An Exit Strategy for Measles Virus Vincent Racaniello Science 334, 1650 (2011); DOI: 10.1126/science.1217378
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here. Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of January 18, 2014 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/334/6063/1650.full.html This article cites 10 articles, 3 of which can be accessed free: http://www.sciencemag.org/content/334/6063/1650.full.html#ref-list-1 This article has been cited by 3 articles hosted by HighWire Press; see: http://www.sciencemag.org/content/334/6063/1650.full.html#related-urls This article appears in the following subject collections: Virology http://www.sciencemag.org/cgi/collection/virology
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2011 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on January 18, 2014
This copy is for your personal, non-commercial use only.
PERSPECTIVES VIROLOGY
An Exit Strategy for Measles Virus Vincent Racaniello
on the respiratory epithelium, a different cell receptor must be involved in infection of these cells. In a key experiment, rhesus macaques infected with a mutant measles virus that could not bind to epithelial cells developed viremia and rash, but virus was not shed into the airways (6). These observations suggested that the epithelial cell receptor for measles virus is present only on the basal surface of respiratory epithelial cells. Infection of the respiratory epithelium clearly is not necessary for systemic spread of measles virus. The epithelial cell receptor for measles has now been identified as nectin-4 (1, 2), an immunoglobulin-like protein present within adherens junctions, Nectin-4 complexes that provide strong mechanical attachment between epithelial cells. Other nectinlike proteins are receptors for poliovirus (PVR/CD155) (7) and Lymphocyte alphaherpesviruses (nectin-1 and -2) (8). Expression of nectin-4 Measles virus in nonsusceptible cells allows infection with measles virus, and Host exit. (Left) Immune cells become infected with measles virus. Nectin-4, expressed in junctional complexes that tightly antibodies and small interfering associate respiratory epithelial cells, is a receptor for measles virus. Replication in nectin-4 expressing cells leads to release RNAs to nectin-4 block measles from the apical surface of the epithelium and movement into the respiratory tract for transmission out of the host (right). virus infection. Primate models of measles wide (164,000 deaths in 2008). Most infec- until late in disease (3, 4). Instead, mea- virus infection reveal that a few days after tions occur in low-income countries with sles virus initially replicates in cells of the infection, most of the infected cells in the poor health infrastructures. The introduction immune system, including alveolar macro- trachea are immune cells located in the subof a live attenuated viral vaccine has substan- phages, dendritic cells, and T lymphocytes. epithelial layer (9). In the lung of infected tially reduced disease incidence, although These infected cells carry the virus from the animals at the peak of disease, virus replioutbreaks continue to occur in developed respiratory tract to local lymphatic tissues. cates in nectin-4–expressing epithelial cells nations in unvaccinated individuals. This appealing model for measles virus near the tracheal lumen (9). Measles virus is spread from person to pathogenesis leads to a conundrum: If meaThese findings illuminate the progression person by the respiratory route. Virus-laden sles virus is carried into the host by immune of measles virus infection and how the virus droplets produced by sneezing or coughing cells, how does the virus get back out—into exits the host (see the figure). When measles enter the respiratory tract. There the virus the airways of the lung—so it can be trans- virus–containing droplets are inhaled, they multiplies, migrates to local lymph nodes, mitted to others? One idea is that later in infect immune cells via the SLAM/CD150 and multiplies again, leading to a viremia, infection, infected lymphocytes carry virus receptor. At this stage, respiratory epithelial the presence of virus in the blood. The virus to the basal side of the respiratory epithe- cells cannot be infected, because they do not then replicates at many other sites, includ- lium. After replication in epithelial cells, the express SLAM, and the nectin-4 receptor is ing lymphoid organs (spleen, lymph nodes), virus is released into the airways at the api- on the basal domain of the epithelium where skin, kidney, lung, and liver. The character- cal domain, facilitating transmission. it is inaccessible to virus. Infected immune istic rash of measles is produced by viral All animal viruses initiate infection by cells transfer the virus to local lymph nodes replication in cells of the skin. binding to a cellular receptor. The measles in which the virus replicates and spreads to Transmission of measles virus by respi- virus entry receptor in immune cells is the other organs. Infected lymphocytes travel signaling lymphocytic activation molecule to the respiratory tract and transfer virus to (SLAM, also called CD150) (5). Because the epithelium, where it binds nectin-4 and Microbiology and Immunology, Columbia University, New this plasma membrane protein is not found commences a replication cycle. Newly synYork, NY 10032, USA. E-mail: [email protected]
1650
ratory secretions requires that the virus replicate in cells of the respiratory tract. Early models of measles pathogenesis hypothesized that virus enters the apical domain of respiratory epithelial cells—the part of the cell that contacts the airways—replicates, and is shed in respiratory secretions. This site of replication also allows the virus to spread systemically in the host. However, in laboratory animals, epithelial cells of the respiratory tract do not become infected
23 DECEMBER 2011 VOL 334 SCIENCE www.sciencemag.org Published by AAAS
CREDIT: B. STRAUCH/SCIENCE
T
he causative agent of measles is one of the most infectious viruses known—each infected person can transmit the virus to 15 to 20 susceptible individuals. Identification of the cell adhesion molecule nectin-4 as an epithelial cell receptor for measles virus (1, 2) provides insight into how this high rate of transmission is achieved. Measles is a childhood infection that causes considerable disease and death world-
A receptor for measles virus on epithelial cells reveals how the virus accesses the respiratory tract.
PERSPECTIVES thesized virus particles are released into the airway, where they are spread by aerosol droplets produced by sneezing and coughing. This mechanism of host exit is consistent with the high infectivity of measles virus–containing aerosols. Viral spread in immune cells followed by their exit through epithelial cells may not be unique to measles infection. A similar pathway is observed during infections by other viruses, including varicella-zoster virus and vaccinia virus (10, 11). An aspect of measles virus pathogenesis not addressed by these findings is how infected lymphocytes deliver virus to the basal domain of the respiratory epithelium. Is
free virus passed from cell to cell, or is transfer mediated by cell-cell contact, and if so, what membrane proteins are involved? The identification of nectin-4 as an epithelial cell receptor for measles virus also has implications for the treatment of tumors by viral oncotherapy. Nectin-4 is abundant in ovarian, lung, and breast tumors. Measles virus is currently being tested in clinical trials for treatment of ovarian tumors, and the high concentrations of nectin-4 protein in these tumors may enhance oncolytic efficacy. Based on the presence of nectin-4, testing the oncolytic activity of measles virus against lung and breast tumors may also be worthwhile.
References
1. M. D. Mühlebach et al., Nature; 10.1038/nature10639 (2011). 2. R. S. Noyce et al., PLoS Pathog. 7, e1002240 (2011). 3. R. L. de Swart et al., PLoS Pathog. 3, e178 (2007). 4. K. Lemon et al., PLoS Pathog. 7, e1001263 (2011). 5. H. Tatsuo, N. Ono, K. Tanaka, Y. Yanagi, Nature 406, 893 (2000). 6. V. H. J. Leonard et al., J. Clin. Invest. 118, 2448 (2008). 7. C. L. Mendelsohn, E. Wimmer, V. R. Racaniello, Cell 56, 855 (1989). 8. R. J. Geraghty, C. Krummenacher, G. H. Cohen, R. J. Eisenberg, P. G. Spear, Science 280, 1618 (1998). 9. M. Ludlow et al., J. Gen. Virol. 91, 971 (2010). 10. J. I. Cohen, S. E. Straus, A. M. Arvin, in Fields Virology, D. M. Knipe, P. M. Howley, Eds. (Lippincott Williams & Wilkins, Philadelphia, 2007), pp. 2773–2818 (2007). 11. P. D. Vermeer et al., J. Virol. 81, 9891 (2007). 10.1126/science.1217378
CHEMISTRY
Efficient Fluorination of Organic Molecules with Chiral Anions
An efficient and flexible method for adding rings bearing fluorine atoms can help improve the biological activity and materials properties of organic molecules.
Mikiko Sodeoka
CREDIT: G. GRULLON/SCIENCE
M
any pharmaceuticals and agrochemicals, as well as liquidcrystal materials, contain fluorine atoms. The introduction of the small, highly electronegative fluorine atom into an organic molecule can greatly change its physical and biological properties and, with careful design, improve its chemical and metabolic stability as well as its biological activity (1). In many cases, fluorine has been introduced on an aromatic ring or as a trifluoromethyl group, but fluorine substitution at a chiral carbon center—one that has right- or left-handed stereochemistry—is attracting increasing attention, because adding a fluorine atom to a chiral center can alter the conformation of the molecule and allow finetuning of its biological activities. On page 1681 of this issue, Rauniyar et al. (2) report on an efficient fluorocyclization reaction that converts achiral compounds containing double bonds into complex, chiral fluorine derivatives. A chiral anionic phase-transfer catalyst helps a normally insoluble reagent enter the organic phase and selectively add fluorine to a carbon atom. Until recently, fluorine-substituted chiral molecules were synthesized mainly by using a stoichiometric amount of chiral sources,
Synthetic Organic Chemistry, RIKEN, and ERATO, JST, 2-1 Hirosawa, Wako, Saitama 351-0198 JAPAN. E-mail: sodeoka@ riken.jp
A
Enolate with chiral cation O –M +
Chiral enamine O
*
*
O
MO
F–N
M+ = metal or ammonium ion
B
*
N+
N
* F
F–N
Dually activated enolate
F–N
Nu
Chiral fluorinating reagent XSiMe3
R1 O
Organic liquid phase
R
3
NH
* F
F– N+ *
Nu–
X = O or CH2
Nu = Nucleophile R1
X
* F
R2
R1
R4
R4
O
F R3
N
Soluble chiral fluorinating reagent Cl N+ + O O N O O P P – O O– F O O
O O P O O–
O O P HO O
Chiral anion phase-transfer catalyst
Solid phase
Insoluble fluorinating reagent (Selectfluor)
NaBF4 BF4
–
F
Cl N+ N+ BF – 4
–
O O P O O Na+
NaHCO3
Na2CO3
Base
Strategies for enantioselective fluorination. (A) Several previously reported approaches for catalytic enantioselective electrophilic fluorination are shown. (B) Rauniyar et al. developed a chiral anion phasetransfer catalyst approach. An insoluble fluorinating reagent (Selectfluor) is solubilized into the nonpolar organic liquid phase by counter anion exchange from tetrafluoroborate (BF4–) to the chiral phosphate anion. Electrophilic fluorination and intramolecular cyclization of the amide carbonyl oxygen produce the fluorinated oxazoline in a highly enantio- and diastereoselective manner.
www.sciencemag.org SCIENCE VOL 334 23 DECEMBER 2011 Published by AAAS
1651
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here. Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here. The following resources related to this article are available online at www.sciencemag.org (this information is current as of January 18, 2014 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/334/6063/1650.full.html This article cites 10 articles, 3 of which can be accessed free: http://www.sciencemag.org/content/334/6063/1650.full.html#ref-list-1 This article has been cited by 3 articles hosted by HighWire Press; see: http://www.sciencemag.org/content/334/6063/1650.full.html#related-urls This article appears in the following subject collections: Virology http://www.sciencemag.org/cgi/collection/virology
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2011 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on January 18, 2014
This copy is for your personal, non-commercial use only.
PERSPECTIVES VIROLOGY
An Exit Strategy for Measles Virus Vincent Racaniello
on the respiratory epithelium, a different cell receptor must be involved in infection of these cells. In a key experiment, rhesus macaques infected with a mutant measles virus that could not bind to epithelial cells developed viremia and rash, but virus was not shed into the airways (6). These observations suggested that the epithelial cell receptor for measles virus is present only on the basal surface of respiratory epithelial cells. Infection of the respiratory epithelium clearly is not necessary for systemic spread of measles virus. The epithelial cell receptor for measles has now been identified as nectin-4 (1, 2), an immunoglobulin-like protein present within adherens junctions, Nectin-4 complexes that provide strong mechanical attachment between epithelial cells. Other nectinlike proteins are receptors for poliovirus (PVR/CD155) (7) and Lymphocyte alphaherpesviruses (nectin-1 and -2) (8). Expression of nectin-4 Measles virus in nonsusceptible cells allows infection with measles virus, and Host exit. (Left) Immune cells become infected with measles virus. Nectin-4, expressed in junctional complexes that tightly antibodies and small interfering associate respiratory epithelial cells, is a receptor for measles virus. Replication in nectin-4 expressing cells leads to release RNAs to nectin-4 block measles from the apical surface of the epithelium and movement into the respiratory tract for transmission out of the host (right). virus infection. Primate models of measles wide (164,000 deaths in 2008). Most infec- until late in disease (3, 4). Instead, mea- virus infection reveal that a few days after tions occur in low-income countries with sles virus initially replicates in cells of the infection, most of the infected cells in the poor health infrastructures. The introduction immune system, including alveolar macro- trachea are immune cells located in the subof a live attenuated viral vaccine has substan- phages, dendritic cells, and T lymphocytes. epithelial layer (9). In the lung of infected tially reduced disease incidence, although These infected cells carry the virus from the animals at the peak of disease, virus replioutbreaks continue to occur in developed respiratory tract to local lymphatic tissues. cates in nectin-4–expressing epithelial cells nations in unvaccinated individuals. This appealing model for measles virus near the tracheal lumen (9). Measles virus is spread from person to pathogenesis leads to a conundrum: If meaThese findings illuminate the progression person by the respiratory route. Virus-laden sles virus is carried into the host by immune of measles virus infection and how the virus droplets produced by sneezing or coughing cells, how does the virus get back out—into exits the host (see the figure). When measles enter the respiratory tract. There the virus the airways of the lung—so it can be trans- virus–containing droplets are inhaled, they multiplies, migrates to local lymph nodes, mitted to others? One idea is that later in infect immune cells via the SLAM/CD150 and multiplies again, leading to a viremia, infection, infected lymphocytes carry virus receptor. At this stage, respiratory epithelial the presence of virus in the blood. The virus to the basal side of the respiratory epithe- cells cannot be infected, because they do not then replicates at many other sites, includ- lium. After replication in epithelial cells, the express SLAM, and the nectin-4 receptor is ing lymphoid organs (spleen, lymph nodes), virus is released into the airways at the api- on the basal domain of the epithelium where skin, kidney, lung, and liver. The character- cal domain, facilitating transmission. it is inaccessible to virus. Infected immune istic rash of measles is produced by viral All animal viruses initiate infection by cells transfer the virus to local lymph nodes replication in cells of the skin. binding to a cellular receptor. The measles in which the virus replicates and spreads to Transmission of measles virus by respi- virus entry receptor in immune cells is the other organs. Infected lymphocytes travel signaling lymphocytic activation molecule to the respiratory tract and transfer virus to (SLAM, also called CD150) (5). Because the epithelium, where it binds nectin-4 and Microbiology and Immunology, Columbia University, New this plasma membrane protein is not found commences a replication cycle. Newly synYork, NY 10032, USA. E-mail: [email protected]
1650
ratory secretions requires that the virus replicate in cells of the respiratory tract. Early models of measles pathogenesis hypothesized that virus enters the apical domain of respiratory epithelial cells—the part of the cell that contacts the airways—replicates, and is shed in respiratory secretions. This site of replication also allows the virus to spread systemically in the host. However, in laboratory animals, epithelial cells of the respiratory tract do not become infected
23 DECEMBER 2011 VOL 334 SCIENCE www.sciencemag.org Published by AAAS
CREDIT: B. STRAUCH/SCIENCE
T
he causative agent of measles is one of the most infectious viruses known—each infected person can transmit the virus to 15 to 20 susceptible individuals. Identification of the cell adhesion molecule nectin-4 as an epithelial cell receptor for measles virus (1, 2) provides insight into how this high rate of transmission is achieved. Measles is a childhood infection that causes considerable disease and death world-
A receptor for measles virus on epithelial cells reveals how the virus accesses the respiratory tract.
PERSPECTIVES thesized virus particles are released into the airway, where they are spread by aerosol droplets produced by sneezing and coughing. This mechanism of host exit is consistent with the high infectivity of measles virus–containing aerosols. Viral spread in immune cells followed by their exit through epithelial cells may not be unique to measles infection. A similar pathway is observed during infections by other viruses, including varicella-zoster virus and vaccinia virus (10, 11). An aspect of measles virus pathogenesis not addressed by these findings is how infected lymphocytes deliver virus to the basal domain of the respiratory epithelium. Is
free virus passed from cell to cell, or is transfer mediated by cell-cell contact, and if so, what membrane proteins are involved? The identification of nectin-4 as an epithelial cell receptor for measles virus also has implications for the treatment of tumors by viral oncotherapy. Nectin-4 is abundant in ovarian, lung, and breast tumors. Measles virus is currently being tested in clinical trials for treatment of ovarian tumors, and the high concentrations of nectin-4 protein in these tumors may enhance oncolytic efficacy. Based on the presence of nectin-4, testing the oncolytic activity of measles virus against lung and breast tumors may also be worthwhile.
References
1. M. D. Mühlebach et al., Nature; 10.1038/nature10639 (2011). 2. R. S. Noyce et al., PLoS Pathog. 7, e1002240 (2011). 3. R. L. de Swart et al., PLoS Pathog. 3, e178 (2007). 4. K. Lemon et al., PLoS Pathog. 7, e1001263 (2011). 5. H. Tatsuo, N. Ono, K. Tanaka, Y. Yanagi, Nature 406, 893 (2000). 6. V. H. J. Leonard et al., J. Clin. Invest. 118, 2448 (2008). 7. C. L. Mendelsohn, E. Wimmer, V. R. Racaniello, Cell 56, 855 (1989). 8. R. J. Geraghty, C. Krummenacher, G. H. Cohen, R. J. Eisenberg, P. G. Spear, Science 280, 1618 (1998). 9. M. Ludlow et al., J. Gen. Virol. 91, 971 (2010). 10. J. I. Cohen, S. E. Straus, A. M. Arvin, in Fields Virology, D. M. Knipe, P. M. Howley, Eds. (Lippincott Williams & Wilkins, Philadelphia, 2007), pp. 2773–2818 (2007). 11. P. D. Vermeer et al., J. Virol. 81, 9891 (2007). 10.1126/science.1217378
CHEMISTRY
Efficient Fluorination of Organic Molecules with Chiral Anions
An efficient and flexible method for adding rings bearing fluorine atoms can help improve the biological activity and materials properties of organic molecules.
Mikiko Sodeoka
CREDIT: G. GRULLON/SCIENCE
M
any pharmaceuticals and agrochemicals, as well as liquidcrystal materials, contain fluorine atoms. The introduction of the small, highly electronegative fluorine atom into an organic molecule can greatly change its physical and biological properties and, with careful design, improve its chemical and metabolic stability as well as its biological activity (1). In many cases, fluorine has been introduced on an aromatic ring or as a trifluoromethyl group, but fluorine substitution at a chiral carbon center—one that has right- or left-handed stereochemistry—is attracting increasing attention, because adding a fluorine atom to a chiral center can alter the conformation of the molecule and allow finetuning of its biological activities. On page 1681 of this issue, Rauniyar et al. (2) report on an efficient fluorocyclization reaction that converts achiral compounds containing double bonds into complex, chiral fluorine derivatives. A chiral anionic phase-transfer catalyst helps a normally insoluble reagent enter the organic phase and selectively add fluorine to a carbon atom. Until recently, fluorine-substituted chiral molecules were synthesized mainly by using a stoichiometric amount of chiral sources,
Synthetic Organic Chemistry, RIKEN, and ERATO, JST, 2-1 Hirosawa, Wako, Saitama 351-0198 JAPAN. E-mail: sodeoka@ riken.jp
A
Enolate with chiral cation O –M +
Chiral enamine O
*
*
O
MO
F–N
M+ = metal or ammonium ion
B
*
N+
N
* F
F–N
Dually activated enolate
F–N
Nu
Chiral fluorinating reagent XSiMe3
R1 O
Organic liquid phase
R
3
NH
* F
F– N+ *
Nu–
X = O or CH2
Nu = Nucleophile R1
X
* F
R2
R1
R4
R4
O
F R3
N
Soluble chiral fluorinating reagent Cl N+ + O O N O O P P – O O– F O O
O O P O O–
O O P HO O
Chiral anion phase-transfer catalyst
Solid phase
Insoluble fluorinating reagent (Selectfluor)
NaBF4 BF4
–
F
Cl N+ N+ BF – 4
–
O O P O O Na+
NaHCO3
Na2CO3
Base
Strategies for enantioselective fluorination. (A) Several previously reported approaches for catalytic enantioselective electrophilic fluorination are shown. (B) Rauniyar et al. developed a chiral anion phasetransfer catalyst approach. An insoluble fluorinating reagent (Selectfluor) is solubilized into the nonpolar organic liquid phase by counter anion exchange from tetrafluoroborate (BF4–) to the chiral phosphate anion. Electrophilic fluorination and intramolecular cyclization of the amide carbonyl oxygen produce the fluorinated oxazoline in a highly enantio- and diastereoselective manner.
www.sciencemag.org SCIENCE VOL 334 23 DECEMBER 2011 Published by AAAS
1651
