Human bodies normally carry 100 trillion bacteria. Most of them live symbiotically to help us digest food and defend against other harmful microbes including bacteria that can cause disease when grown out of control. How the body’s immune system distinguishes between beneficial and harmful bacteria and mount immune response are central questions in biological research. In the past ten years, Dr. Shao’s laboratory has provided comprehensive answers by identifying several cytosolic pattern recognition receptors (PRRs) that specifically recognize the invading bacteria and by revealing the molecular mechanisms through which host cells mount inflammatory responses. Most notable was the discovery of the inflammatory proteases caspase-4 and -5 as the intracellular receptors for endotoxin LPS of gram-negative bacteria. The direct recognition of LPS by caspase 4/5 triggers host immune reaction by activating cytokines. In addition, Dr. Shao’s laboratory as well as Dr. Vishva M. Dixit’s laboratory discovered gasdermin D as a substrate of caspase 4/5, whose cleavage triggers pyroptosis. Therefore, Dr. Shao’s studies not only shed new light on our understanding of innate immune mechanisms, but also paved the way for designing potential new therapeutic strategies or vaccines for hard-to-treat bacterial infections and related diseases.