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Environmental Regulation of Toxin Production in Bacillus anthracis
Open accessPreprint — published as 10.1371/journal.ppat.1013587 · Paper page
Abstract
Pathogenic Bacillus anthracis strains carry two plasmids - pX01, which encodes a tripartite protein exotoxin complex (PA, LF, and EF); and pX02, which encodes a poly-D-gamma-glutamic acid capsule. A multidomain transcription factor, AtxA, regulates the expression of these virulence genes. AtxA has two DNA-binding Helix-Turn-Helix (HTH) domains, two phosphoenolpyruvate:carbohydrate phosphotransferase system regulatory domains (PRD1 and PRD2), and a putative EIIB domain (a component of PTS sugar transport EII-complexes). Previous studies showed that glucose and CO2 increase AtxA-dependent toxin gene transcription, along with histidine phosphorylation of PRD1 and PRD2. Our transcriptional profiling of virulence factors, PA secretion, and fluorescent reporter strain analyses confirms a synergistic effect of glucose and CO2 on AtxA-dependent toxin production. Deletion of AtxA (Δ atxA ) significantly reduced glucose uptake in bacteria, suggesting that AtxA may act within the glucose-PTS system. Mutation analysis of the EIIB domain of AtxA identified the cysteine at position 402 as essential for the transcriptional activity of AtxA. Deletion of glucose PTS permease PtsG (Δ ptsG ) significantly reduced the expression of PA, LF, and EF. Loss of PtsG also caused attenuation in a mouse model of infection. Intracellular imaging using FLIM confirms a physical interaction of PtsG and AtxA through EIIB domain of AtxA. Using phosphomimetic and phosphoablative mutants of AtxA, we confirmed that the physical interaction of PtsG and AtxA is essential for AtxA activity. Finally, the synergy between glucose and CO2 was targeted by deleting pyruvate carboxylase Pyc (Δ pyc ), which regulates anaplerosis. This deletion confirms that Pyc stimulates the level of phosphoenolpyruvate (PEP) and increases the phosphorelay in glucose-PTS to enhance AtxA activity. Therefore, we propose that a histidine-phosphorelay from PEP regulates AtxA via PTS enzymatic activity, impacting AtxA activity through physical interaction of AtxA and PtsG. Finally, we propose AtxA as an integral component of the glucose-PTS, where transcriptional activity of AtxA is regulated by environmental signals including glucose and CO2.
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Metadata
- Authors
- Bothra, A., Pomerantsev, A., Schwarz, B., Mondal, A., Bohrnsen, E., Sangwan, N., Stromberg, K. A., Moayeri, M., Ma, Q., Fattah, R., Ganesan, S., Bosio, C. M., & Leppla, S. H.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Bothra, Ankur
- ORCID
- Venue
- PLoS Pathogens
- Publisher
- openRxiv
- Published
- 2025-10-07
- Volume
- 21
- Issue
- 12
- Pages
- e1013587-e1013587
- ISSN
- 1553-7366 (ISSN-L)
- PMC
- PMC12680359
- OpenAlex
- W4416946995
- Cited by
- 2
- References
- 1
- Citations by year
- 2026: 1 · 2025: 1
- FWCI
- 0.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- Locations
- PLoS Pathogens (publishedVersion, public-domain)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, public-domain)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, public-domain)
- Funders
- U.S. Department of Health and Human Services
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- National Institutes of Health
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacillus and Francisella bacterial research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Immunology and Microbiology › Microbiology › Escherichia coli research studies
- Keywords
- Bacillus anthracis, AtxA, toxin gene regulation, pyruvate carboxylase, anaplerosis, carbon dioxide, histidine phosphorylation, virulence gene expression, protein-protein interaction
- MeSH terms
- Animals, Anthrax, Antigens, Bacterial, Bacillus anthracis, Bacterial Proteins, Bacterial Toxins, Carbon Dioxide, Female, Glucose, Virulence, Trans-Activators, Gene Expression Regulation, Bacterial, Virulence Factors, Mice
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