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Administration of a Synthetic TLR4 Agonist Protects Mice from Pneumonic Tularemia¹

Annalisa Lembo^*, Mark Pelletier^*, Ravi Iyer^*, Michele Timko^*, Jan C. Dudda, T. Eoin West^*, Christopher B. Wilson, Adeline M. Hajjar and Shawn J. Skerrett^2,*

^* Department of Medicine and Department of Immunology, University of Washington, Seattle, WA 98104; and Benaroya Research Institute, Seattle, WA 98101

Francisella tularensis is a Gram-negative intracellular pathogen that causes the zoonosis tularemia. Because F. tularensis LPS causes weak TLR4 activation, we hypothesized that administration of a synthetic TLR4 agonist, aminoalkyl glucosaminide phosphate (AGP), would boost the innate immune system and compensate for reduced TLR4 stimulation. Intranasal administration of AGPs induced intrapulmonary production of proinflammatory cytokines and chemokines. Mice treated with AGPs before and after inhalation of Francisella novicida exhibited augmented cytokine and inflammatory responses to infection; reduced bacterial replication in lung, liver, and spleen; and increased survival, whereas all PBS-treated control mice died within 4 days of infection, all AGP-treated mice showed prolonged time-to-death, and 30–60% of AGP-treated mice survived. The protective effect of AGP was lost in mice lacking IFN-. Long-term survivors developed specific Th1 splenocyte responses and specific Abs dominated by IgG2 isotypes. Survivors were fully protected from rechallenge with aerosolized F. novicida. Thus, preventive administration of AGP successfully modulated innate immune responses to aerosolized F. novicida, leading to protective immunity to pneumonic tularemia. This is the first report of the protective effect of a TLR ligand on resistance to F. novicida-induced pneumonic tularemia.

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 AI057141 and AI-50023.

² Address correspondence and reprint requests to Dr. Shawn J. Skerrett, Harborview Medical Center Box 359640, 325 Ninth Avenue, Seattle, WA 98104. E-mail address: shawn{at}u.washington.edu

³ Abbreviations used in this paper: LVS, live vaccine strain; AGP, aminoalkyl glucosaminide phosphate; BMDC, bone marrow-derived dendritic cell; i.n., intranasal.