Publication Date:
2012-12-14
Description:
Pore-forming toxins are critical virulence factors for many bacterial pathogens and are central to Staphylococcus aureus-mediated killing of host cells. S. aureus encodes pore-forming bi-component leukotoxins that are toxic towards neutrophils, but also specifically target other immune cells. Despite decades since the first description of staphylococcal leukocidal activity, the host factors responsible for the selectivity of leukotoxins towards different immune cells remain unknown. Here we identify the human immunodeficiency virus (HIV) co-receptor CCR5 as a cellular determinant required for cytotoxic targeting of subsets of myeloid cells and T lymphocytes by the S. aureus leukotoxin ED (LukED). We further demonstrate that LukED-dependent cell killing is blocked by CCR5 receptor antagonists, including the HIV drug maraviroc. Remarkably, CCR5-deficient mice are largely resistant to lethal S. aureus infection, highlighting the importance of CCR5 targeting in S. aureus pathogenesis. Thus, depletion of CCR5(+) leukocytes by LukED suggests a new immune evasion mechanism of S. aureus that can be therapeutically targeted.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536884/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536884/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alonzo, Francis 3rd -- Kozhaya, Lina -- Rawlings, Stephen A -- Reyes-Robles, Tamara -- DuMont, Ashley L -- Myszka, David G -- Landau, Nathaniel R -- Unutmaz, Derya -- Torres, Victor J -- F32 AI098395/AI/NIAID NIH HHS/ -- R01 AI065303/AI/NIAID NIH HHS/ -- R01-AI065303/AI/NIAID NIH HHS/ -- R21 AI087973/AI/NIAID NIH HHS/ -- R21-AI087973/AI/NIAID NIH HHS/ -- R42-MH084372-02A1/MH/NIMH NIH HHS/ -- R56-AI091856-01A1/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Jan 3;493(7430):51-5. doi: 10.1038/nature11724. Epub 2012 Dec 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23235831" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Bacterial Toxins/*metabolism
;
CCR5 Receptor Antagonists
;
Cell Death
;
Cells, Cultured
;
Dendritic Cells/cytology/immunology/metabolism
;
Exotoxins/*metabolism
;
Female
;
Humans
;
Immune Evasion
;
Immunologic Memory
;
Jurkat Cells
;
Mice
;
Myeloid Cells/cytology/immunology/metabolism
;
Receptors, CCR5/*metabolism
;
Staphylococcus aureus/immunology/*pathogenicity
;
T-Lymphocytes/cytology/immunology/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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