Response to Staphylococcus aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain

Abstract

Phagocyte recognition and clearance of bacteria play essential roles in the host response to infection. In an on-going forward genetic screen, we identify the Drosophila melanogaster scavenger receptor Croquemort as a receptor for Staphylococcus aureus, implicating for the first time the CD36 family as phagocytic receptors for bacteria. In transfection assays, the mammalian Croquemort paralogue CD36 confers binding and internalization of Gram-positive and, to a lesser extent, Gram-negative bacteria. By mutational analysis, we show that internalization of S. aureus and its component lipoteichoic acid requires the COOH-terminal cytoplasmic portion of CD36, specifically Y463 and C464, which activates Toll-like receptor (TLR) 2/6 signaling. Macrophages lacking CD36 demonstrate reduced internalization of S. aureus and its component lipoteichoic acid, accompanied by a marked defect in tumor necrosis factor-α and IL-12 production. As a result, Cd36 −/− mice fail to efficiently clear S. aureus in vivo resulting in profound bacteraemia. Thus, response to S. aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain, which initiates TLR2/6 signaling.

Divergent roles of Toll‐like receptor 2 in response to lipoteichoic acid and Staphylococcus aureus in vivo

“…Because macrophages play a major role in protection against extracellular and intracellular pathogens, investigations have concentrated on the response of this cell type to S. aureus or its ligands. Thus the higher mortality due to infection with S. aureus in TLR2 knockout mice was attributed to the impairment of TNF-a and IL-6 production by peritoneal macropahges in response to heat-killed bacteria or the ligand LTA in vitro [2,3,22]. More recent studies on the role of TLR2 in localized infections in vivo have revealed a much more complex interaction between TLR2 and microbial pathogens.…”

“…In addition to further increases in TLR2, CD14 and CXCL10 transcripts (6.171.4-, 14.874.8-and 3.971.5-fold, respectively) compared to treatment with IFN-g alone, there was significant upregulation of a number of inflammatory genes including the chemokines CCL2 and IL-8 (6.372.1-and 28.2719.3-fold, respectively), cytokines To further define the interaction between LTA and TLR2 on primary human endothelial cells, the role of co-receptors was examined. The requirement of CD36 and CD14 for murine macrophages and human monocytes in response to LTA in vitro is well documented [3,8,22,23]. The scavenger molecule CD36, in particular, is deemed to be critical in vivo as CD36-deficient mice suffer significantly higher mortality from a systemic S. aureus infection compared to WT mice [3,22].…”

CD36: Implications in cardiovascular disease

“…More recently, expression has been reported on hepatocytes under certain circumstances (Vosper, et al, 2001,Yu, et al, 2001,Zhou, et al, 2006 and smooth muscle cells (Lim, et al, 2006,de Oliveira Silva, Delbosc, Arais, Monnier, Cristol, & Pares-Herbute, 2006, Kwok, Juan, and Ho, 2006. CD36 plays a role in uptake of apoptotic cells (Savill, Hogg, Ren, and Haslett, 1992), shed photoreceptor outer segments , and modified lipoproteins (Endemann, Stanton, Madden, Bryant, White, & Protter, 1993,Podrez, et al,2000, and in recognition of ligands that trigger an innate immune response, including components of gram positive bacteria cell walls (Hoebe, et al, 2005,Stuart, et al, 2005 (as a co-receptor with Toll Like Receptor (TLR) 2), fibrillar amyloid β (Bamberger, Harris, McDonald, Husemann, & Landreth, 2003,El Khoury, et al, 2003, which is a constituent of Alzheimer plaque, and resembles fibrillar amyloid protein (Medeiros, et al, 2004), that may occur in atherosclerotic plaque. In addition to facilitating fatty acid transport into adipocytes and cardiac and skeletal muscle (and perhaps other cells), CD36 was recently shown to be a sensor for fatty acids in taste buds, eliciting a secretory response in the gut (Laugerette, et al, 2005).…”

“…Hoebe et al reported it to be lipoteichoic acid, but one group argues that the actual ligand is a lipoprotein that co-isolates with lipoteichoic acid, and that when bacteria are mutated such that the lipoprotein cannot be biosynthesized, the resulting lipoteichoic acid has only 1/100 of the activating properties as lipoprotein (Hashimoto, et al, 2006). Whether lipoprotein or lipoteichoic acid, macrophages from CD36 KO mice were less efficient at phagocytosis of gram positive Staphylococcus aureus, less able to clear infection, and more susceptible to abscess and death (Stuart, et al, 2005).…”

“…The newly formed receptor complex is then recruited to lipid rafts where activation/signaling occurs. Using CD36 mutants, Stuart, et al (2005) went on to show that phagocytosis of gram positive bacteria was mediated by specific amino acids (tyrosine 463 and cysteine 464) in the C-terminal cytoplasmic tail of CD36, which apparently are necessary for TLR2/6 signaling. In contrast, for binding and capture of oxLDL, the terminal 6 amino acids (467−472) have been implicated (Malaud, Hourton, Giroux, Ninio, Buckland, & McGregor, 2002).…”