Inhibition of platelet aggregation by anthrax edema toxin.
Edema toxin is a key virulence determinant in anthrax pathogenesis that causes augmentation of cAMP inside host cells. This exotoxin has been implicated in facilitating bacterial invasion by impairing host defenses. Here, we report for the first time that edema toxin plays an important role in suppression of platelet aggregation; an effect that could be of vital significance in anthrax afflicted subjects. It was found that edema toxin induces a dose dependent and time dependent increase in cAMP inside rabbit platelets. Elevation of cAMP led to suppression of platelet aggregation as demonstrated by in vitro aggregation assays. A 95% suppression of platelet aggregation in response to thrombin and a complete suppression in response to ADP, at toxin concentrations of 7 and 2.2 nM, respectively, were observed. Antibody neutralized wild type edema factor and non-toxic mutants of this binary toxin failed to show any alteration in the normal aggregation pattern. Edema toxin caused the activation of cAMP dependent protein kinase A inside platelets, a phenomenon that could be speculated to initiate the cascade of events responsible for suppressing platelet aggregation. Furthermore, in vivo bleeding time registered a sharp increase in response to edema toxin. These findings can explicate the systemic occurrence of hemorrhage, which is a prominent symptom of anthrax. This study exemplifies how Bacillus anthracis has evolved the ability to use host's physiological processes by mimicking the eukaryotic signal transduction machinery, thus inflicting persistent infection.
Alam
Sheeba
S
Centre for Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
Gupta
Megha
M
Bhatnagar
Rakesh
R
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology / Q000502:physiology*; D001408:Bacillus anthracis / Q000502:physiology*; D001427:Bacterial Toxins / Q000494:pharmacology; D001760:Bleeding Time; D001792:Blood Platelets / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D013917:Thrombin / Q000494:pharmacology
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D000244:Adenosine Diphosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D013917:Thrombin