into host cells and blocks the action of Sec61, the molecular channel that serves as a gateway to the endoplasmic reticulum. When Sec61 is blocked, proteins that would normally enter the endoplasmic reticulum are mistargeted to the cytosol, causing a pathological stress response that leads to cell death by apoptosis. This results in tissue death at the site of infection, causing the open ulcer characteristic of the disease. At the same time, Sec61 inhibition prevents cells from signaling to activate the immune system, leaving ulcers largely free of immune cells. Immune cells that do reach the ulcer are killed by mycolactone, and tissue examinations of the ulcer show a core of growing bacteria surrounded by debris from dead and dying neutrophils (the most common immune cell). Transmission It is not known how M. ulcerans is introduced to humans. Buruli ulcer does not spread from one person to another. In areas endemic for Buruli ulcer, disease occurs near stagnant bodies of water, leading to the long-standing hypothesis that M. ulcerans is somehow transmitted to humans from aquatic environments. M. ulcerans is widespread in these environments, where it can survive as free-living or in association with other aquatic organisms. Live M. ulcerans has been isolated from aquatic insects, mosses, and animal feces; and its DNA has been found in water, soil, mats of bacteria and algae, fish, crayfish, aquatic insects, and other animals that live in or near water. A role for biting insects in transmission has been investigated, with particular focus on mosquitoes, giant water bugs, and Naucoridae. M. ulcerans is occasionally found in these insects, and they can sometimes transmit the bacteria in laboratory settings. Whether these insects are regularly involved in transmission remains unclear. Pre-existing wounds have been implicated in disease transmission, and people who immediately wash and bandage open wounds are less likely to acquire Buruli ulcer. Wearing pants and long-sleeved shirts is associated with a lower risk of Buruli ulcer, possibly by preventing insect bites or protecting wounds. Genetic susceptibility While Buruli ulcer is not contagious, susceptibility sometimes runs in families, suggesting genetics could play a role in who develops the disease. Severe Buruli ulcer in a Beninese family was attributed to a loss of 37 kilobases of chromosome 8 in a region that included a long non-coding RNA and was near the genes for beta-defensins, which are antimicrobial peptides involved in immunity and wound healing. Broader