A Case of Naturally Acquired Inhalation Anthrax: Clinical Care and Analyses of Anti-Protective Antigen Immunoglobulin G and Lethal Factor

Walsh, James J.; Pesik, Nicki; Quinn, Conrad P.; Urdaneta, Verónica; Dykewicz, Clare A.; Boyer, Anne; Guarner, Jeannette; Wilkins, Patricia P.; Norville, Kim; Barr, John R.; Zaki, Sherif R.; Patel, Jean B.; Reagan, Sarah; Pirkle, James L.; Treadwell, Tracee A.; Messonnier, Nancy Rosenstein; Rotz, Lisa D.; Meyer, Richard F.; Stephens, David S.

doi:10.1086/512372

Cited by 107 publications

(100 citation statements)

References 7 publications

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“…Using a highly sensitive assay for detection of LF activity, Boyer et al found that LF in the serum of infected macaques exhibited a triphasic kinetic profile, increasing with time after infection (41). By using the same method to monitor LF concentrations in the plasma of a human patient with naturally acquired anthrax, LF levels were highest (294.30 ng/ml) in the initial 24 h and remained detectable after the clearance of bacilli with antibiotic treatment (42). The interplay between the expression of InhA1 and LF in vivo may be important for the progression of anthrax disease.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the Bacillus anthracis Secretome by the Immune Inhibitor A1 Protease

Pflughoeft

Swick

Engler

et al. 2013

Journal of Bacteriology

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The Bacillus anthracis secretome includes protective antigen, lethal factor, and edema factor, which are the components of anthrax toxin, and other proteins with known or potential roles in anthrax disease. Immune inhibitor A1 (InhA1) is a secreted metalloprotease that is unique to pathogenic members of the Bacillus genus and has been associated with cleavage of host proteins during infection. Here, we report the effect of InhA1 on the B. anthracis secretome. Differential in-gel electrophoresis of proteins present in culture supernatants from a parent strain and an isogenic inhA1-null mutant revealed multiple differences. Of the 1,340 protein spots observed, approximately one-third were less abundant and one-third were more abundant in the inhA1 secretome than in the parent strain secretome. Proteases were strongly represented among those proteins exhibiting a 9-fold or greater change. InhA1 purified from a B. anthracis culture supernatant directly cleaved each of the anthrax toxin proteins as well as an additional secreted protease, Npr599. The conserved zinc binding motif HEXXH of InhA1 (HEYGH) was critical for its proteolytic activity. Our data reveal that InhA1 directly and indirectly modulates the form and/or abundance of over half of all the secreted proteins of B. anthracis. The proteolytic activity of InhA1 on established secreted virulence factors, additional proteases, and other secreted proteins suggests that this major protease plays an important role in virulence not only by cleaving mammalian substrates but also by modulating the B. anthracis secretome itself.

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Section: Discussionmentioning

confidence: 99%

Modulation of the Bacillus anthracis Secretome by the Immune Inhibitor A1 Protease

Pflughoeft

Swick

Engler

et al. 2013

Journal of Bacteriology

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“…Once patients display symptoms of inhalational anthrax, unfortunately, the infection has generally progressed to a point where even effective bactericidal antibiotic treatment can save only 55% of the infected individuals (8). This "point of no return" may reflect the fact that infection has progressed so far as to have disseminated from the original site of infection and spread hematogenously into the lungs and mediastinum to cause the classical diagnostic mediastinal widening associated with advanced inhalational anthrax, a point where it has been suggested that enough total exotoxin has been released to kill the host even in the absence of viable bacteria (73). This idea has some historical precedent, having first been proposed in 1924 by Fraenkel, who proposed that the initiating site of infection was in the tracheo-bronchial mucosa and that pneumonia developed after infection had been established (23).…”

Section: Reforming the Trojan Horse Model In Light Of New Datamentioning

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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“…Studies of adaptive immunity to anthrax infection have focused overwhelmingly on serology, with only one study reporting T cell responses to PA (10)(11)(12)(13). Data from animal or human vaccination studies show that the induction of LT-neutralizing Ab by vaccines containing PA correlates with protection (14)(15)(16).…”

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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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A Case of Naturally Acquired Inhalation Anthrax: Clinical Care and Analyses of Anti-Protective Antigen Immunoglobulin G and Lethal Factor

Cited by 107 publications

References 7 publications

Modulation of the Bacillus anthracis Secretome by the Immune Inhibitor A1 Protease

Modulation of the Bacillus anthracis Secretome by the Immune Inhibitor A1 Protease

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

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

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