Exploiting dominant-negative toxins to combat Staphylococcus aureus pathogenesis

EMBO Reports
Tamara Reyes-RoblesVictor J Torres

Abstract

Staphylococcus aureus (S. aureus) is a human pathogen that relies on the subversion of host phagocytes to support its pathogenic lifestyle. S. aureus strains can produce up to five beta-barrel, bi-component, pore-forming leukocidins that target and kill host phagocytes. Thus, preventing immune cell killing by these toxins is likely to boost host immunity. Here, we describe the identification of glycine-rich motifs within the membrane-penetrating stem domains of the leukocidin subunits that are critical for killing primary human neutrophils. Remarkably, leukocidins lacking these glycine-rich motifs exhibit dominant-negative inhibitory effects toward their wild-type toxin counterparts as well as other leukocidins. Biochemical and cellular assays revealed that these dominant-negative toxins work by forming mixed complexes that are impaired in pore formation. The dominant-negative leukocidins inhibited S. aureus cytotoxicity toward primary human neutrophils, protected mice from lethal challenge by wild-type leukocidin, and reduced bacterial burden in a murine model of bloodstream infection. Thus, we describe the first example of staphylococcal bi-component dominant-negative toxins and their potential as novel therapeutics to combat...Continue Reading

References

Dec 20, 1994·Proceedings of the National Academy of Sciences of the United States of America·J E GouauxH Bayley
Dec 23, 1999·The Journal of Biological Chemistry·A D Vinion-DubielT L Cover
Sep 9, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jovanka M VoyichFrank R DeLeo
Nov 1, 2006·Proceedings of the National Academy of Sciences of the United States of America·Yukiko K Stranger-JonesOlaf Schneewind
Jul 4, 2007·The Journal of Allergy and Clinical Immunology·Victor Nizet
Dec 24, 2008·Infection and Immunity·Xudong LiangYinduo Ji
Aug 15, 2009·Nature Reviews. Microbiology·Henry F Chambers, Frank R Deleo
Mar 9, 2010·Lancet·Frank R DeLeoHenry F Chambers
Aug 18, 2010·The Journal of Experimental Medicine·Hwan Keun KimOlaf Schneewind
Jan 25, 2011·Molecular Microbiology·Ashley L DumontVictor J Torres
Sep 21, 2011·Proceedings of the National Academy of Sciences of the United States of America·Benoît-Joseph LaventieDubravka Drabek
Oct 5, 2011·Proceedings of the National Academy of Sciences of the United States of America·Keitaro YamashitaIsao Tanaka
Jul 25, 2012·Infection and Immunity·Hwan Keun KimOlaf Schneewind
Dec 14, 2012·Nature·Francis AlonzoVictor J Torres
Mar 8, 2013·Current Opinion in Microbiology·Pauline Yoong, Victor J Torres
Mar 20, 2013·Infection and Immunity·Ashley L DuMontVictor J Torres
Apr 4, 2013·JAMA : the Journal of the American Medical Association·Vance G FowlerAjoke Sobanjo-ter Meulen
May 21, 2013·Cell Host & Microbe·András N SpaanJos A G van Strijp
Jun 12, 2013·Proceedings of the National Academy of Sciences of the United States of America·Ashley L DuMontVictor J Torres
Jun 26, 2013·Human Vaccines & Immunotherapeutics·Gerald B Pier
Jul 10, 2013·Annual Review of Microbiology·András N SpaanJos A G van Strijp
Nov 16, 2013·Trends in Microbiology·Ashley L DuMont, Victor J Torres
Apr 18, 2014·The Journal of Infectious Diseases·Georgia R SampedroJuliane Bubeck Wardenburg
May 23, 2014·Microbiology and Molecular Biology Reviews : MMBR·Francis Alonzo, Victor J Torres

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Citations

Apr 20, 2017·Nature Reviews. Microbiology·András N SpaanVictor J Torres
Feb 18, 2016·EMBO Reports·Dane Parker, Alice Prince
May 31, 2019·Clinical Microbiology Reviews·Jennifer A GrousdJohn F Alcorn
May 1, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Joseph C DevlinP'ng Loke
Jul 1, 2020·The Journal of Experimental Medicine·Kayan TamVictor J Torres
Jul 29, 2020·Infection and Immunity·Mohini BhattacharyaDaniel J Wozniak
May 6, 2016·The Biochemical Journal·Gisela von HovenMatthias Husmann
May 8, 2018·Nature Communications·Bastian BräuningMichael Groll
Jun 27, 2018·Proceedings of the National Academy of Sciences of the United States of America·Mohini BhattacharyaDaniel J Wozniak
Mar 2, 2019·Journal of Biological Engineering·Eric Krueger, Angela C Brown
Oct 15, 2020·The Journal of Biological Chemistry·Marilyn T VasquezVictor J Torres
Jan 18, 2021·The Journal of Biological Chemistry·Marilyn T VasquezVictor J Torres
Mar 16, 2019·Microbiology Spectrum·Kayan Tam, Victor J Torres
Jun 3, 2021·Membranes·Marcelo AyllonDaniel Fologea
Jul 27, 2021·Curēus·Meletis RozisSpyros G Pneumaticos
Feb 1, 2022·ACS Infectious Diseases·Moona SakariArto T Pulliainen

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