Bacterial lipolysis of immune-activating ligands promotes evasion of innate defenses

Abstract

Commensal and pathogenic bacteria hydrolyze host lipid substrates with secreted lipases and phospholipases for nutrient acquisition, colonization, and infection. Bacterial lipase activity on mammalian lipids and phospholipids can promote release of free fatty acids from lipid stores, detoxify antimicrobial lipids, and facilitate membrane dissolution. The gram-positive bacterium Staphylococcus aureus secretes at least two lipases, Sal1 and glycerol ester hydrolase (Geh), with specificities for short- and long-chain fatty acids, respectively, each with roles in the hydrolysis of environmental lipids. In a recent study from our group, we made the unexpected observation that Geh released by S. aureus inhibits activation of innate immune cells. Herein, we investigated the possibility that S. aureus lipases interface with the host immune system to blunt innate immune recognition of the microbe. We found that the Geh lipase, but not other S. aureus lipases, prevents activation of innate cells in culture. Mutation of geh leads to enhancement of proinflammatory cytokine production during infection, increased innate immune activity, and improved clearance of the bacterium in infected tissue. These in vitro and in vivo effects on innate immunity were not due to direct functions of the lipase on mammalian cells, but rather a result of inactivation of S. aureus lipoproteins, a major pathogen-associated molecular pattern (PAMP) of extracellular gram-positive bacteria, via ester hydrolysis. Altogether, these studies provide insight into an adaptive trait that masks microbial recognition by innate immune cells through targeted inactivation of a broadly conserved PAMP.

TLR2 and caspase-1 signaling are critical for bacterial containment but not clearance during craniotomy-associated biofilm infection

“…First, prior work from our laboratory in a mouse model of S. aureus catheterassociated biofilm infection also demonstrated a TLR9independent phenotype [22], confirming the findings obtained during craniotomy infection. Second, as previously mentioned, numerous S. aureus virulence determinants have recently been identified that interfere with TLR2 recognition or signaling [46][47][48][49]; however, to date, no S. aureus inhibitors of TLR9-dependent pathways have been reported. By extension, this suggests that TLR2-mediated recognition of S. aureus is more relevant for bacterial clearance, since this pathway has been extensively targeted by the organism.…”

“…IL-1β is critical for S. aureus containment during craniotomy infection, but is not sufficient for bacterial clearance, since biofilm infections persist in an immune competent host during craniotomy infection. Prior studies have identified several molecules that are produced by planktonic S. aureus that interfere with TLR2-dependent recognition, including lipase (Geh) [46], staphylococcal superantigenlike protein 3 (SSL3) [47], and molecular mimicry via blocking the Toll-interacting receptor (Tir) domain of TLR2 [48,49]. In addition, the paired-immunoglobulinlike receptor (PIR)-B contains an inhibitory immunoreceptor tyrosine-based inhibition (ITIM) motif that upon binding S. aureus lipoteichoic acid, dampens proinflammatory cytokine production [50,51].…”

Lipidomic and Ultrastructural Characterization of Cell Envelope ofStaphylococcus aureusGrown in the Presence of Human Serum

“…C-terminally 6xHis-tagged S.aureus Geh was expressed in E. coli lysY/I q and purified as described previously (56).…”

Xuebijing Injection Alleviates Pam3CSK4-Induced Inflammatory Response and Protects Mice From Sepsis Caused by Methicillin-Resistant Staphylococcus aureus

“…Toll-like receptors (TLRs) are a specific family of PRRs for host cells to recognize different PAMPs. TLR2-based signaling in response to S. aureus infection plays a critical role in the initiation of an effective innate response (Chen and Alonzo, 2019). During S. aureus infection, PAMPs recognized by TLR2 trigger the production of inflammatory mediators such as interleukin (IL)-6, tumor necrosis factor (TNF)-a, IL-1b, nitric oxide (NO), chemokines, interferons, and IL-10 through the activation of TLR2-mediated nuclear factor kB (NF-kB), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3 kinase (PI3K)/Akt pathways (Takeuchi and Akira, 2010).…”