Dr. Beutler’s work in the 1980s showed that the production of a protein called “tumor necrosis factor” or “TNF” is greatly increased early during infection and that this substance is responsible for the symptoms and signs of infection, including the signs of sepsis. In the 1990s, he researched the cause of the increased production of TNF and showed that its production is regulated by a molecular “fire alarm,” a detector of bacteria called the toll-like receptor 4 (TLR4). TLR4 detects endotoxin, a coating material on many types of bacteria (including those that infect the lung) such as E. coli, Salmonella and Y. pestis (the bacteria that cause bubonic plague). Endotoxin can stimulate inflammation and sepsis even when the bacteria are killed by our defenses or by antibiotics. In the 2000s, Dr. Beutler’s laboratory worked out the pathways by which TLR4 and other TLRs regulate inflammation and host defense. Dr. Beutler’s work has answered some of the oldest and most basic questions in medicine: why infections (including pneumonias) with different microbes give rise to often similar illnesses with fever and malaise, what causes sepsis, and why sepsis is life threatening even if the infectious microbes are killed by our defenses or by antibiotics.