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Salmonella typhimurium paves its own road into target cells
Gastroenterology News John H. Walsh, Section Editor
Salmonella typhimurium Paves Its Own Road into Target Cells
cell invasion. This ruffling was similar to the changes produced by constituitively active Rac-1 and was accompaalmonella typhimurium enters nied by lamellopodia activity typiintestinal mucosal cells after adcally caused by activated CDC42. hering to their extracellular memInvolvement of these two substances brane. Entry is accomplished only in bacterial invasion was proven by after the adjacent cell membrane is finding that their inhibition by overaltered by a type of cytoskeletal rearexpression of dominant negative rangement known as membrane rufRac-1 or CDC42 prevented cytoskelfling. A mechanism used by Salmoetal changes and prevented bacterial nella to initiate membrane ruffling invasion. and bacterial penetration was deSopE also induced JNK-1 activscribed recently by Hardt et al. in ity by activating Rac-1 and the May 29 issue of Cell. SalmoCDC42, but did not activate the nella uses type III secretion to alternate Erk MAP kinase pathinject a toxin into its host cell way. Thus, type III secretion of that causes a series of biochemical SopE into cells by Salmonella changes that weaken cellular resisnot only causes changes that tance and ultimately lead to phagolead to bacterial internalization, cytosis of the bacterium. but also activates transcription Type III secretion is a recently factors that stimulate production described mechanism used by of TNF-a and other inflammatory bacteria to secrete proteins into cytokines. SopE was found to form cells to which they form attachspecific molecular interactions with ments. In the case of Salmonella, Rac-1 and with CDC-42 that led to cellular resistance to bacterial loss of GDP binding and to formaphagocytosis is diminished by a After S. typhimurium binds to the surface of an intestinal tion of the active GTP bound forms. process that also initiates inflamma- mucosal cell, it injects bacterial proteins through the host Once Salmonella enters the cell membrane by a type III secretory mechanism. One of tory reactions in the host cell. host cell, stimulation of inflammathese proteins, Sop E, causes a series of events leading An S. typhimurium protein to entry of the organism into the epithelial cell and tory products is enhanced and known as SopE has been identi- ultimately to inflammation and diarrhea. Sop E seletively ultimately causes tissue inflammaactivates two members of the rho family of small GTP fied as a key player in cellular binding proteins, CDC-42 and Rac-1, that cause rear- tion and diarrhea that are known infection. SopE is a GDP/GTP rangements of the actin cytoskeleton in the adjacent consequences of this infection. exchange factor that activates plasma membrane, leading to localized membrane ruf- This is another example of alterfling and enabling the bacterium to enter the cell. Activaseveral small-molecular-weight tion of CDC-42 and Rac-1 also leads to JNK-1 activation ation of specific intracellular GTPases in the Rho family, espe- which, along with other products of the internalized pathways by bacterial toxins that cially Rac-1 and CDC42. Activa- S. typhimurium, induces production of cytotoxic cyto- enable enteric pathogens to mulkines leading to inflammation and diarrhea tion of Rac-1 or of CDC42 causes tiply and survive.
S
New Therapy Packs Powerful One-Two Punch Against HCV leading hepatologist refers to the recently approved combination antiviral therapy for chronic hepatitis C (HCV) as a significant breakthrough. Rebetron, manufactured by Schering-Plough Corp., (Kenilworth, NJ) consists of a 6-month course of interferon injections combined with ribavirin capsules. It was approved by
A
changes in cellular morphology and motility including membrane ruffling formation of filopodia, and their activation by SopE appears to be a principal step leading to Salmonella invasion and pathogenesis. SopE, either microinjected or artificially expressed in cultured cells, caused membrane ruffling and led to internalization of a strain of S. typhimurium that lacks SopE, does not induce ruffling, and is incapable of
the FDA in June for adult hepatitis C patients who initially respond to and later relapse with standard treatment (interferon alone). An estimated 4 million Americans are believed to be infected with HCV. The virus is responsible for about 10,000 deaths a year in this country, and is the leading indication for liver transplantation. Interferon alone eliminates the virus in only 10%–20% of patients, but another 25%–40% respond and subse-
quently relapse. In patients for whom the FDA approved the therapy, nearly half experienced a sustained remission (6 months or more) when administered the interferon/ribavirin combination in trials held in both the United States and Europe, roughly 10-fold better than the patients who received interferon alone. Although the FDA approved the therapy specifically for the subgroup of patients who relapse after responding to interferon alone, physicians GASTROENTEROLOGY 1998;115:255–256
Salmonella typhimurium Paves Its Own Road into Target Cells
cell invasion. This ruffling was similar to the changes produced by constituitively active Rac-1 and was accompaalmonella typhimurium enters nied by lamellopodia activity typiintestinal mucosal cells after adcally caused by activated CDC42. hering to their extracellular memInvolvement of these two substances brane. Entry is accomplished only in bacterial invasion was proven by after the adjacent cell membrane is finding that their inhibition by overaltered by a type of cytoskeletal rearexpression of dominant negative rangement known as membrane rufRac-1 or CDC42 prevented cytoskelfling. A mechanism used by Salmoetal changes and prevented bacterial nella to initiate membrane ruffling invasion. and bacterial penetration was deSopE also induced JNK-1 activscribed recently by Hardt et al. in ity by activating Rac-1 and the May 29 issue of Cell. SalmoCDC42, but did not activate the nella uses type III secretion to alternate Erk MAP kinase pathinject a toxin into its host cell way. Thus, type III secretion of that causes a series of biochemical SopE into cells by Salmonella changes that weaken cellular resisnot only causes changes that tance and ultimately lead to phagolead to bacterial internalization, cytosis of the bacterium. but also activates transcription Type III secretion is a recently factors that stimulate production described mechanism used by of TNF-a and other inflammatory bacteria to secrete proteins into cytokines. SopE was found to form cells to which they form attachspecific molecular interactions with ments. In the case of Salmonella, Rac-1 and with CDC-42 that led to cellular resistance to bacterial loss of GDP binding and to formaphagocytosis is diminished by a After S. typhimurium binds to the surface of an intestinal tion of the active GTP bound forms. process that also initiates inflamma- mucosal cell, it injects bacterial proteins through the host Once Salmonella enters the cell membrane by a type III secretory mechanism. One of tory reactions in the host cell. host cell, stimulation of inflammathese proteins, Sop E, causes a series of events leading An S. typhimurium protein to entry of the organism into the epithelial cell and tory products is enhanced and known as SopE has been identi- ultimately to inflammation and diarrhea. Sop E seletively ultimately causes tissue inflammaactivates two members of the rho family of small GTP fied as a key player in cellular binding proteins, CDC-42 and Rac-1, that cause rear- tion and diarrhea that are known infection. SopE is a GDP/GTP rangements of the actin cytoskeleton in the adjacent consequences of this infection. exchange factor that activates plasma membrane, leading to localized membrane ruf- This is another example of alterfling and enabling the bacterium to enter the cell. Activaseveral small-molecular-weight tion of CDC-42 and Rac-1 also leads to JNK-1 activation ation of specific intracellular GTPases in the Rho family, espe- which, along with other products of the internalized pathways by bacterial toxins that cially Rac-1 and CDC42. Activa- S. typhimurium, induces production of cytotoxic cyto- enable enteric pathogens to mulkines leading to inflammation and diarrhea tion of Rac-1 or of CDC42 causes tiply and survive.
S
New Therapy Packs Powerful One-Two Punch Against HCV leading hepatologist refers to the recently approved combination antiviral therapy for chronic hepatitis C (HCV) as a significant breakthrough. Rebetron, manufactured by Schering-Plough Corp., (Kenilworth, NJ) consists of a 6-month course of interferon injections combined with ribavirin capsules. It was approved by
A
changes in cellular morphology and motility including membrane ruffling formation of filopodia, and their activation by SopE appears to be a principal step leading to Salmonella invasion and pathogenesis. SopE, either microinjected or artificially expressed in cultured cells, caused membrane ruffling and led to internalization of a strain of S. typhimurium that lacks SopE, does not induce ruffling, and is incapable of
the FDA in June for adult hepatitis C patients who initially respond to and later relapse with standard treatment (interferon alone). An estimated 4 million Americans are believed to be infected with HCV. The virus is responsible for about 10,000 deaths a year in this country, and is the leading indication for liver transplantation. Interferon alone eliminates the virus in only 10%–20% of patients, but another 25%–40% respond and subse-
quently relapse. In patients for whom the FDA approved the therapy, nearly half experienced a sustained remission (6 months or more) when administered the interferon/ribavirin combination in trials held in both the United States and Europe, roughly 10-fold better than the patients who received interferon alone. Although the FDA approved the therapy specifically for the subgroup of patients who relapse after responding to interferon alone, physicians GASTROENTEROLOGY 1998;115:255–256