[Frontiers in Bioscience 14, 2335-2357, January 1, 2009]

[Frontiers in Bioscience 14, 2335-2357, January 1, 2009]

Anthrax toxin: pathologic effects on the cardiovascular system

Honey B. Golden¹, Linley E. Watson², Hind Lal¹, Suresh K. Verma¹, Donald M. Foster³, Shu-ru Kuo⁴, Avadhesh Sharma⁵, Arthur Frankel⁴, David E. Dostal¹

1Division of Molecular Cardiology, Cardiovascular Research Institute, The Texas A and M University System Health Science Center, College of Medicine, Scott and White, ²Division of Cardiology, Scott and White Memorial Hospital,³Central Texas Veterans Health Care System, Temple, Texas, ⁴Scott and White Cancer Research Institute, Temple, TX, ⁵Department of Biomedical Science, Baylor College of Dentistry, The Texas A and M Health Science Center, Dallas, TX

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Structure and biochemistry of anthrax toxins: 3.1. Lethal factor; 3.2. Edema factor
4. Anthrax Toxin receptors: 4.1. Basic structure of TEM8 and CMG2 receptors; 4.2. Expression and function of TEM8 (ATR1); 4.3. Expression and function of CMG2 (ATR2); 4.4. Ligand binding and anthrax receptor function; 4.5. LPR6 as a co-receptor for TEM8 and CMG2
5. Internalization of Anthrax Toxins: 5.1. Protective antigen and internalization of lethal factor and edema factor; 5.2. Molecular modeling of anthrax toxin internalization
6. General effects of anthrax toxicity: 6.1. Clinical presentation of anthrax toxicity; 6.2. Cellular Effects of Lethal Toxin; 6.3. Cellular effects of edema toxin
7. Cardiovascular effects of anthrax toxicity: 7.1. Hemodynamic effects of inhalational anthrax; 7.2. Cardiovascular effects observed in animal studies; 7.3. Cardiovascular effects of MAP kinase kinase (MEK) cleavage
8. Therapeutic approaches: 8.1. Vaccines; 8.2. Antibodies; 8.3. Types of anthrax toxin inhibitors; 8.4. Novel anti-anthrax approaches
9. Summary and future perspectives
10. Acknowledgement
11. References

1. ABSTRACT

Anthrax is a disease caused by infection with spores from the bacteria Bacillus anthracis. After entering the body, the spores germinate into bacteria and secrete a toxin that causes local edema and, in systemic infections, cardiovascular collapse and death. The toxin is a tripartite polypeptide, consisting of protective antigen (PA), lethal factor (LF) and edema factor (EF), which have key roles in the bacterial pathogenesis and disease progression. PA facilitates transfer of LF and EF to the cytosol. Lethal toxin is a zinc metalloproteinase, which has the capacity to inactivate mitogen-activated protein (MAP) kinase kinase (MEK) and stimulates the release of sepsis-related cytokines tumor necrosis factor-alpha and interleukin-1beta. Edema factor is a calmodulin (CaM)-dependent adenylate cyclase, which increases levels of cyclic AMP, causing impaired neutrophil function and disruption of water balance that ultimately results in massive tissue edema. Together, the toxins effectively inhibit host innate and adaptive immune responses, allowing the bacteria to grow unrestrained and overwhelming any resistance. Clinically, inhalational anthrax presents in a biphasic pattern with initial nonspecific "flu-like" symptoms nausea and vomiting 1 to 4 days after exposure, followed by severe illness with dyspnea, high fever and circulatory shock. The latter symptoms represent a terminal stage and treatment is often ineffective when started at that time. Key indicators of early anthrax cardiovascular-related pathogenesis include mediastinal widening in association with pleural effusion and edema. In this review, we describe the current understanding of anthrax toxins on cellular function in the context of cardiovascular function and discuss potential therapeutic strategies.