The staphylococcal toxins γ-haemolysin AB and CB differentially target phagocytes by employing specific chemokine receptors.
Evasion of the host phagocyte response by Staphylococcus aureus is crucial to successful infection with the pathogen. γ-haemolysin AB and CB (HlgAB, HlgCB) are bicomponent pore-forming toxins present in almost all human S. aureus isolates. Cellular tropism and contribution of the toxins to S. aureus pathophysiology are poorly understood. Here we identify the chemokine receptors CXCR1, CXCR2 and CCR2 as targets for HlgAB, and the complement receptors C5aR and C5L2 as targets for HlgCB. The receptor expression patterns allow the toxins to efficiently and differentially target phagocytic cells. Murine neutrophils are resistant to HlgAB and HlgCB. CCR2 is the sole murine receptor orthologue compatible with γ-haemolysin. In a murine peritonitis model, HlgAB contributes to S. aureus bacteremia in a CCR2-dependent manner. HlgAB-mediated targeting of CCR2(+) cells highlights the involvement of inflammatory macrophages during S. aureus infection. Functional quantification identifies HlgAB and HlgCB as major secreted staphylococcal leukocidins.
1] Department of Medical Microbiology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands [2] CIRI, International Center for Infectiology Research, Université Lyon 1 and Ecole Normale Supérieure de Lyon, 69007 Lyon, France [3] Inserm, U1111, 69007 Lyon, France.
András N
AN
Spaan
Department of Medical Microbiology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands.
Manouk
M
Vrieling
1] CIRI, International Center for Infectiology Research, Université Lyon 1 and Ecole Normale Supérieure de Lyon, 69007 Lyon, France [2] Inserm, U1111, 69007 Lyon, France [3] CNRS, UMR5308, 69007 Lyon, France.
Pierre
P
Wallet
1] CIRI, International Center for Infectiology Research, Université Lyon 1 and Ecole Normale Supérieure de Lyon, 69007 Lyon, France [2] Inserm, U1111, 69007 Lyon, France [3] CNRS, UMR5308, 69007 Lyon, France.
Cédric
C
Badiou
Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
Tamara
T
Reyes-Robles
Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
Elizabeth A
EA
Ohneck
1] CIRI, International Center for Infectiology Research, Université Lyon 1 and Ecole Normale Supérieure de Lyon, 69007 Lyon, France [2] Inserm, U1111, 69007 Lyon, France [3] CNRS, UMR5308, 69007 Lyon, France [4] Centre National de Référence des Staphylocoques, Hospices Civils de Lyon, 69007 Lyon, France.
Yvonne
Y
Benito
Department of Medical Microbiology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands.
Carla J C
CJ
de Haas
Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia.
Christopher J
CJ
Day
Institute for Glycomics, Griffith University, Gold Coast, Queensland 4222, Australia.
Michael P
MP
Jennings
1] CIRI, International Center for Infectiology Research, Université Lyon 1 and Ecole Normale Supérieure de Lyon, 69007 Lyon, France [2] Inserm, U1111, 69007 Lyon, France [3] CNRS, UMR5308, 69007 Lyon, France [4] Centre National de Référence des Staphylocoques, Hospices Civils de Lyon, 69007 Lyon, France.
Gérard
G
Lina
1] CIRI, International Center for Infectiology Research, Université Lyon 1 and Ecole Normale Supérieure de Lyon, 69007 Lyon, France [2] Inserm, U1111, 69007 Lyon, France [3] CNRS, UMR5308, 69007 Lyon, France [4] Centre National de Référence des Staphylocoques, Hospices Civils de Lyon, 69007 Lyon, France.
François
F
Vandenesch
Department of Medical Microbiology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands.
Kok P M
KP
van Kessel
Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
Victor J
VJ
Torres
Department of Medical Microbiology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands.
Jos A G
JA
van Strijp
1] CIRI, International Center for Infectiology Research, Université Lyon 1 and Ecole Normale Supérieure de Lyon, 69007 Lyon, France [2] Inserm, U1111, 69007 Lyon, France.
Thomas
T
Henry
D000818:Animals; D001426:Bacterial Proteins / Q000502:physiology*; D001427:Bacterial Toxins; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006460:Hemolysin Proteins / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010538:Peritonitis / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D010586:Phagocytes / Q000382:microbiology* / Q000473:pathology; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019707:Receptors, Chemokine / Q000502:physiology*; D011951:Receptors, Complement / Q000502:physiology; D023062:Receptors, Interleukin-8A / Q000502:physiology; D023063:Receptors, Interleukin-8B / Q000502:physiology; D013203:Staphylococcal Infections / Q000473:pathology / Q000503:physiopathology*; D013211:Staphylococcus aureus
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D011951:Receptors, Complement; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; C037956:gamma-hemolysin, Staphylococcus aureus