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Impaired Host Defense in Mice Lacking ONZIN¹

Julie G. Ledford^*, Martina Kovarova and Beverly H. Koller^2,*,,

^* Curriculum in Genetics and Molecular Biology, Department of Genetics, and Department of Medicine, Division of Pulmonary and Critical Care, University of North Carolina at Chapel Hill, North Carolina 27599

ONZIN is a small, cysteine-rich peptide of unique structure that is conserved in all vertebrates examined to date. We show that ONZIN is expressed at high levels in epithelial cells of the intestinal tract, the lung, and in cells of the immune system including macrophages and granulocytes. Because this pattern of expression is suggestive of a role in innate immune function, we have generated mice lacking this protein and examined their ability to respond to challenge with infectious agents. Onzin^–/– mice show a heightened innate immune response after induction of acute peritonitis with Klebsiella pneumoniae. This increased response is consistent with an increased bacterial burden in the Onzin^–/– mice. Ex vivo studies show that, whereas phagocytosis is not altered in Onzin^–/– neutrophils, phagocytes lacking this protein kill bacteria less effectively. This result identifies ONZIN as a novel class of intracellular protein required for optimal function of the neutrophils after uptake of bacteria.

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 Grant HL076790 (to B.H.K.).

² Address correspondence and reprint requests to Dr. Beverly H. Koller, 4341 Medical Biomolecular Research Building, CB 7264, 103 Mason Farm Road, Chapel Hill, NC 27599. E-mail address: treawouns{at}aol.com

³ Abbreviations used in this paper: MPO, myeloperoxidase; ROS, reactive oxygen species; CGD, chronic granulomatous disease; 7-AAD, 7-aminoactinomycin D; LN, lymph node; PS, phosphatidylserine.

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