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Francisella tularensis Live Vaccine Strain Induces Macrophage Alternative Activation as a Survival Mechanism¹

Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD 21201

Francisella tularensis (Ft), the causative agent of tularemia, elicits a potent inflammatory response early in infection, yet persists within host macrophages and can be lethal if left unchecked. We report in this study that Ft live vaccine strain (LVS) infection of murine macrophages induced TLR2-dependent expression of alternative activation markers that followed the appearance of classically activated markers. Intraperitoneal infection with Ft LVS also resulted in induction of alternatively activated macrophages (AA-M). Induction of AA-M by treatment of cells with rIL-4 or by infection with Ft LVS promoted replication of intracellular Ftn, in contrast to classically activated (IFN- plus LPS) macrophages that promoted intracellular killing of Ft LVS. Ft LVS failed to induce alternative activation in IL-4R^–/– or STAT6^–/– macrophages and prolonged the classical inflammatory response in these cells, resulting in intracellular killing of Ft. Treatment of macrophages with anti-IL-4 and anti-IL-13 Ab blunted Ft-induced AA-M differentiation and resulted in increased expression of IL-12 p70 and decreased bacterial replication. In vivo, Ft-infected IL-4R^–/– mice exhibited increased survival compared with wild-type mice. Thus, redirection of macrophage differentiation by Ft LVS from a classical to an alternative activation state enables the organism to survive at the expense of the host.

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 in part by National Institutes of Health Grants AI18797 and AI157168 (to S.N.V.) and AI38985 and AI59775 (to A.D.K.).

² Address correspondence and reprint requests to Dr. Stefanie N. Vogel, Department of Microbiology and Immunology, University of Maryland, 660 West Redwood Street, Room 324, Baltimore, MD 21201. E-mail address: svogel{at}som.umaryland.edu

³ Abbreviations used in this paper: Ft, Francisella tularensis; AA-M, alternatively activated macrophages; CA-M, classically activated macrophages; FIZZ, found in inflammatory zone; iNOS, inducible NO synthase; LVS, live vaccine strain; MOI, multiplicity of infection; WT, wild type.

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