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Prophylactic and Therapeutic Use of Antibodies for Protection against Respiratory Infection with Francisella tularensis¹

Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208

The role of Abs in protection against respiratory infection with the intracellular bacterium Francisella tularensis is not clear. To investigate the ability of Abs to clear bacteria from the lungs and prevent systemic spread, immune serum was passively administered i.p. to naive mice before intranasal F. tularensis live vaccine strain infection. It was found that immune serum treatment provided 100% protection against lethal challenge while normal serum or Ig-depleted immune serum provided no protection. Protective efficacy was correlated with increased clearance of bacteria from the lung and required expression of FcR on phagocytes, including macrophages and neutrophils. However, complement was not required for protection. In vitro experiments demonstrated that macrophages were more readily infected by Ab-opsonized bacteria but became highly efficient in killing upon activation by IFN-. Consistent with this finding, in vivo Ab-mediated protection was found to be dependent upon IFN-. SCID mice were not protected by passive Ab transfer, suggesting that T cells but not NK cells serve as the primary source for IFN-. These data suggest that a critical interaction of humoral and cellular immune responses is necessary to provide sterilizing immunity against F. tularensis. Of considerable interest was the finding that serum Abs were capable of conferring protection against lethal respiratory tularemia when given 24–48 h postexposure. Thus, this study provides the first evidence for the therapeutic use of Abs in Francisella-infected individuals.

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 PO1 AI056320 (to D.W.M.) and Career Development Award U54 AI057158 from the Northeast Regional Center of Excellence in Biodefense and Emerging Infections (to G.S.K.).

² Address correspondence and reprint requests to Dr. Dennis W. Metzger, Center for Immunology and Microbial Disease, Albany Medical College, MC-151, 47 New Scotland Avenue, Albany, NY 12208. E-mail address: metzged{at}mail.amc.edu

³ Abbreviations used in this paper: i.d., intradermal; LVS, live vaccine strain; i.n., intranasal; MOI, multiplicity of infection.

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