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Comparative analysis of rat hepatocytes invasion by Listeria monocytogenes and Salmonella typhimurium: morphological characterization, quantification of TNF-alpha production and cellular death by apoptosis

Grant number: 06/05002-8
Support Opportunities:Regular Research Grants
Duration: December 01, 2007 - November 30, 2009
Field of knowledge:Biological Sciences - Microbiology - Applied Microbiology
Principal Investigator:Dahir Ramos de Andrade Júnior
Grantee:Dahir Ramos de Andrade Júnior
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Listeria monocytogenes is a gram positive cocco-bacillus presents in the ground and water that can be found in the gastrointestinal tract of up to 5% of healthy human adults. It is a food borne pathogen capable to invade the intestinal epithelium, and it is responsible for several diseases as gastroenteritis, meningitis, meningoencefalitis, septicemia and abortions. The immunocompromised patients have a more severe illness. The infections by Listeria monocytogenes reach a rate of global mortality of 20%. The clinical manifestations occur by the ability of this organism to cross three barriers during the infection: intestinal, blood-brain, and placentary barriers. About 25% of cases of listeriosis occur in pregnant women.Listeria monocytogenes replicates in macrophages and provokes its internalization in non-phagocytic cells. After the bacterial entrance occurs lysis of phagocytic vacuole, via listeriolysin O. Following that, the bacteria are released to the citosol, where occurs its replication, as well as the tail formation composed by polymerization of actin monomers of cellular cytoskeleton. This phenomenon allows the bacteria movement in direction to the plasmatic membrane, where they induce formation of pseudopods (listeriopods). The listeriopods invagin into the neighboring cells, allowing entry of bacteria in another cell. This mechanism becomes possible bacterial spreading inside of host tissues, and they protect themselves of the immune system attack.Salmonella typhimurium causes murine salmonelosis, a model for human typhoid fever. This bacterium penetrates in the intestinal wall and it reaches the regional lymphonodes, and later arrives predominantly in the liver and the spleen. After that it has a latency phase, in which the number of bacteria in the liver and spleen remains constant for about one week, until a gradual increase of the bacteria. The hepatocytes, and other non-phagocytic parenchimal cells, may be a safe place for the Salmonella replication, protecting them of immune defense. The interaction between bacteria and cells results in the release of cytokines, constituting part of the innate immune response. Apoptosis is a process of cellular death biochemically conserved characterized by cell shrinking, formation of apoptotic bodies and fragmentation of the internucleosomal DNA. Apoptosis is a cytotoxic phenomenon mediated by TNF, occurring through TNFR-1 signalizing way. L. monocytogenes induces apoptosis of hepatocytes both in vitro and in vivo. The hepatocyte is the higher site of the L. monocytogenes replication in the liver, and its apoptosis allows the removal of intracellular bacteria before the arrival of specific cytotoxic T cells. Concomitant, the infected hepatocytes release proinflammatory cytokines that attract and activate neutrophils. The hepatocytes present potential role in initiating or amplifying the acute inflammatory response in the liver, through the release of pro-inflammatory cytokines, and thus they complement the action of the Kupffer cells and endothelial cells. The bacterial invasion of the hepatocytes is one of the stimuli for the cytokines production (i.e. TNF alpha) by the hepatic cell, and this may induces its death by apoptosis. This cytokine can be a cytotoxic agent, and also the activator of NF-kappaB (one of the most cellular protectors studied currently). The suicide of the hepatocyte had a purpose of the release the bacteria that would be destroyed by the activated hepatic immune system. The study of the cellular bacterial invasion, using specific pathogenic microorganisms, can clarify its way of action in the intracellular medium. These discoveries will allow developing advanced methodologies in the treatment of patients with serious infectious processes caused by these infectious agents. (AU)

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