Derepression of Salmonella pathogenicity island 1 genes within macrophages leads to rapid apoptosis via caspase-1- and caspase-3-dependent pathways.
Salmonella enterica serovar Typhimurium has been reported to induce apoptosis in infected macrophages within 14 h from the time of infection by a caspase-1-dependent mechanism. Here, we demonstrate that depletion of Lon protease in serovar Typhimurium induces rapid and massive apoptosis in macrophages by a mechanism involving both caspases-1 and -3. This excessive induction of apoptosis was abrogated by disruption of invF, which is required for the expression of the Salmonella pathogenicity island 1 (SPI1) genes. Expression of hilA, a central regulator of SPI1 transcription, was repressed in the macrophages after phagocytosis, but this gene was continuously expressed when the DeltaLon mutant grew within the macrophages, so the SPI1 proteins accumulated. Thus, the increase in macrophage apoptosis induced by the DeltaLon mutant could result from continued expression of SPI1 genes under conditions where they are normally repressed. Once Salmonella has established a systemic infection, excess apoptosis of macrophages cells upon which the organism is reliant would be detrimental to the pathogen. Therefore, the Lon protease may be required to suppress apoptosis sufficiently to allow time for the bacterium to replicate, escape and invade new macrophages.
Takaya
Akiko
A
Department of Microbiology and Molecular Genetics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.
Suzuki
Akiko
A
Kikuchi
Yuji
Y
Eguchi
Masahiro
M
Isogai
Emiko
E
Tomoyasu
Toshifumi
T
Yamamoto
Tomoko
T
D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D020170:Caspase 1 / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D044404:Genomic Islands / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000382:microbiology* / Q000473:pathology; D051379:Mice; D009154:Mutation; D049070:Protease La / Q000096:biosynthesis / Q000235:genetics; D012486:Salmonella typhimurium / Q000235:genetics / Q000472:pathogenicity*; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C102236:HilA protein, Salmonella; D015534:Trans-Activators; D014157:Transcription Factors; C090990:invF protein, Salmonella; D049070:Protease La; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1