially transduces the basolateral surface of well-differentiated human airway epithelia. J. Virol. 2002, 76, 2403–2409. [Google Scholar] [CrossRef]
  54. Ludlow, M.; Lemon, K.; de Vries, R.D.; McQuaid, S.; Millar, E.L.; van Amerongen, G.; Yuksel, S.; Verburgh, R.J.; Osterhaus, A.D.; de Swart, R.L.; et al. Measles virus infection of epithelial cells in the macaque upper respiratory tract is mediated by subepithelial immune cells. J. Virol. 2013, 87, 4033–4042. [Google Scholar] [CrossRef]
  55. Frenzke, M.; Sawatsky, B.; Wong, X.X.; Delpeut, S.; Mateo, M.; Cattaneo, R.; von Messling, V. Nectin-4-dependent measles virus spread to the cynomolgus monkey tracheal epithelium: Role of infected immune cells infiltrating the lamina propria. J. Virol. 2013, 87, 2526–2534. [Google Scholar] [CrossRef]
  56. Ludlow, M.; de Vries, R.D.; Lemon, K.; McQuaid, S.; Millar, E.; van Amerongen, G.; Yuksel, S.; Verburgh, R.J.; Osterhaus, A.D.; de Swart, R.L.; et al. Infection of lymphoid tissues in the macaque upper respiratory tract contributes to the emergence of transmissible measles virus. J. Gen. Virol. 2013, 94, 1933–1944. [Google Scholar] [CrossRef]
  57. Blau, D.M.; Compans, R.W. Entry and release of measles virus are polarized in epithelial cells. Virology 1995, 210, 91–99. [Google Scholar] [CrossRef]
  58. Blau, D.M.; Compans, R.W. Adaptation of measles virus to polarized epithelial cells: Alterations in virus entry and release. Virology 1997, 231, 281–289. [Google Scholar] [CrossRef]
  59. Maisner, A.; Klenk, H.; Herrler, G. Polarized budding of measles virus is not determined by viral surface glycoproteins. J. Virol. 1998, 72, 5276–5278. [Google Scholar]
  60. Naim, H.Y.; Ehler, E.; Billeter, M.A. Measles virus matrix protein specifies apical virus release and glycoprotein sorting in epithelial cells. Embo J. 2000, 19, 3576–3585. [Google Scholar] [CrossRef]
  61. Couacy-Hymann, E.; Bodjo, C.; Danho, T.; Libeau, G.; Diallo, A. Evaluation of the virulence of some strains of peste-des-petits-ruminants virus (PPRV) in experimentally infected West African dwarf goats. Vet. J. 2007, 173, 178–183. [Google Scholar] [CrossRef]
  62. Hammouchi, M.; Loutfi, C.; Sebbar, G.; Touil, N.; Chaffai, N.; Batten, C.; Harif, B.; Oura, C.; El Harrak, M. Experimental infection of alpine goats with a Moroccan strain of peste des petits ruminants virus (PPRV). Vet. Microbiol. 2012, 160, 240–244. [Google Scholar] [CrossRef]
  63. Ward, S.V.; George, C.X.; Welch, M.J.; Liou, L.Y.; Hahm, B.; Lewicki, H.; de la Torre, J.C.; Samuel, C.E.; Oldstone, M.B. RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis. Proc. Natl. Acad. Sci. USA 2011, 108, 331–336. [Google Scholar] [CrossRef]
  64. Kurita, S.; Ogita, H.; Takai, Y. Cooperative role of nectin-nectin and nectin-afadin interactions in formation of nectin-based cell-cell adhesion. J. Biol. Chem. 2011, 286, 36297–3303. [Google Scholar] [CrossRef]
  65. Takai, Y.; Miyoshi, J.; Ikeda, W.; Ogita, H. Nectins and nectin-like molecules: Roles in contact inhibition of cell movement and proliferation. Nat. Rev. Mol. Cell Biol. 2008, 9, 603–615. [Google Scholar] [CrossRef]
  66. Takai, Y.; Ikeda, W.; Ogita, H.; Rikitake, Y. The immunoglobulin-like cell adhesion molecule nectin and its associated protein afadin. Annu. Rev. Cell Dev. Biol. 2008, 24, 309–342. [Google Scholar] [CrossRef]
  67. Mendelsohn, C.L.; Wimmer, E.; Racaniello, V.R. Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell 1989, 56, 855–865. [Google Scholar] [CrossRef]
  68. Campadelli-Fiume, G.; Cocchi, F.; Menotti, L.; Lopez, M. The novel receptors that mediate the entry of herpes simplex viruses and animal alphaherpesviruses into cells. Rev. Med. Virol. 2000, 10, 305–319. [Google Scholar] [CrossRef]
  69. Fabre, S.; Reymond, N.; Cocchi, F.; Menotti, L.; Dubreuil, P.; Campadelli-Fiume, G.; Lopez, M. Prominent role of the Ig-like V domain in trans-interactions of nectins. Nectin3 and nectin 4 bind to the predicted C-C’-C”-D beta-strands of the nectin1 V domain. J. Biol. Chem. 2002, 277, 27006–27013. [Google Scholar]
  70. Satoh-Horikawa, K.; Nakanishi, H.; Takahashi, K.; Miyahara, M.; Nishimura, M.; Tachibana, K.; Mizoguchi, A.; Takai, Y. Nectin-3, a new member of immunoglobulin-like cell adhesion molecules that shows homophilic and heterophilic cell-cell adhesion activities. J. Biol. Chem. 2000, 275, 10291–10299. [Google Scholar] [CrossRef]
  71. Reymond, N.; Fabre, S.; Lecocq, E.; Adelaide, J.; Dubreuil, P.; Lopez, M. Nectin4/PRR4, a new afadin-associated member of the nectin family that trans-interacts with nectin1/PRR1 through V domain interaction. J. Biol. Chem. 2001, 276, 43205–43215. [Google Scholar]
  72. Yasumi, M.; Shimizu, K.; Honda, T.; Takeuchi, M.; Takai, Y. Role of each immunoglobulin-like loop of nectin for its cell-cell adhesion activity. Biochem. Biophys. Res. Commun. 2003, 302, 61–66. [Google Scholar] [CrossRef]
  73. Mizoguchi, A.; Nakanishi, H.; Kimura, K.; Matsubara, K.; Ozaki-Kuroda, K.; Katata, T.; Honda, T.; Kiyohara, Y.; Heo, K.; Higashi, M.; et al. Nectin: An adhesion molecule involved in formation of synapses. J. Cell Biol. 2002, 156, 555–565. [Google Scholar] [CrossRef]
  74. Ono, N.; Tatsuo, H.; Tanaka, K.; Minagawa, H.; Yanagi, Y. V domain of human SLAM (CDw150) is essential for its function as a measles virus receptor. J. Virol. 2001, 75, 1594–1600. [Google Scholar] [CrossRef]
  75. Delpeut, S.; Noyce, R.S.; Richardson, C.D. The V domain of dog PVRL4 (nectin-4) mediates canine distemper virus entry and virus cell-to-cell spread. Virology 2014, 454–455, 109–117. [Google Scholar] [CrossRef]
  76. Zhang, X.; Lu, G.; Qi, J.; Li, Y.; He, Y.; Xu, X.; Shi, J.; Zhang, C.W.; Yan, J.; Gao, G.F. Structure of measles virus hemagglutinin bound to its epithelial receptor nectin-4. Nat. Struct. Mol. Biol. 2013, 20, 67–72. [Google Scholar]
  77. Harrison, O.J.; Vendome, J.; Brasch, J.; Jin, X.; Hong, S.; Katsamba, P.S.; Ahlsen, G.; Troyanovsky, R.B.; Troyanovsky, S.M.; Honig, B.; et al. Nectin ectodomain structures reveal a canonical adhesive interface. Nat. Struct. Mol. Biol. 2012, 19, 906–915. [Google Scholar]
  78. Drumond, A.; Ashton, B.; Buxton, S.; Cheung, M.; Heled, J.; Kearse, M.; Moir, R.; Stones-Havas, S.; Sturrock, S.; Thierer, T.; Wilson, A. Geneious v5.0. Available online: http://www.geneious.com (accessed on 1 March 2014).
  79. Bieringer, M.; Han, J.W.; Kendl, S.; Khosravi, M.; Plattet, P.; Schneider-Schaulies, J. Experimental adaptation of wild-type canine distemper virus (CDV) to the human entry receptor CD150. PLoS One 2013, 8, e57488. [Google Scholar]
  80. Sakai, K.; Yoshikawa, T.; Seki, F.; Fukushi, S.; Tahara, M.; Nagata, N.; Ami, Y.; Mizutani, T.; Kurane, I.; Yamaguchi, R.; et al. Canine distemper virus associated with a lethal outbreak in monkeys can readily adapt to use human receptors. J. Virol. 2013, 87, 7170–7175. [Google Scholar] [CrossRef]
  81. Otsuki, N.; Sekizuka, T.; Seki, F.; Sakai, K.; Kubota, T.; Nakatsu, Y.; Chen, S.; Fukuhara, H.; Maenaka, K.; Yamaguchi, R.; et al. Canine distemper virus with the intact C protein has the potential to replicate in human epithelial cells by using human nectin4 as a receptor. Virology 2013, 435, 485–492. [Google Scholar] [CrossRef]
  82. De Vries, R.D.; Ludlow, M.; Verburgh, R.J.; van Amerongen, G.; Yuksel, S.; Nguyen, D.T.; McQuaid, S.; Osterhaus, A.D.; Duprex, W.P.; de Swart, R.L. Measles Vaccination of Non-Human Primates Provides Partial Protection against Infection with Canine Distemper Virus. J. Virol. 2014, 88, 4423–4433. [Google Scholar] [CrossRef]
  83. Beauverger, P.; Buckland, R.; Wild, T.F. Measles virus antigens induce both type-specific and canine distemper virus cross-reactive cytotoxic T lymphocytes in mice: localization of a common Ld-restricted nucleoprotein epitope. J. Gen. Virol. 1993, 74, 2357–2363. [Google Scholar] [CrossRef]
  84. Beauverger, P.; Chadwick, J.; Buckland, R.; Wild, T.F. Serotype-specific and canine distemper virus cross-reactive H-2Kk-restricted cytotoxic T lymphocyte epitopes in the measles virus nucleoprotein. Virology 1994, 203, 172–177. [Google Scholar] [CrossRef]
  85. Stephenson, J.R.; Ter Meulen, V. Antigenic relationships between measles and canine distemper viruses: Comparison of immune response in animals and humans to individual virus-specific polypeptides. Proc. Natl. Acad. Sci. USA 1979, 76, 6601–6605. [Google Scholar] [CrossRef]
  86. Knuchel, M.C.; Marty, R.R.; Morin, T.N.; Ilter, O.; Zuniga, A.; Naim, H.Y. Relevance of a pre-existing measles immunity prior immunization with a recombinant measles virus vector. Hum. Vaccin. Immunother. 2013, 9, 23241. [Google Scholar]
  87. Lorin, C.; Mollet, L.; Delebecque, F.; Combredet, C.; Hurtrel, B.; Charneau, P.; Brahic, M.; Tangy, F. A single injection of recombinant measles virus vaccines expressing human immunodeficiency virus (HIV) type 1 clade B envelope glycoproteins induces neutralizing antibodies and cellular immune responses to HIV. J. Virol. 2004, 78, 146–157. [Google Scholar] [CrossRef]
  88. Msaouel, P.; Opyrchal, M.; Domingo Musibay, E.; Galanis, E. Oncolytic measles virus strains as novel anticancer agents. Expert Opin. Biol. Ther. 2013, 13, 483–502. [Google Scholar] [CrossRef]
  89. Rager-Zisman, B.; Bazarsky, E.; Skibin, A.; Chamney, S.; Belmaker, I.; Shai, I.; Kordysh, E.; Griffin, D.E. The effect of measles-mumps-rubella (MMR) immunization on the immune responses of previously immunized primary school children. Vaccine 2003, 21, 2580–2588. [Google Scholar] [CrossRef]
  90. Singh, M.; Cattaneo, R.; Billeter, M.A. A recombinant measles virus expressing hepatitis B virus surface antigen induces humoral immune responses in genetically modified mice. J. Virol. 1999, 73, 4823–4828. [Google Scholar]
  91. Wong-Chew, R.M.; Beeler, J.A.; Audet, S.; Santos, J.I. Cellular and humoral immune responses to measles in immune adults re-immunized with measles vaccine. J. Med. Virol. 2003, 70, 276–280. [Google Scholar] [CrossRef]
  92. Nakamura, T.; Russell, S.J. Oncolytic measles viruses for cancer therapy. Expert Opin. Biol. Ther 2004, 4, 1685–1692. [Google Scholar] [CrossRef]
  93. Bazan-Peregrino, M.; Sainson, R.C.; Carlisle, R.C.; Thoma, C.; Waters, R.A.; Arvanitis, C.; Harris, A.L.; Hernandez-Alcoceba, R.; Seymour, L.W. Combining virotherapy and angiotherapy for the treatment of breast cancer. Cancer Gene Ther. 2013, 20, 461–468. [Google Scholar]
  94. Bluming, A.Z.; Ziegler, J.L. Regression of Burkitt's lymphoma in association with measles infection. Lancet 1971, 2, 105–106. [Google Scholar] [CrossRef]
  95. Taqi, A.M.; Abdurrahman, M.B.; Yakubu, A.M.; Fleming, A.F. Regression of Hodgkin’s disease after measles. Lancet 1981, 1. [Google Scholar] [CrossRef]
  96. Nagy, N.; Cerboni, C.; Mattsson, K.; Maeda, A.; Gogolak, P.; Sumegi, J.; Lanyi, A.; Szekely, L.; Carbone, E.; Klein, G.; et al. SH2D1A and SLAM protein expression in human lymphocytes and derived cell lines. Int. J. Cancer 2000, 88, 439–447. [Google Scholar] [CrossRef]
  97. Parrula, C.; Fernandez, S.A.; Zimmerman, B.; Lairmore, M.; Niewiesk, S. Measles virotherapy in a mouse model of adult T-cell leukaemia/lymphoma. J. Gen. Virol. 2011, 92, 1458–1466. [Google Scholar] [CrossRef]
  98. Grote, D.; Russell, S.J.; Cornu, T.I.; Cattaneo, R.; Vile, R.; Poland, G.A.; Fielding, A.K. Live attenuated measles virus induces regression of human lymphoma xenografts in immunodeficient mice. Blood 2001, 97, 3746–3754. [Google Scholar] [CrossRef]
  99. Seya, T.; Taniguchi, M.; Matsumoto, M. [Membrane cofactor protein (MCP, CD46)]. Nihon Rinsho 1999, 57, 75–78. [Google Scholar]
  100. Ong, H.T.; Timm, M.M.; Greipp, P.R.; Witzig, T.E.; Dispenzieri, A.; Russell, S.J.; Peng, K.W. Oncolytic measles virus targets high CD46 expression on multiple myeloma cells. Exp. Hematol. 2006, 34, 713–720. [Google Scholar] [CrossRef]
  101. Bjorge, L.; Hakulinen, J.; Wahlstrom, T.; Matre, R.; Meri, S. Complement-regulatory proteins in ovarian malignancies. Int. J. Cancer 1997, 70, 14–25. [Google Scholar] [CrossRef]
  102. Varsano, S.; Rashkovsky, L.; Shapiro, H.; Radnay, J. Cytokines modulate expression of cell-membrane complement inhibitory proteins in human lung cancer cell lines. Am. J. Respir. Cell Mol. Biol. 1998, 19, 522–529. [Google Scholar] [CrossRef]
  103. Blok, V.T.; Daha, M.R.; Tijsma, O.M.; Weissglas, M.G.; van den Broek, L.J.; Gorter, A. A possible role of CD46 for the protection in vivo of human renal tumor cells from complement-mediated damage. Lab. Invest. 2000, 80, 335–344. [Google Scholar]
  104. Simpson, K.L.; Jones, A.; Norman, S.; Holmes, C.H. Expression of the complement regulatory proteins decay accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46) and CD59 in the normal human uterine cervix and in premalignant and malignant cervical disease. Am. J. Pathol. 1997, 151, 1455–1467. [Google Scholar]
  105. Kinugasa, N.; Higashi, T.; Nouso, K.; Nakatsukasa, H.; Kobayashi, Y.; Ishizaki, M.; Toshikuni, N.; Yoshida, K.; Uematsu, S.; Tsuji, T. Expression of membrane cofactor protein (MCP, CD46) in human liver diseases. Br. J. Cancer 1999, 80, 1820–1825. [Google Scholar] [CrossRef]
  106. Juhl, H.; Helmig, F.; Baltzer, K.; Kalthoff, H.; Henne-Bruns, D.; Kremer, B. Frequent expression of complement resistance factors CD46, CD55, and CD59 on gastrointestinal cancer cells limits the therapeutic potential of monoclonal antibody 17–1A. J. Surg. Oncol. 1997, 64, 222–230. [Google Scholar] [CrossRef]
  107. Anderson, B.D.; Nakamura, T.; Russell, S.J.; Peng, K.W. High CD46 receptor density determines preferential killing of tumor cells by oncolytic measles virus. Cancer Res. 2004, 64, 4919–4926. [Google Scholar] [CrossRef]
  108. Peng, K.W.; TenEyck, C.J.; Galanis, E.; Kalli, K.R.; Hartmann, L.C.; Russell, S.J. Intraperitoneal therapy of ovarian cancer using an engineered measles virus. Cancer Res. 2002, 62, 4656–4662. [Google Scholar]
  109. Fabre-Lafay, S.; Garrido-Urbani, S.; Reymond, N.; Goncalves, A.; Dubreuil, P.; Lopez, M. Nectin-4, a new serological breast cancer marker, is a substrate for tumor necrosis factor-alpha-converting enzyme (TACE)/ADAM-17. J. Biol. Chem. 2005, 280, 19543–19550. [Google Scholar]
  110. Takano, A.; Ishikawa, N.; Nishino, R.; Masuda, K.; Yasui, W.; Inai, K.; Nishimura, H.; Ito, H.; Nakayama, H.; Miyagi, Y.; et al. Identification of nectin-4 oncoprotein as a diagnostic and therapeutic target for lung cancer. Cancer Res. 2009, 69, 6694–6703. [Google Scholar] [CrossRef]
  111. Derycke, M.S.; Pambuccian, S.E.; Gilks, C.B.; Kalloger, S.E.; Ghidouche, A.; Lopez, M.; Bliss, R.L.; Geller, M.A.; Argenta, P.A.; Harrington, K.M.; et al. Nectin 4 overexpression in ovarian cancer tissues and serum: Potential role as a serum biomarker. Am. J. Clin Pathol 2011, 134, 835–845. [Google Scholar]
  112. Pavlova, N.N.; Pallasch, C.; Elia, A.E.; Braun, C.J.; Westbrook, T.F.; Hemann, M.; Elledge, S.J. A role for PVRL4-driven cell-cell interactions in tumorigenesis. Elife 2013, 2, e00358. [Google Scholar] [CrossRef]
  113. Sugiyama, T.; Yoneda, M.; Kuraishi, T.; Hattori, S.; Inoue, Y.; Sato, H.; Kai, C. Measles virus selectively blind to signaling lymphocyte activation molecule as a novel oncolytic virus for breast cancer treatment. Gene Ther. 2013, 20, 338–347. [Google Scholar] [CrossRef]
  114. Cao, L.; Si, J.; Wang, W.; Zhao, X.; Yuan, X.; Zhu, H.; Wu, X.; Zhu, J.; Shen, G. Intracellular localization and sustained prodrug cell killing activity of TAT-HSVTK fusion protein in hepatocelullar carcinoma cells. Mol. Cells 2006, 21, 104–111. [Google Scholar]
  115. Fillat, C.; Carrio, M.; Cascante, A.; Sangro, B. Suicide gene therapy mediated by the Herpes Simplex virus thymidine kinase gene/Ganciclovir system: fifteen years of application. Curr. Gene Ther. 2003, 3, 13–26. [Google Scholar]
  116. Hermiston, T.W.; Kuhn, I. Armed therapeutic viruses: strategies and challenges to arming oncolytic viruses with therapeutic genes. Cancer Gene Ther. 2002, 9, 1022–1035. [Google Scholar] [CrossRef]
  117. Hastie, E.; Grdzelishvili, V.Z. Vesicular stomatitis virus as a flexible platform for oncolytic virotherapy against cancer. J. Gen. Virol. 2012, 93, 2529–2545. [Google Scholar] [CrossRef]
  118. Liu, Y.P.; Russell, S.P.; Ayala-Breton, C.; Russell, S.J.; Peng, K.W. Ablation of Nectin4 Binding Compromises CD46 Usage by a Hybrid Vesicular Stomatitis Virus/Measles Virus. J. Virol. 2014, 88, 2195–2204. [Google Scholar] [CrossRef]
  119. Naik, S.; Russell, S.J. Engineering oncolytic viruses to exploit tumor specific defects in innate immune signaling pathways. Expert Opin. Biol. Ther. 2009, 9, 1163–1176. [Google Scholar] [CrossRef]
  120. Stojdl, D.F.; Lichty, B.; Knowles, S.; Marius, R.; Atkins, H.; Sonenberg, N.; Bell, J.C. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat. Med. 2000, 6, 821–825. [Google Scholar] [CrossRef]
  121. Diaz, R.M.; Galivo, F.; Kottke, T.; Wongthida, P.; Qiao, J.; Thompson, J.; Valdes, M.; Barber, G.; Vile, R.G. Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus. Cancer Res. 2007, 67, 2840–2848. [Google Scholar]
  122. Grote, D.; Cattaneo, R.; Fielding, A.K. Neutrophils contribute to the measles virus-induced antitumor effect: enhancement by granulocyte macrophage colony-stimulating factor expression. Cancer Res. 2003, 63, 6463–6468. [Google Scholar]
  123. Guillerme, J.B.; Boisgerault, N.; Roulois, D.; Menager, J.; Combredet, C.; Tangy, F.; Fonteneau, J.F.; Gregoire, M. Measles virus vaccine-infected tumor cells induce tumor antigen cross-presentation by human plasmacytoid dendritic cells. Clin. Cancer Res. 2013, 19, 1147–58. [Google Scholar] [CrossRef]
  124. Ong, H.T.; Hasegawa, K.; Dietz, A.B.; Russell, S.J.; Peng, K.W. Evaluation of T cells as carriers for systemic measles virotherapy in the presence of antiviral antibodies. Gene Ther. 2007, 14, 324–333. [Google Scholar] [CrossRef]
  125. Miest, T.S.; Cattaneo, R. New viruses for cancer therapy: meeting clinical needs. Nat. Rev. Microbiol. 2014, 12, 23–34. [Google Scholar] [CrossRef]

Share and Cite

MDPI and ACS Style

Delpeut, S.; Noyce, R.S.; Richardson, C.D. The Tumor-Associated Marker, PVRL4 (Nectin-4), Is the Epithelial Receptor for Morbilliviruses. Viruses 2014, 6, 2268-2286. https://doi.org/10.3390/v6062268

AMA Style

Delpeut S, Noyce RS, Richardson CD. The Tumor-Associated Marker, PVRL4 (Nectin-4), Is the Epithelial Receptor for Morbilliviruses. Viruses. 2014; 6(6):2268-2286. https://doi.org/10.3390/v6062268

Chicago/Turabian Style

Delpeut, Sebastien, Ryan S. Noyce, and Christopher D. Richardson. 2014. "The Tumor-Associated Marker, PVRL4 (Nectin-4), Is the Epithelial Receptor for Morbilliviruses" Viruses 6, no. 6: 2268-2286. https://doi.org/10.3390/v6062268

Article Metrics

Back to TopTop