Anthrax Edema Toxin Impairs Clearance in Mice Inka Sastalla a , Shixing Tang b , Devorah Crown a , Shihui Liu a , Michael A. Eckhaus c , Indira K. Hewlett b , Stephen H. Leppla a and Mahtab Moayeri a a Bacterial Toxins and Therapeutics Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA b Laboratory of Molecular Virology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA c Diagnostic and Research Services Branch, Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, Maryland, USA J. B. Bliska , Editor ABSTRACT The anthrax edema toxin (ET) of Bacillus anthracis is composed of the receptor-binding component protective antigen (PA) and of the adenylyl cyclase catalytic moiety, edema factor (EF). Uptake of ET into cells raises intracellular concentrations of the secondary messenger cyclic AMP, thereby impairing or activating host cell functions. We report here on a new consequence of ET action in vivo . We show that in mouse models of toxemia and infection, serum PA concentrations were significantly higher in the presence of enzymatically active EF. These higher concentrations were not caused by ET-induced inhibition of PA endocytosis; on the contrary, ET induced increased PA binding and uptake of the PA oligomer in vitro and in vivo through upregulation of the PA receptors TEM8 and CMG2 in both myeloid and nonmyeloid cells. ET effects on protein clearance from circulation appeared to be global and were not limited to PA. ET also impaired the clearance of ovalbumin, green fluorescent protein, and EF itself, as well as the small molecule biotin when these molecules were coinjected with the toxin. Effects on injected protein levels were not a result of general increase in protein concentrations due to fluid loss. Functional markers for liver and kidney were altered in response to ET. Concomitantly, ET caused phosphorylation and activation of the aquaporin-2 water channel present in the principal cells of the collecting ducts of the kidneys that are responsible for fluid homeostasis. Our data suggest that in vivo , ET alters circulatory protein and small molecule pharmacokinetics by an as-yet-undefined mechanism, thereby potentially allowing a prolonged circulation of anthrax virulence factors such as EF during infection.
Anthrax Edema Toxin Impairs Clearance in Mice
Abstract
Anthrax Edema Toxin Impairs Clearance in Mice Inka Sastalla a , Shixing Tang b , Devorah Crown a , Shihui Liu a , Michael A. Eckhaus c , Indira K. Hewlett b , Stephen H. Leppla a and Mahtab Moayeri a a Bacterial Toxins and Therapeutics Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA b Laboratory of Molecular Virology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA c Diagnostic and Research Services Branch, Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, Maryland, USA J. B. Bliska , Editor ABSTRACT The anthrax edema toxin (ET) of Bacillus anthracis is composed of the receptor-binding component protective antigen (PA) and of the adenylyl cyclase catalytic moiety, edema factor (EF). Uptake of ET into cells raises intracellular concentrations of the secondary messenger cyclic AMP, thereby impairing or activating host cell functions. We report here on a new consequence of ET action in vivo . We show that in mouse models of toxemia and infection, serum PA concentrations were significantly higher in the presence of enzymatically active EF. These higher concentrations were not caused by ET-induced inhibition of PA endocytosis; on the contrary, ET induced increased PA binding and uptake of the PA oligomer in vitro and in vivo through upregulation of the PA receptors TEM8 and CMG2 in both myeloid and nonmyeloid cells. ET effects on protein clearance from circulation appeared to be global and were not limited to PA. ET also impaired the clearance of ovalbumin, green fluorescent protein, and EF itself, as well as the small molecule biotin when these molecules were coinjected with the toxin. Effects on injected protein levels were not a result of general increase in protein concentrations due to fluid loss. Functional markers for liver and kidney were altered in response to ET. Concomitantly, ET caused phosphorylation and activation of the aquaporin-2 water channel present in the principal cells of the collecting ducts of the kidneys that are responsible for fluid homeostasis. Our data suggest that in vivo , ET alters circulatory protein and small molecule pharmacokinetics by an as-yet-undefined mechanism, thereby potentially allowing a prolonged circulation of anthrax virulence factors such as EF during infection.Preview Only. This article cannot be rented because we do not currently have permission from the publisher.
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Anthrax Edema Toxin Impairs Clearance in Mice
Sastalla, Inka; Tang, Shixing; Crown, Devorah; Liu, Shihui; Eckhaus, Michael A.; Hewlett, Indira K.; Leppla, Stephen H.; Moayeri, Mahtab
Follow Infection and Immunity
, Volume 80 (2): 529
American Society For Microbiology – Feb 1, 2012
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