We establish that LACC1 is expressed in human peripheral and intestinal myeloid-derived cells, define roles for human LACC1 in amplifying PRR-induced outcomes in macrophages, dissect mechanisms wherein LACC1 contributes to PRR outcomes and determine that the CD- and leprosy-associated LACC1 Val254 risk variant results in lower PRR-initiated polyphenol oxidase activity, mtROS and cellular ROS, signalling, cytokine secretion, broad transcriptional regulation and intracellular bacterial clearance (Supplementary Fig. 19). The gene discussed is LACC1; the disease is leprosy.