Identification of In Vivo-Expressed Immunogenic Proteins by Serological Proteome Analysis of the
            <i>Bacillus anthracis</i>
            Secretome

Chitlaru, Theodor; Gat, Orit; Grosfeld, Haim; Inbar, Itzhak; Gozlan, Yael; Shafferman, Avigdor

doi:10.1128/iai.02029-06

Cited by 108 publications

(105 citation statements)

References 85 publications

(130 reference statements)

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“…8) showed that VWF was present in a cleaved, dimeric form, in agreement with the presence of InhA and other proteolytic enzymes among B. anthracissecreted proteins (41,42). Consistent with the fact that AnlO is a pore-forming toxin but not a protease, the AnlO-induced VWF was highly aggregated (Fig.…”

Section: Anthrax Proteases Are Capable Of Inducing and Then Degradingsupporting

confidence: 59%

Degradation of Circulating von Willebrand Factor and Its Regulator ADAMTS13 Implicates Secreted Bacillus anthracis Metalloproteases in Anthrax Consumptive Coagulopathy

Chung

Popova

Jorgensen

et al. 2008

Journal of Biological Chemistry

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Pathology data from the anthrax animal models show evidence of significant increases in vascular permeability coincident with hemostatic imbalances manifested by thrombocytopenia, transient leucopenia, and aggressive disseminated intravascular coagulation. In this study we hypothesized that anthrax infection modulates the activity of von Willebrand factor (VWF) and its endogenous regulator ADAMTS13, which play important roles in hemostasis and thrombosis, including interaction of endothelial cells with platelets. We previously demonstrated that purified anthrax neutral metalloproteases Npr599 and InhA are capable of cleaving a variety of host structural and regulatory proteins. Incubation of human plasma with these proteases at 37°C in the presence of urea as a mild denaturant results in proteolysis of VWF. Also in these conditions, InhA directly cleaves plasma ADAMTS13 protein. Npr599 and InhA digest synthetic VWF substrate FRETS-VWF73. Amino acid sequencing of VWF fragments produced by InhA suggests that one of the cleavage sites of VWF is located at domain A2, the target domain of ADAMTS13. Proteolysis of VWF by InhA impairs its collagen binding activity (VWF:CBA) and ristocetin-induced platelet aggregation activity. In plasma from anthrax spore-challenged DBA/2 mice, VWF antigen levels increase up to 2-fold at day 3 post-infection with toxigenic Sterne 34F 2 strain, whereas VWF:CBA levels drop in a time-dependent manner, suggesting dysfunction of VWF instead of its quantitative deficiency. This conclusion is further supported by significant reduction in the amount of VWF circulating in blood in the ultra-large forms. In addition, Western blot analysis shows proteolytic depletion of ADAMTS13 from plasma of spore-challenged mice despite its increased expression in the liver. Our results suggest a new mechanism of anthrax coagulopathy affecting the levels and functional activities of both VWF and its natural regulator ADAMTS13. This mechanism may contribute to hemorrhage and thrombosis typical in anthrax.Bacillus anthracis, the causative agent of anthrax, is a zoonotic, Gram-positive, spore-forming Bacillus. It is capable of causing a highly lethal systemic infection in people and experimental animals upon inhalation of the spores. The pathological mechanisms underlying high mortality of inhalation anthrax infection are complex and remain insufficiently understood. The major virulence factors, lethal toxin (LT) 2 and edema toxin (ET) produced by B. anthracis can cause death of experimental animals with symptoms resembling those of anthrax infection. Therefore, many studies have been focused on the cytotoxic effects of LT, including the cells of monocyte lineage (peripheral blood monocytes, macrophages, and dendritic cells) (1) and epithelial cells (2). It has also been reported that the LT-induced cell death could cause a massive release of the pro-inflammatory cytokines, such as the tumor necrosis factor ␣ (TNF␣), which may result in lethality (3), but recent data clearly indicate that the intoxication mediate...

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Section: Anthrax Proteases Are Capable Of Inducing and Then Degradingsupporting

confidence: 59%

Degradation of Circulating von Willebrand Factor and Its Regulator ADAMTS13 Implicates Secreted Bacillus anthracis Metalloproteases in Anthrax Consumptive Coagulopathy

Chung

Popova

Jorgensen

et al. 2008

Journal of Biological Chemistry

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“…This suggests that individual NEAT domains can serve as immunogens for induction of neutralizing antibodies, and protection is probably due to inhibition of NEAT function by the antibody binding to the heme binding structure. Interestingly, IsdX2 was one of the top five most robust inducers of antibody production in a serum screen of potential anthrax immunogens (63). Such studies highlight the importance of understanding the mechanism of action of NEAT proteins for both vaccine and anti-infective development.…”

Section: Discussionmentioning

confidence: 99%

The Five Near-iron Transporter (NEAT) Domain Anthrax Hemophore, IsdX2, Scavenges Heme from Hemoglobin and Transfers Heme to the Surface Protein IsdC

Honsa

Fabián

Cárdenas

et al. 2011

Journal of Biological Chemistry

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“…Research has for decades focused on the precept that the protective immune response to anthrax is directed at PA and LF (although with the caveat that in many studies, other targets have not been investigated) (10,17). Bacterial immunomics highlights other potential immune targets from the B. anthracis proteome (18), although only PA and LF have a track record in conferring both active and passive immunity in response to experimental bacterial challenge (10,19). Early serological studies of responses from naturally infected individuals in Zimbabwe showed that most individuals generated Abs to PA and LF and a minority also made a response to EF (10).…”

mentioning

confidence: 99%

Natural Exposure to Cutaneous Anthrax Gives Long-Lasting T Cell Immunity Encompassing Infection-Specific Epitopes

Ingram

Metan²,

Maillère³

et al. 2010

The Journal of Immunology

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Identification of In Vivo-Expressed Immunogenic Proteins by Serological Proteome Analysis of the Bacillus anthracis Secretome

Cited by 108 publications

References 85 publications

Degradation of Circulating von Willebrand Factor and Its Regulator ADAMTS13 Implicates Secreted Bacillus anthracis Metalloproteases in Anthrax Consumptive Coagulopathy

Degradation of Circulating von Willebrand Factor and Its Regulator ADAMTS13 Implicates Secreted Bacillus anthracis Metalloproteases in Anthrax Consumptive Coagulopathy

The Five Near-iron Transporter (NEAT) Domain Anthrax Hemophore, IsdX2, Scavenges Heme from Hemoglobin and Transfers Heme to the Surface Protein IsdC

Natural Exposure to Cutaneous Anthrax Gives Long-Lasting T Cell Immunity Encompassing Infection-Specific Epitopes

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