<named-content content-type="genus-species">Staphylococcus aureus</named-content> Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5

ABSTRACT Leukocidin ED (LukED) is a bicomponent pore-forming toxin produced by Staphylococcus aureus that lyses host cells by targeting the chemokine receptors CC chemokine receptor type 5 (CCR5), CXCR1, CXCR2, and DARC. In addition to its role as a receptor for LukED, CCR5 is the major coreceptor f...

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Autores principales:	Kayan Tam, Megan Schultz, Tamara Reyes-Robles, Bénédicte Vanwalscappel, Joshua Horton, Francis Alonzo, Beili Wu, Nathaniel R. Landau, Victor J. Torres
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/2d3a8571d04d47e2af728faf7069e218
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spelling	oai:doaj.org-article:2d3a8571d04d47e2af728faf7069e2182021-11-15T15:50:16Z<named-content content-type="genus-species">Staphylococcus aureus</named-content> Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR510.1128/mBio.02024-162150-7511https://doaj.org/article/2d3a8571d04d47e2af728faf7069e2182016-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02024-16https://doaj.org/toc/2150-7511ABSTRACT Leukocidin ED (LukED) is a bicomponent pore-forming toxin produced by Staphylococcus aureus that lyses host cells by targeting the chemokine receptors CC chemokine receptor type 5 (CCR5), CXCR1, CXCR2, and DARC. In addition to its role as a receptor for LukED, CCR5 is the major coreceptor for primary isolates of human immunodeficiency virus type 1 (HIV-1) and has been extensively studied. To compare how LukED and HIV-1 target CCR5, we analyzed their respective abilities to use CCR5/CCR2b chimeras to mediate cytotoxicity and virus entry. These analyses showed that the second and third extracellular loops (ECL) of CCR5 are necessary and sufficient for LukED to target the receptor and promote cell lysis. In contrast, the second ECL of CCR5 is necessary but not sufficient for HIV-1 infectivity. The analysis of CCR5 point mutations showed that glycine-163 is critical for HIV-1 infectivity, while arginine-274 and aspartic acid-276 are critical for LukED cytotoxicity. Point mutations in ECL2 diminished both HIV-1 infectivity and LukED cytotoxicity. Treatment of cells with LukED did not interfere with CCR5-tropic HIV-1 infectivity, demonstrating that LukED and the viral envelope glycoprotein use nonoverlapping sites on CCR5. Analysis of point mutations in LukE showed that amino acids 64 to 69 in the rim domain are required for CCR5 targeting and cytotoxicity. Taking the results together, this study identified the molecular basis by which LukED targets CCR5, highlighting the divergent molecular interactions evolved by HIV-1 and LukED to interact with CCR5. IMPORTANCE The bicomponent pore-forming toxins are thought to play a vital role in the success of Staphylococcus aureus as a mammalian pathogen. One of the leukocidins, LukED, is necessary and sufficient for lethality in mice. At the molecular level, LukED causes cell lysis through binding to specific cellular receptors. CCR5 is one of the receptors targeted by LukED and is the major coreceptor for CCR5-tropic HIV-1. While the molecular interaction of CCR5 and HIV-1 is well characterized, the means by which LukED interacts with CCR5 is less clear. In this study, we demonstrated that receptor specificity is conferred through unique interactions between key domains on CCR5 and LukE. Although HIV-1 and LukED target the same receptor, our data demonstrated that they interact with CCR5 differently, highlighting the molecular complexity of host-pathogen interactions.Kayan TamMegan SchultzTamara Reyes-RoblesBénédicte VanwalscappelJoshua HortonFrancis AlonzoBeili WuNathaniel R. LandauVictor J. TorresAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 6 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Kayan Tam Megan Schultz Tamara Reyes-Robles Bénédicte Vanwalscappel Joshua Horton Francis Alonzo Beili Wu Nathaniel R. Landau Victor J. Torres <named-content content-type="genus-species">Staphylococcus aureus</named-content> Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5
description	ABSTRACT Leukocidin ED (LukED) is a bicomponent pore-forming toxin produced by Staphylococcus aureus that lyses host cells by targeting the chemokine receptors CC chemokine receptor type 5 (CCR5), CXCR1, CXCR2, and DARC. In addition to its role as a receptor for LukED, CCR5 is the major coreceptor for primary isolates of human immunodeficiency virus type 1 (HIV-1) and has been extensively studied. To compare how LukED and HIV-1 target CCR5, we analyzed their respective abilities to use CCR5/CCR2b chimeras to mediate cytotoxicity and virus entry. These analyses showed that the second and third extracellular loops (ECL) of CCR5 are necessary and sufficient for LukED to target the receptor and promote cell lysis. In contrast, the second ECL of CCR5 is necessary but not sufficient for HIV-1 infectivity. The analysis of CCR5 point mutations showed that glycine-163 is critical for HIV-1 infectivity, while arginine-274 and aspartic acid-276 are critical for LukED cytotoxicity. Point mutations in ECL2 diminished both HIV-1 infectivity and LukED cytotoxicity. Treatment of cells with LukED did not interfere with CCR5-tropic HIV-1 infectivity, demonstrating that LukED and the viral envelope glycoprotein use nonoverlapping sites on CCR5. Analysis of point mutations in LukE showed that amino acids 64 to 69 in the rim domain are required for CCR5 targeting and cytotoxicity. Taking the results together, this study identified the molecular basis by which LukED targets CCR5, highlighting the divergent molecular interactions evolved by HIV-1 and LukED to interact with CCR5. IMPORTANCE The bicomponent pore-forming toxins are thought to play a vital role in the success of Staphylococcus aureus as a mammalian pathogen. One of the leukocidins, LukED, is necessary and sufficient for lethality in mice. At the molecular level, LukED causes cell lysis through binding to specific cellular receptors. CCR5 is one of the receptors targeted by LukED and is the major coreceptor for CCR5-tropic HIV-1. While the molecular interaction of CCR5 and HIV-1 is well characterized, the means by which LukED interacts with CCR5 is less clear. In this study, we demonstrated that receptor specificity is conferred through unique interactions between key domains on CCR5 and LukE. Although HIV-1 and LukED target the same receptor, our data demonstrated that they interact with CCR5 differently, highlighting the molecular complexity of host-pathogen interactions.
format	article
author	Kayan Tam Megan Schultz Tamara Reyes-Robles Bénédicte Vanwalscappel Joshua Horton Francis Alonzo Beili Wu Nathaniel R. Landau Victor J. Torres
author_facet	Kayan Tam Megan Schultz Tamara Reyes-Robles Bénédicte Vanwalscappel Joshua Horton Francis Alonzo Beili Wu Nathaniel R. Landau Victor J. Torres
author_sort	Kayan Tam
title	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5
title_short	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5
title_full	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5
title_fullStr	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5
title_full_unstemmed	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5
title_sort	<named-content content-type="genus-species">staphylococcus aureus</named-content> leukocidin luked and hiv-1 gp120 target different sequence determinants on ccr5
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/2d3a8571d04d47e2af728faf7069e218
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<named-content content-type="genus-species">Staphylococcus aureus</named-content> Leukocidin LukED and HIV-1 gp120 Target Different Sequence Determinants on CCR5

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