The life cycle of Bacillus anthracis includes both vegetative and endospore morphologies which alternate based on nutrient availability, and there is considerable evidence indicating that the ability of this organism to cause anthrax depends on its ability to progress through this life cycle in a regulated manner. Here we report the use of a custom B. anthracis GeneChip in defining the gene expression patterns that occur throughout the entire life cycle in vitro. Nearly 5,000 genes were expressed in five distinct waves of transcription as the bacteria progressed from germination through sporulation, and we identified a specific set of functions represented within each wave. We also used these data to define the temporal expression of the spore proteome, and in doing so we have demonstrated that much of the spore's protein content is not synthesized de novo during sporulation but rather is packaged from preexisting stocks. We explored several potential mechanisms by which the cell could control which proteins are packaged into the developing spore, and our analyses were most consistent with a model in which B. anthracis regulates the composition of the spore proteome based on protein stability. This study is by far the most comprehensive survey yet of the B. anthracis life cycle and serves as a useful resource in defining the growth-phase-dependent expression patterns of each gene. Additionally, the data and accompanying bioinformatics analyses suggest a model for sporulation that has broad implications for B. anthracis biology and offer new possibilities for microbial forensics and detection.The members of the Bacillus genus are spore-forming bacteria that switch between two morphologies-the dormant endospore and the vegetative cell-depending on whether the local environment will facilitate growth. In spore form, the bacterium is resistant to a variety of physical extremes, including heat, desiccation, UV and ␥-irradiation, and oxidation, and the ability to switch between this cell type and the rapidly dividing vegetative form provides the bacilli with a highly effective strategy for persistence in the environment (28). Given the different functions of each, it is unsurprising that the two morphologies are microscopically and biochemically distinct, and the processes by which one form converts to the other, termed germination and sporulation, are known to be highly complex (10,30,35).In several Bacillus species, the two forms of the bacterium play very different roles in the establishment and progression of disease. The most prominent example of this is Bacillus anthracis, the causative agent of anthrax; in this case, the spore morphology allows the bacterium to evade host defenses and establish infection, and the disease state is then perpetuated by growth of (and toxin/capsule production by) vegetative cells within the body (9). Because the two morphologies each play a distinct role, the transitions between germination and sporulation represent key phases in the pathogenesis of this organism, and it is clear t...
The interaction between Bacillus anthracis and the mammalian phagocyte is one of the central stages in the progression of inhalational anthrax, and it is commonly believed that the host cell plays a key role in facilitating germination and dissemination of inhaled B. anthracis spores. Given this, a detailed definition of the survival strategies used by B. anthracis within the phagocyte is critical for our understanding of anthrax. In this study, we report the first genome-wide analysis of B. anthracis gene expression during infection of host phagocytes. We developed a technique for specific isolation of bacterial RNA from within infected murine macrophages, and we used custom B. anthracis microarrays to characterize the expression patterns occurring within intracellular bacteria throughout infection of the host phagocyte. We found that B. anthracis adapts very quickly to the intracellular environment, and our analyses identified metabolic pathways that appear to be important to the bacterium during intracellular growth, as well as individual genes that show significant induction in vivo. We used quantitative reverse transcription-PCR to verify that the expression trends that we observed by microarray analysis were valid, and we chose one gene (GBAA1941, encoding a putative transcriptional regulator) for further characterization. A deletion strain missing this gene showed no phenotype in vitro but was significantly attenuated in a mouse model of inhalational anthrax, suggesting that the microarray data described here provide not only the first comprehensive view of how B. anthracis survives within the host cell but also a number of promising leads for further research in anthrax.Bacillus anthracis, the causative agent of anthrax, has come under increased scrutiny in recent years because of its potential role as a bioweapon (35). In the environment, B. anthracis exists primarily as a metabolically dormant endospore, and in this morphology the bacterium is both highly infectious and resistant to a wide range of harsh conditions (42). When the spores are inhaled, they reach the alveolar spaces of the lung, where they are efficiently taken up by resident phagocytes (5, 9, 48). It is commonly believed that the host cells then migrate across the alveolocapillary barrier, transporting the intracellular bacteria into the lymphatic system (26,40). During this time, the bacteria germinate, transforming from spores into vegetative bacilli, which begin to replicate within the phagocytes (15, 50). Eventually, the bacteria kill the phagocytes and escape into the extracellular environment, and the resulting sepsis ultimately leads to death of the host (23,24,43,52,57).Since the progression of anthrax is typically quite rapid once the systemic phase of the infection begins (16, 24), successful intervention depends on early diagnosis and treatment. Given this fact, it is particularly important from a therapeutic standpoint that the early events in anthrax are well understood. Most of these events occur within the context of the h...
Purpose: To compare the safety and clinical outcomes of combined transjugular intrahepatic portosystemic shunt (TIPS) plus variceal obliteration to those of TIPS alone for the treatment of gastric varices (GVs). Materials and Methods:A single-center, retrospective study of 40 patients with bleeding or high-risk GVs between 2008 and 2019 was performed. The patients were treated with combined therapy (n ¼ 18) or TIPS alone (n ¼ 22). There were no significant differences in age, sex, model for end-stage liver disease score, or GV type between the groups. The primary outcomes were the rates of GV eradication and rebleeding. The secondary outcomes included portal hypertensive complications and hepatic encephalopathy. Results:The mean follow-up period was 15.4 months for the combined therapy group and 22.9 months for the TIPS group (P ¼ .32). After combined therapy, there was a higher rate of GV eradication (92% vs 47%, P ¼ .01) and a trend toward a lower rate of GV rebleeding (0% vs 23%, P ¼ .056). The estimated rebleeding rates were 0% versus 5% at 3 months, 0% versus 11% at 6 months, 0% versus 18% at 1 year, and 0% versus 38% at 2 years after combined therapy and TIPS, respectively (P ¼ .077). There was no difference in ascites (13% vs 11%, P ¼ .63), hepatic encephalopathy (47% vs 55%, P ¼ .44), or esophageal variceal bleeding (0% vs 0%, P > .999) after the procedure between the groups. Conclusions:The GV eradication rate is significantly higher after combined therapy, with no associated increase in portal hypertensive complications. This translates to a clinically meaningful trend toward a reduction in GV rebleeding. The value of a combined treatment strategy should be prospectively studied in a larger cohort to determine the optimal management of GVs. ABBREVIATIONSBATO ¼ balloon-occluded antegrade transvenous obliteration, BRTO ¼ balloon-occluded retrograde transvenous obliteration, EV ¼ esophageal varice, GV ¼ gastric varice, HE ¼ hepatic encephalopathy, PSG ¼ portosystemic pressure gradient, TIPS ¼ transjugular intrahepatic portosystemic shunt From the Department of Radiology (K.
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