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Cathelicidin Administration Protects Mice from Bacillus anthracis Spore Challenge¹

Mark W. Lisanby^2,*, Melissa K. Swiecki^2,*, Brian L. P. Dizon^*, Kathryn J. Pflughoeft, Theresa M. Koehler and John F. Kearney^3,*

^* Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294; and Department of Microbiology and Molecular Genetics, University of Texas-Houston Medical School, Houston, TX 77030

Cathelicidins are a family of cationic peptides expressed in mammals that possess numerous bactericidal and immunomodulatory properties. In vitro analyses showed that human, mouse, and pig cathelicidins inhibited Bacillus anthracis bacterial growth at micromolar concentrations in the presence or absence of capsule. Combined in vitro analyses of the effects of each peptide on spore germination and vegetative outgrowth by time lapse phase contrast microscopy, transmission electron microscopy, and flow cytometric analysis showed that only the pig cathelicidin was capable of directly arresting vegetative outgrowth and killing the developing bacilli within the confines of the exosporium. C57BL/6 mice were protected from spore-induced death by each cathelicidin in a time- and dose-dependent manner. Protection afforded by the porcine cathelicidin was due to its bactericidal effects, whereas the human and mouse cathelicidins appeared to mediate protection through increased recruitment of neutrophils to the site of infection. These findings suggest that cathelicidins might be utilized to augment the initial innate immune response to B. anthracis spore exposure and prevent the development of anthrax.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI057699-03 (to J.F.K.) and AI057156 and AI33537 (to T.M.K.). M.W.L. and M.K.S. were supported by Grant T32AI55438, B.L.P.D. was supported by Grant 5T32GM008361-16, and K.J.P. was supported by T32AI055449. This research is part of the dissertation research conducted by M.W.L. a predoctoral student in the Department of Microbiology, University of Alabama at Birmingham.

² These authors contributed equally to the manuscript.

³ Address correspondence and reprint requests to Dr. John F. Kearney, Shelby Building, Suite 401, 1825 University Boulevard, Birmingham, AL 35294-2182. E-mail address: jfk{at}uab.edu

⁴ Abbreviations used in this paper: LeTx, lethal toxin; CRAMP, cathelin-related antimicrobial peptide; PG-1, protegrin-1; UAB, University of Alabama at Birmingham; DI, distilled; RDA, radial diffusion assay; MHB, Mueller-Hinton broth; MBDA, microbroth dilution assay; i.t., intratracheal; PEC, peritoneal cell; MEC, minimum effective concentration; FPRL-1, formyl peptide receptor-like 1; HNP-1, human neutrophil protein-1.