Protection from lethal gram-positive infection by macrophage scavenger receptor-dependent phagocytosis.
Infections with gram-positive bacteria are a major cause of morbidity and mortality in humans. Opsonin-dependent phagocytosis plays a major role in protection against and recovery from gram-positive infections. Inborn and acquired defects in opsonin generation and/or recognition by phagocytes are associated with an increased susceptibility to bacterial infections. In contrast, the physiological significance of opsonin-independent phagocytosis is unknown. Type I and II class A scavenger receptors (SR-AI/II) recognize a variety of polyanions including bacterial cell wall products such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA), suggesting a role for SR-AI/II in innate immunity to bacterial infections. Here, we show that SR-AI/II-deficient mice (MSR-A(-/-)) are more susceptible to intraperitoneal infection with a prototypic gram-positive pathogen, Staphylococcus aureus, than MSR-A(+/+) control mice. MSR-A(-/-) mice display an impaired ability to clear bacteria from the site of infection despite normal killing of S. aureus by neutrophils and die as a result of disseminated infection. Opsonin-independent phagocytosis of gram-positive bacteria by MSR-A(-/-) macrophages is significantly decreased although their phagocytic machinery is intact. Peritoneal macrophages from control mice phagocytose a variety of gram-positive bacteria in an SR-AI/II-dependent manner. Our findings demonstrate that SR-AI/II mediate opsonin-independent phagocytosis of gram-positive bacteria, and provide the first evidence that opsonin-independent phagocytosis plays a critical role in host defense against bacterial infections in vivo.
Thomas
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CA
Department of Medicine, Division of Medical Oncology, Columbia Presbyterian Medical Center, New York, New York 10032, USA. christian.thomas@vetmednet.org
Li
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Kodama
T
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Suzuki
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Silverstein
S C
SC
El Khoury
J
J
D000818:Animals; D016908:Gram-Positive Bacterial Infections / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009895:Opsonin Proteins / Q000502:physiology; D010587:Phagocytosis; D011971:Receptors, Immunologic / Q000502:physiology*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D013203:Staphylococcal Infections / Q000276:immunology; D013682:Teichoic Acids / Q000494:pharmacology
D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009895:Opsonin Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D013682:Teichoic Acids; C009900:lipoteichoic acid