Phosphate starvation enhances the pathogenesis of Bacillus anthracis

Aggarwal, Somya; Somani, Vikas Kumar; Bhatnagar, Rakesh

doi:10.1016/j.ijmm.2015.06.001

Cited by 16 publications

(8 citation statements)

References 50 publications

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“…As a consequence, severe hypophosphatemia in sepsis has become a predictor of mortality 9 . This Pi mediated regulation of virulence has also been observed for other pathogens, for example, Agrobacterium tumefaciens 10 , Vibrio cholerae 11 and Bacillus anthracis 12 .…”

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confidence: 58%

Two different mechanisms mediate chemotaxis to inorganic phosphate in Pseudomonas aeruginosa

Rico-Jiménez

Reyes-Darias

Ortega

et al. 2016

Sci Rep

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Inorganic phosphate (Pi) is a central signaling molecule that modulates virulence in various pathogens. In Pseudomonas aeruginosa, low Pi concentrations induce transcriptional alterations that increase virulence. Also, under low Pi levels, P. aeruginosa exhibits Pi chemotaxis—a process mediated by the two non-paralogous receptors CtpH and CtpL. Here we show that the two receptors operate via different mechanisms. We demonstrate that the ligand binding domain (LBD) of CtpH but not CtpL binds Pi directly. We identify the periplasmic ligand binding protein PstS as the protein that binds in its Pi loaded state to CtpL, resulting in receptor stimulation. PstS forms part of the Pi transporter and has thus a double function in Pi transport and chemotaxis. The affinity of Pi for CtpH was modest whereas that for PstS very high, which may explain why CtpH and CtpL mediate chemotaxis to high and low Pi concentrations, respectively. The pstS/ctpH double mutant was almost devoid of Pi taxis, indicating that PstS is the only CtpL Pi-shuttle. Chemotaxis mechanisms based on indirect ligand recognition were unambiguously identified in enterobacteria. The discovery of a similar mechanism in a different bacterial order, involving a different chemoreceptor type and chemoeffector suggests that such systems are widespread.

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confidence: 58%

Two different mechanisms mediate chemotaxis to inorganic phosphate in Pseudomonas aeruginosa

Rico-Jiménez

Reyes-Darias

Ortega

et al. 2016

Sci Rep

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“…For example, P i availability controls motility, biofilm formation, colonization, induction of virulence factors such as C phospholipases in Pseudomonas aeruginosa, colonization factor and toxin synthesis in Vibrio cholerae, enteropathogenic and enterohemorrhagic Escherichia coli (review in Reference [58]). In Bacillus anthracis, P i starvation enhances spore germination, invasiveness in macrophages and toxin secretion [59]. It can be speculated that P i availability might also facilitate wound colonization by C. tetani and in situ TeNT production.…”

Section: Discussionmentioning

confidence: 99%

Tetanus Toxin Synthesis is Under the Control of A Complex Network of Regulatory Genes in Clostridium tetani

Chapeton-Montes

Plourde

Denève

et al. 2020

Toxins

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Clostridium tetani produces a potent neurotoxin, the tetanus toxin (TeNT), which is responsible for an often-fatal neurological disease (tetanus) characterized by spastic paralysis. Prevention is efficiently acquired by vaccination with the TeNT toxoid, which is obtained by C. tetani fermentation and subsequent purification and chemical inactivation. C. tetani synthesizes TeNT in a regulated manner. Indeed, the TeNT gene (tent) is mainly expressed in the late exponential and early stationary growth phases. The gene tetR (tetanus regulatory gene), located immediately upstream of tent, encodes an alternative sigma factor which was previously identified as a positive regulator of tent. In addition, the genome of C. tetani encodes more than 127 putative regulators, including 30 two-component systems (TCSs). Here, we investigated the impact of 12 regulators on TeNT synthesis which were selected based on their homology with related regulatory elements involved in toxin production in other clostridial species. Among nine TCSs tested, three of them impact TeNT production, including two positive regulators that indirectly stimulate tent and tetR transcription. One negative regulator was identified that interacts with both tent and tetR promoters. Two other TCSs showed a moderate effect: one binds to the tent promoter and weakly increases the extracellular TeNT level, and another one has a weak inverse effect. In addition, CodY (control of dciA (decoyinine induced operon) Y) but not Spo0A (sporulation stage 0) or the DNA repair protein Mfd (mutation frequency decline) positively controls TeNT synthesis by interacting with the tent promoter. Moreover, we found that inorganic phosphate and carbonate are among the environmental factors that control TeNT production. Our data show that TeNT synthesis is under the control of a complex network of regulators that are largely distinct from those involved in the control of toxin production in Clostridium botulinum or Clostridium difficile.

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“…The level of primary virulence factors like PA, LF, and EF secreted in the presence of different inhibitors were quantitated using ELISA as described previously (Aggarwal et al, 2015 ). Briefly, the media supernatants from BHI with 1% NaHCO 3 grown B. anthracis cultures containing various inhibitors were first concentrated.…”

Section: Methodsmentioning

confidence: 99%

Identification of Novel Raft Marker Protein, FlotP in Bacillus anthracis

et al. 2016

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Lipid rafts are dynamic, nanoscale assemblies of specific proteins and lipids, distributed heterogeneously on eukaryotic membrane. Flotillin-1, a conserved eukaryotic raft marker protein (RMP) harbor SPFH (Stomatin, Prohibitin, Flotillin, and HflK/C) and oligomerization domains to regulate various cellular processes through its interactions with other signaling or transport proteins. Rafts were thought to be absent in prokaryotes hitherto, but recent report of its presence and significance in physiology of Bacillus subtilis prompted us to investigate the same in pathogenic bacteria (PB) also. In prokaryotes, proteins of SPFH2a subfamily show highest identity to SPFH domain of Flotillin-1. Moreover, bacterial genome organization revealed that Flotillin homolog harboring SPFH2a domain exists in an operon with an upstream gene containing NFeD domain. Here, presence of RMP in PB was initially investigated in silico by analyzing the presence of SPFH2a, oligomerization domains in the concerned gene and NfeD domain in the adjacent upstream gene. After investigating 300 PB, four were found to harbor RMP. Among them, domains of Bas0525 (FlotP) of Bacillus anthracis (BA) showed highest identity with characteristic domains of RMP. Considering the global threat of BA as the bioterror agent, it was selected as a model for further in vitro characterization of rafts in PB. In silico and in vitro analysis showed significant similarity of FlotP with numerous attributes of Flotillin-1. Its punctate distribution on membrane with exclusive localization in detergent resistant membrane fraction; strongly favors presence of raft with RMP FlotP in BA. Furthermore, significant effect of Zaragozic acid (ZA), a raft associated lipid biosynthesis inhibitor, on several patho-physiological attributes of BA such as growth, morphology, membrane rigidity etc., were also observed. Specifically, a considerable decrease in membrane rigidity, strongly recommended presence of an unknown raft associated lipid molecule on membrane of BA. In addition, treatment with ZA decreased secretion of anthrax toxins and FlotP expression, suggesting potential role of raft in pathogenesis and physiology of BA. Thus, the present study not only suggest the existence and role of raft like entity in pathophysiology of BA but also its possible use for the development of novel drugs or vaccines against anthrax.

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Phosphate starvation enhances the pathogenesis of Bacillus anthracis

Cited by 16 publications

References 50 publications

Two different mechanisms mediate chemotaxis to inorganic phosphate in Pseudomonas aeruginosa

Two different mechanisms mediate chemotaxis to inorganic phosphate in Pseudomonas aeruginosa

Tetanus Toxin Synthesis is Under the Control of A Complex Network of Regulatory Genes in Clostridium tetani

Identification of Novel Raft Marker Protein, FlotP in Bacillus anthracis

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