UCLA

Necrotizing fasciitis (NF) is a severe bacterial infection characterized by extensive tissue destruction of skin and underlying fascia. The development of NF can be rapid and requires immediate hospitalization. Treatment requires aggressive, surgical debridement of involved tissues, resection of surrounding healthy tissues, accompanied by systemic antibiotics. Even with these extreme therapeutic measures, mortality can reach upwards of 30% for patients. Thus, a better understanding of host factors that predispose individuals to the rapid and extensive tissue damage observed in necrotizing fasciitis and other necrotizing soft tissue infections remains imperative. Metabolic dysfunctions such as diabetes and obesity have been reported as risk factors for NF. We show that Western diet-feeding of mice increases the magnitude of tissue destruction from necrotizing Group A Streptococcus (GAS; S. pyogenes) skin infection. The increased tissue destruction is not observed in mice a fed a high-fat diet, indicating that the effect was specific to cholesterol-enriched Western diet rather than a consequence of obesity per se. Remarkably, the increased tissue destruction observed in Western-diet fed mice is dependent on the expression of the pore-forming toxin Streptolysin-O (SLO), a member of the cholesterol-dependent cytolysins (CDCs). Because SLO is known to target cholesterol in the host plasma membrane, we reasoned that cholesterol metabolism could be a targetable signaling axis to combat SLO-induced tissue destruction. Liver X receptor (LXR) is a set of nuclear receptors that transactivate a broad number of genes implicated in lipid homeostasis, such as cholesterol efflux and inhibition of cholesterol import. We show that treatment of GW3965, a potent LXR agonist, on mice skin reduced SLO-induced tissue damage, both prophylactically and as late as 6h post-SLO challenge. Our shotgun lipidomics reveal that LXR activation leads to decreased abundance of lysophosphatidylcholine (LPC). Mechanistically, we discover that modulating host LPC homeostasis influences the magnitude of tissue destruction to SLO toxin alone and in GAS infection by modulating the accessibility of cholesterol targeted by SLO. The recognition that diet and the lipid metabolic state of individuals regulates the degree of tissue destruction in GAS infection advances our understanding of the pathogenesis of these challenging infections.