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Protection from lethal gram-positive infection by macrophage scavenger receptor-dependent phagocytosis
1Department of Medicine, Division of Medical Oncology, Columbia Presbyterian Medical Center, New York, New York 10032, USA. christian.thomas@vetmednet.org
Abstract:
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.
Insights
Scavenger receptors (SR-AI/II) mediate opsonin-independent phagocytosis of gram-positive bacteria. These receptors are critical for host defense against bacterial infections, as shown in SR-AI/II-deficient mice.
Area of Science:
- Immunology
- Microbiology
- Infectious Diseases
Background:
- Gram-positive bacterial infections cause significant human morbidity and mortality.
- Opsonin-dependent phagocytosis is key for fighting these infections, but the role of opsonin-independent phagocytosis is unclear.
- Type I and II class A scavenger receptors (SR-AI/II) recognize bacterial components like LPS and LTA, suggesting a role in innate immunity.
Purpose of the Study:
- To investigate the role of SR-AI/II in host defense against gram-positive bacterial infections.
- To determine if SR-AI/II mediate opsonin-independent phagocytosis of bacteria.
- To elucidate the in vivo significance of opsonin-independent phagocytosis.
Main Methods:
- Utilized SR-AI/II-deficient mice (MSR-A(-/-)) and wild-type controls (MSR-A(+/+)).
- Infected mice intraperitoneally with Staphylococcus aureus, a gram-positive pathogen.
- Assessed bacterial clearance, neutrophil killing activity, and macrophage phagocytosis.
- Examined opsonin-independent phagocytosis by peritoneal macrophages.
Main Results:
- SR-AI/II-deficient mice were more susceptible to Staphylococcus aureus infection than controls.
- Mice lacking SR-AI/II showed impaired bacterial clearance and died from disseminated infection.
- Neutrophil killing of S. aureus was normal, but opsonin-independent phagocytosis by MSR-A(-/-) macrophages was significantly reduced.
- Macrophages from control mice phagocytosed gram-positive bacteria in an SR-AI/II-dependent manner.
Conclusions:
- SR-AI/II mediate opsonin-independent phagocytosis of gram-positive bacteria.
- Opsonin-independent phagocytosis, via SR-AI/II, plays a critical role in host defense against bacterial infections in vivo.
- These findings highlight a novel mechanism in innate immunity against bacterial pathogens.