The Macrophage Scavenger Receptor A Is Host-Protective in Experimental Meningococcal Septicaemia

Abstract

Macrophage Scavenger Receptor A (SR-A) is a major non-opsonic receptor for Neisseria meningitidis on mononuclear phagocytes in vitro, and the surface proteins NMB0278, NMB0667, and NMB1220 have been identified as ligands for SR-A. In this study we ascertain the in vivo role of SR-A in the recognition of N. meningitidis MC58 (serogroup B) in a murine model of meningococcal septicaemia. We infected wild-type and SR-A−/− animals intraperitoneally with N. meningitidis MC58 and monitored their health over a period of 50 hours. We also determined the levels of bacteraemia in the blood and spleen, and measured levels of the pro-inflammatory cytokine interleukin-6 (IL-6). The health of SR-A−/− animals deteriorated more rapidly, and they showed a 33% reduction in survival compared to wild-type animals. SR-A−/− animals consistently exhibited higher levels of bacteraemia and increased levels of IL-6, compared to wild-type animals. Subsequently, we constructed a bacterial mutant (MC58-278-1220) lacking two of the SR-A ligands, NMB0278 and NMB1220. Mutation of NMB0667 proved to be lethal. When mice were infected with the mutant bacteria MC58-278-1220, no significant differences could be observed in the health, survival, bacteraemia, and cytokine production between wild-type and SR-A−/− animals. Overall, mutant bacteria appeared to cause less severe symptoms of septicaemia, and a competitive index assay showed that higher levels of wild-type bacteria were recovered when animals were infected with a 1∶1 ratio of wild-type MC58 and mutant MC58-278-1220 bacteria. These data represent the first report of the protective role of SR-A, a macrophage-restricted, non-opsonic receptor, in meningococcal septicaemia in vivo, and the importance of the recognition of bacterial protein ligands, rather than lipopolysaccharide.

SR-A/MARCO–mediated ligand delivery enhances intracellular TLR and NLR function, but ligand scavenging from cell surface limits TLR4 response to pathogens

“…36 Infection of SR-A Ϫ/Ϫ mice with a pathogenic strain of NM was associated with strikingly high proinflammatory cytokine secretion and septic shock in addition to defective bacterial clearance. 20 Our current finding that SR-A Ϫ/Ϫ , MARCO Ϫ/Ϫ , and DKO mice showed defective bacterial clearance but produced higher levels of inflammatory cytokines after intraperitoneal NM challenge is consistent with most previous reports 11,36 ; although enhancement of LPS responses has also been reported. 37 Apart from the secretion of bioactive mediators, another hallmark of inflammation is the infiltration of specific leukocyte populations into affected tissue.…”

“…These findings are consistent with a previous report that SR-A mice show enhanced bacterial load and produce strikingly high levels of proinflammatory cytokines during NM infection. 20 The use of ethanol-fixed organisms in the present study ruled out any potential immune modulation by replicating pathogens while retaining the SR-A/MARCO and TLR4 ligand activity. …”

“…10 Both receptors have been shown to bind a range of isolated microbial components [11][12][13][14] and intact Grampositive and Gram-negative organisms, 15,16 and their nonredundant role in host defense has been established in a variety of bacterial infection models. [17][18][19][20] Although SR-A and MARCO recognize a range of highly inflammatory ligands, these receptors by themselves are unable to initiate inflammatory signaling, which is usually triggered by sensing PRRs that share overlapping ligand repertoires. However, SR-A and MARCO have been implicated in the pathogenesis of a range of chronic and acute inflammatory pathologies, including atherosclerosis, Alzheimer disease, granuloma formation, and septic shock.…”

Surfactant Protein A (SP-A)-mediated Clearance of Staphylococcus aureus Involves Binding of SP-A to the Staphylococcal Adhesin Eap and the Macrophage Receptors SP-A Receptor 210 and Scavenger Receptor Class A

“…A significant 2-3-fold reduction in uptake of Eap Ϫ S. aureus was measured in the SR-A-enriched SP-R210(DN) macrophages, suggesting that SR-A binds Eap. Recent studies expanded the ligand repertoire of SR-A ligands to surface proteins of Neisseria meningitides (72). Mutation in N. meningitides SR-Abinding protein NMB0667 was lethal in WT mice.…”

Scavenger Receptor in Fish Is a Lipopolysaccharide Recognition Molecule Involved in Negative Regulation of NF-κB Activation by Competing with TNF Receptor-Associated Factor 2 Recruitment into the TNF-α Signaling Pathway

“…Subsequently, the lipoteichoic acid of some Gram-positive bacteria such as Staphylococcus aureus was also shown to be recognized by MSR depending on the exposed negative surface charge (6). Recently, unmethylated CpG DNA and several outer membrane proteins of bacteria, such as Neisseria meningitidis and Klebsiella pneumoniae, have been identified as ligands of MSR and MARCO (7)(8)(9)(10)(11). These two receptors are also found to mediate the direct nonopsonic phagocytosis of several bacteria and viruses, including S. aureus, E. coli, N. meningitidis, Streptococcus pneumoniae, and adenovirus (12)(13)(14)(15)(16).…”