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Rat survival to anthrax lethal toxin is likely controlled by a single gene

The Pharmacogenomics Journal volume 8, pages 16–22 (2008)Cite this article

Abstract

We examined whether survival of different rat strains administered anthrax lethal toxin is genetically determined. A reproducible test population of first filial generation hybrid rats was bred based on the susceptibility of progenitors to anthrax lethal toxin and to maximize genetic diversity across the strains. These rats were then tested with varying doses of anthrax lethal toxin. We found that all ‘sensitive’ strains died within 2 h following systemic administration of 240 μg/kg lethal toxin, while one strain survived following a five times higher dose (1.4 mg/kg). The ability of lethal toxin to lyse macrophage cultures derived from the bone marrow of these strains corresponded with in vivo results. We conclude that a rat test population can detect strain differences in response to anthrax lethal toxin. Survival is influenced by the host genome background and is likely due to a single gene with a recessive mode of inheritance.

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Abbreviations

LeTx:

lethal toxin

LF:

lethal factor

PA:

protective antigen

F1:

first filial generation

SSLP:

simple sequence length polymorphism

F344:

Fischer 344 rat

LEW:

Lewis rat

WKY:

Wistar-Kyoto rat

BN:

Brown Norway rat

CD-IGS:

Caesarian-Derived-International Genetic Standard rat

LD100:

lethal dose resulting in 100% death

QTL:

quantitative trait loci

RMM:

rat macrophage medium

GM-CSF:

granulocyte–macrophage colony stimulating factor

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Acknowledgements

The authors are grateful to Jordan Baye, Sally Korb and Yvette Harrington for excellent technical assistance. We thank Eric Boyden at Harvard University for assistance with the rat macrophage assay and Dr Simon Twigger at the Medical College of Wisconsin for development of the Strain Calculator. We thank Dr Ty Shockley for reviewing the manuscript. This work was funded through a grant provided by the National Institutes of Allergy and Infectious Diseases.

Author information

Author notes

  1. A L Wittenburg

    Present address: 6Current address: Medical College of Wisconsin, Milwaukee, WI, USA,

  2. J A O'Connor

    Present address: 7Current address: Covance Laboratories Inc., Madison, WI, USA,

Authors and Affiliations

  1. PhysioGenix Inc., Wauwatosa, WI, USA

    S H Nye, A L Wittenburg, D L Evans, J A O'Connor, R J Roman & H J Jacob

  2. Department of Physiology Medical College of Wisconsin, Milwaukee, WI, USA

    R J Roman & H J Jacob

  3. Kidney Disease Center, Medical College of Wisconsin, Milwaukee, WI, USA

    R J Roman

  4. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA

    H J Jacob

  5. Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA,

    H J Jacob

Authors
  1. S H Nye
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  2. A L Wittenburg
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  3. D L Evans
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  4. J A O'Connor
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Correspondence to S H Nye.

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Duality of interest

RJ Roman and HJ Jacob are PhysioGenix founders and major stock holders.

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Nye, S., Wittenburg, A., Evans, D. et al. Rat survival to anthrax lethal toxin is likely controlled by a single gene. Pharmacogenomics J 8, 16–22 (2008). https://doi.org/10.1038/sj.tpj.6500448

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