Enteropathogenic E. coli infection co-elicits lysosomal exocytosis and lytic host cell death

Abstract

ABSTRACT Enteropathogenic Escherichia coli (EPEC) is a primary human enteric bacterial pathogen causing acute diarrhea in children. EPEC colonizes the small intestine, and the disease is induced, in part, by the ability of the pathogen to utilize a type III secretion machinery to inject a battery of proteins, termed “effectors,” from the bacterial cytoplasm into the intestinal enterocytes. Host cell responses to the infecting pathogen are also essential for disease development. Despite intensive research, the mechanisms of EPEC infection and host cell responses need to be better understood. Here, we show that specific EPEC type III secreted effectors, EspF and Map, induce lytic host cell death and also lysosomal exocytosis (LE), resulting in the secretion of lysosomal enzymes into the extracellular environment and the appearance of the lysosomal membrane proteins, Lamp-1, on the infected cell surface. The mitochondrial cytotoxicity and the guanine nucleotide exchange factor domains of Map have been identified to be involved in these processes. In contrast, EspZ, an EPEC effector that protects against lytic cell death, also inhibits LE. Our results combined suggest that LE and host cell death are tightly interconnected processes. The mechanisms and functional significance of these processes on EPEC infection are discussed. IMPORTANCE Enteropathogenic Escherichia coli (EPEC) infection is a significant cause of gastroenteritis, mainly in children. Therefore, studying the mechanisms of EPEC infection is an important research theme. EPEC modulates its host cell life by injecting via a type III secretion machinery cell death modulating effector proteins. For instance, while EspF and Map promote mitochondrial cell death, EspZ antagonizes cell death. We show that these effectors also control lysosomal exocytosis, i.e., the trafficking of lysosomes to the host cell plasma membrane. Interestingly, the capacity of these effectors to induce or protect against cell death correlates completely with their ability to induce LE, suggesting that the two processes are interconnected. Modulating host cell death is critical for establishing bacterial attachment to the host and subsequent dissemination. Therefore, exploring the modes of LE involvement in host cell death is crucial for elucidating the mechanisms underlying EPEC infection and disease.