Effective antiprotease-antibiotic treatment of experimental anthrax

Попов, Сергей Витальевич; Popova, Taissia G.; Hopkins, Svetlana; Weinstein, Raymond S.; MacAfee, Rebecca; Fryxell, Karl J.; Chandhoke, Vikas; Bailey, Charles; Alibek, Ken

doi:10.1186/1471-2334-5-25

Cited by 42 publications

(53 citation statements)

References 45 publications

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“…There is strong evidence that proteases contribute substantially to anthrax as well, and the InhA1 protease, which is suggested from the findings of the present study to degrade hemoglobin, is involved in a number of pathogenic properties for Bacillus species. Popov and colleagues (57) found that protease inhibitors showed a synergistic protective effect when administered with antibiotics in mice given a lethal dose of B. anthracis, suggesting that proteolytic activity contributes to the onset of anthrax. Indeed, mice infected with a B. anthracis strain lacking inhA1 survived longer than their wild-type-infected counterparts, a property potentially related to the fact that many fewer bacilli penetrate the bloodbrain barrier and infect the brain (58).…”

Section: Discussionmentioning

confidence: 99%

Bacillus anthracis Overcomes an Amino Acid Auxotrophy by Cleaving Host Serum Proteins

et al. 2015

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Bacteria sustain an infection by acquiring nutrients from the host to support replication. The host sequesters these nutrients as a growth-restricting strategy, a concept termed "nutritional immunity." Historically, the study of nutritional immunity has centered on iron uptake because many bacteria target hemoglobin, an abundant circulating protein, as an iron source. Left unresolved are the mechanisms that bacteria use to attain other nutrients from host sources, including amino acids. We employed a novel medium designed to mimic the chemical composition of human serum, and we show here that Bacillus anthracis, the causative agent of anthrax disease, proteolyzes human hemoglobin to liberate essential amino acids which enhance its growth. This property can be traced to the actions of InhA1, a secreted metalloprotease, and extends to at least three other serum proteins, including serum albumin. The results suggest that we must also consider proteolysis of key host proteins to be a way for bacterial pathogens to attain essential nutrients, and we provide an experimental framework to determine the host and bacterial factors involved in this process. IMPORTANCEThe mechanisms by which bacterial pathogens acquire nutrients during infection are poorly understood. Here we used a novel defined medium that approximates the chemical composition of human blood serum, blood serum mimic (BSM), to better model the nutritional environment that pathogens encounter during bacteremia. Removing essential amino acids from BSM revealed that two of the most abundant proteins in blood-hemoglobin and serum albumin-can satiate the amino acid requirement for Bacillus anthracis, the causative agent of anthrax. We further demonstrate that hemoglobin is proteolyzed by the secreted protease InhA1. These studies highlight that common blood proteins can be a nutrient source for bacteria. They also challenge the historical view that hemoglobin is solely an iron source for bacterial pathogens. There are three broad, necessary, and common elements inherent in most if not all bacterial infections of vertebrate hosts. They are (i) the initial entry of the bacterial invader and adherence to host tissues, (ii) the production of virulence factors or toxins (usually proteins) that subvert host innate and acquired immune defense mechanisms, and (iii) the acquisition and construction of biomolecules to drive cellular metabolism for the production of progeny. There has been intense investigation, and knowledge of the biochemistry, cell biology, and contribution to disease of a diverse array of bacterial adhesins and virulence factors (points i and ii identified above) is growing. However, our knowledge of nutrient acquisition during pathogenesis has lagged, perhaps because it is viewed as being a necessary and somewhat mundane process that may lack the elegant sophistication observed with virulence factors. Considering that all systemic infections are absolutely dependent on the replication of bacterial cells, identifying the mechanisms by which ba...

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Section: Discussionmentioning

confidence: 99%

Bacillus anthracis Overcomes an Amino Acid Auxotrophy by Cleaving Host Serum Proteins

et al. 2015

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“…anthracis produces, in addition to the major virulence factors, at least four separate proteases that promote host tissue degradation to break down barriers to bacterial dissemination (59). These proteases break down gelatin, casein, fibronectin, laminin, and collagen.…”

Section: Dissemination Factorsmentioning

confidence: 99%

Updating Perspectives on the Initiation of Bacillus anthracis Growth and Dissemination through Its Host

Weiner

Glomski

2012

Infect Immun

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ABSTRACTSince 1957, it has been proposed that the dissemination of inhalational anthrax required spores to be transported from the lumena of the lungs into the lymphatic system. In 2002, this idea was expanded to state that alveolar macrophages act as a “Trojan horse” capable of transporting spores across the lung epithelium into draining mediastinal lymph nodes. Since then, the Trojan horse model of dissemination has become the most widely cited model of inhalational infection as well as the focus of the majority of studies aiming to understand events initiating inhalational anthrax infections. However, recent observations derived from animal models ofBacillus anthracisinfection are inconsistent with aspects of the Trojan horse model and imply that bacterial dissemination patterns during inhalational infection may be more similar to the cutaneous and gastrointestinal forms than previously thought. In light of these studies, it is of significant importance to reassess the mechanisms of inhalational anthrax dissemination, since it is this form of anthrax that is most lethal and of greatest concern whenB. anthracisis weaponized. Here we propose a new “jailbreak” model ofB. anthracisdissemination which applies to the dissemination of all common manifestations of the disease anthrax. The proposed model impacts the field by deemphasizing the role of host cells as conduits for dissemination and increasing the role of phagocytes as central players in innate defenses, while moving the focus toward interactions betweenB. anthracisand lymphoid and epithelial tissues.

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“…It has been suggested that the evolutionary inactivation of the PlcR regulon in B. anthracis was due to incompatibility with the AtxAcontrolled regulon and reflects the fact that the PlcR target genes are not essential for anthrax pathogenicity (96). Several studies have postulated that secreted proteases, other than those belonging to the silenced PlcR regulon, are responsible for some clinical manifestations of anthrax (1,9,117,140). Such proteases could damage host tissues, interfere with immune effectors of the host, and/or provide nutrients for bacterial survival (103).…”

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Differential Proteomic Analysis of theBacillus anthracisSecretome: Distinct Plasmid and Chromosome CO₂-Dependent Cross Talk Mechanisms Modulate Extracellular Proteolytic Activities

et al. 2006

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The secretomes of a virulent Bacillus anthracis strain and of avirulent strains (cured of the virulence plasmids pXO1 and pXO2), cultured in rich and minimal media, were studied by a comparative proteomic approach. More than 400 protein spots, representing the products of 64 genes, were identified, and a unique pattern of protein relative abundance with respect to the presence of the virulence plasmids was revealed. In minimal medium under high CO 2 tension, conditions considered to simulate those encountered in the host, the presence of the plasmids leads to enhanced expression of 12 chromosome-carried genes (10 of which could not be detected in the absence of the plasmids) in addition to expression of 5 pXO1-encoded proteins. Furthermore, under these conditions, the presence of the pXO1 and pXO2 plasmids leads to the repression of 14 chromosomal genes. On the other hand, in minimal aerobic medium not supplemented with CO 2 , the virulent and avirulent B. anthracis strains manifest very similar protein signatures, and most strikingly, two proteins (the metalloproteases InhA1 and NprB, orthologs of gene products attributed to the Bacillus cereus group PlcR regulon) represent over 90% of the total secretome. Interestingly, of the 64 identified gene products, at least 31 harbor features characteristic of virulence determinants (such as toxins, proteases, nucleotidases, sulfatases, transporters, and detoxification factors), 22 of which are differentially regulated in a plasmid-dependent manner. The nature and the expression patterns of proteins in the various secretomes suggest that distinct CO 2 -responsive chromosome-and plasmid-encoded regulatory factors modulate the secretion of potential novel virulence factors, most of which are associated with extracellular proteolytic activities.Bacillus anthracis is a gram-positive spore-forming bacterium that is the etiological agent of anthrax, a lethal disease sporadically affecting humans and animals, in particular herbivores. In its most severe manifestation, B. anthracis infection is initiated by inhalation of spores, which are taken up by alveolar macrophages and germinate into fast-dividing vegetative cells which secrete toxins and virulence factors during growth (81,99). If untreated by prompt antibiotic administration, the bacteria invade the bloodstream, resulting in massive bacteremia and consequently generalized systemic failure and death. B. anthracis is considered to represent a potential biothreat agent, owing to the severity of the anthrax disease, the ease of respiratory contamination, and the perpetual environmental stability of the infective spores. The recent deliberate dissemination of B. anthracis (15) accelerated the efforts to identify new B. anthracis virulence-related determinants for the design of novel diagnostic, preventive, and/or therapeutic strategies.Fully virulent B. anthracis strains harbor two native plasmids, pXO1 and pXO2, which encode critical pathogenicity factors. The absence of either one of the two plasmids results in a pronounce...

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Effective antiprotease-antibiotic treatment of experimental anthrax

Cited by 42 publications

References 45 publications

Bacillus anthracis Overcomes an Amino Acid Auxotrophy by Cleaving Host Serum Proteins

Bacillus anthracis Overcomes an Amino Acid Auxotrophy by Cleaving Host Serum Proteins

Updating Perspectives on the Initiation of Bacillus anthracis Growth and Dissemination through Its Host

Differential Proteomic Analysis of theBacillus anthracisSecretome: Distinct Plasmid and Chromosome CO₂-Dependent Cross Talk Mechanisms Modulate Extracellular Proteolytic Activities

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Effective antiprotease-antibiotic treatment of experimental anthrax

Cited by 42 publications

References 45 publications

Bacillus anthracis Overcomes an Amino Acid Auxotrophy by Cleaving Host Serum Proteins

Bacillus anthracis Overcomes an Amino Acid Auxotrophy by Cleaving Host Serum Proteins

Updating Perspectives on the Initiation of Bacillus anthracis Growth and Dissemination through Its Host

Differential Proteomic Analysis of theBacillus anthracisSecretome: Distinct Plasmid and Chromosome CO2-Dependent Cross Talk Mechanisms Modulate Extracellular Proteolytic Activities

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About

Differential Proteomic Analysis of theBacillus anthracisSecretome: Distinct Plasmid and Chromosome CO₂-Dependent Cross Talk Mechanisms Modulate Extracellular Proteolytic Activities