UC San Diego

Phagocytic leukocytes, such as neutrophils and macrophages, play a key role in host defense against bacterial pathogens. Classically, they are thought to kill bacteria through a combination of phagocytosis, oxidative burst and degranulation. Recently, leukocytes have been found to produce extracellular webs of DNA, known as extracellular traps (ETs). These structures play an important role in host defense, and represent a fundamentally new mechanism of bacterial clearance. Serum has been found to inhibit ETs in a concentration dependent manner. We have found that serum contains heat-stable nucleases that are capable of degrading traps. These findings have important implications for the visualization and identification of extracellular traps. Statins are amongst the most widely- used chronic medication in the world. They act by inhibiting 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis. Several recent clinico-epidemiologic studies have revealed that patients receiving statin therapy have reduced mortality associated with severe bacterial infection. We studied the pharmacological effect of statins on the innate immune capacity of phagocytic cells, focusing on the leading human bacterial pathogen Staphylococcus aureus. These studies revealed a beneficial effect of statins on S. aureus clearance using in vivo, ex vivo and in vitro models of phagocyte function, although paradoxically both phagocytosis and oxidative burst were inhibited. Probing instead for an extracellular mechanism of killing, we found statins boosted the production of ETs by human and murine neutrophils and also monocyte/ macrophages, representing the first report of the ET phenomenon in the later cell type. The effect of statins to induce phagocyte ETs was linked to sterol pathway inhibition by RNA interference and specific pharmacologic inhibitors. We conclude that statins, a drug therapy taken chronically by tens of millions of individuals, alters the functional behavior of phagocytic cells, which could have ramifications for susceptibility and response to bacterial infections in these patients. In sum, our findings have important implications for our understanding of ETs, the cell biological processes that lead to their production and their clinical relevance in the context of bacterial infections