Survival and dissemination of enteric pathogens through activation and subsequent inhibition of programmed cell death pathways

点击翻译按钮获取中文摘要

After being ingested on infected food pathogenic bacteria are taken up by cells in the intestine, entering the cells and attempting to grow. An infected cell recognizing the danger undergoes a tightly controlled form of cell suicide known as apoptosis. Thus the cell removes itself and the danger whilst simultaneously sending out warning signals to the immune system. E. coli and Salmonella are two of the most common food poisoning associated pathogens in the U.K. Based on our knowledge of the body's response to infection we would expect cells to undergo apoptosis when they come into contact with E. coli and Salmonella. In the case of these pathogens however the infected cells survive for some time following infection allowing the bacteria to grow within the infected cell. This extra time for growth is crucial, allowing these pathogens time to multiply and cause a more serious prolonged infection. Through this proposal we aim to understand how these pathogens are prolonging the life of infected cells. This work will have relevance for numerous bacterial pathogens, many of which we now know also attempt to interfere with this process of apoptosis during infection. Our previous work has shed new light on the complex interactions occurring in Salmonella infected cells. During infection the bacteria deliberately target proteins in the cell that respond to the infection by inducing cell suicide. In particular one extremely potent host cell enzyme called caspase-3, or the 'executioner caspase' is targeted. This is the key enzyme in inducing cell suicide, killing the cell quickly but in a controlled fashion. Due to the destructive power of caspase-3 its activation is tightly regulated, making its targeting by bacterial pathogens all the more surprising. However instead of trying to prevent caspase-3 from working these bacteria initially try to harness its activity bypassing the stringent controls put in place to ensure caspase-3 activity is kept in check. We now know Salmonella infection is activating caspase-3 by a unique mechanism and understanding and exploiting this is a key objective for this proposal. Activation of an enzyme as destructive as caspase-3 is a risky strategy for a pathogen that only has a limited time to try to grow within an infected cell. Salmonella and E. coli however have developed a mechanism to control the destructive power of the enzyme. Host cells have a natural recycling system called the proteasome that is used to take old or damaged proteins and break them down and use the building blocks to form new proteins. These bacterial pathogens tap into this recycling system, using their own proteins to mimic proteins from the cell that sort host proteins for recycling. Using this tactic the bacteria divert caspase-3 from its normal role, causing the host cell to inadvertently send it for recycling. This delays cell death meaning the bacteria can now multiply within the cell. This tactic we believe is replicated by numerous other bacterial pathogens during infection, meaning this proposal will have repercussions for the study of numerous microbial infections.