15 October 2014
Vol 6, Issue 258

About The Cover

Cover image expansion

ONLINE COVER Shockproofing Pathogen Poisons. A patient suffering from septic shock teeters on the edge of life and death, surrounded by tubes, wires, monitors, and medical staff commensurate with his dire condition. Microbial infections can spur sepsis via pathogenic endotoxins that superstimulate the host innate immune response, often leading to organ failure and death. Despite nearly 100 clinical trials, drugs against therapeutic targets discovered in mouse models of sepsis have been immune to translation. But what if sepsis can be stopped before the patient crashes? Now, Walley et al show that host cholesterol and pathogen-derived lipid endotoxins use common clearance mechanisms and pinpoint PCSK9—a well-characterized kinase—as a possible therapeutic target for sepsis patients who carry a PCSK9 gain-of-function variant. Cholesterol-reducing drugs that work by blocking PCSK9 action are already being tested in clinical trials as treatments for cardiovascular disease. See accompanying Focus by dos Santos and Marshall . [CREDIT: CHAD BAKER/CORBIS]