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Department of Microbiology, Immunology and Pathology, Colorado State University, Ft. Collins, CO 80523
Francisella tularensis is an obligate, intracellular bacterium that causes acute, lethal disease following inhalation. As an intracellular pathogen F. tularensis must invade cells, replicate, and disseminate while evading host immune responses. The mechanisms by which virulent type A strains of Francisella tularensis accomplish this evasion are not understood. Francisella tularensis has been shown to target multiple cell types in the lung following aerosol infection, including dendritic cells (DC) and macrophages. We demonstrate here that one mechanism used by a virulent type A strain of F. tularensis (Schu4) to evade early detection is by the induction of overwhelming immunosuppression at the site of infection, the lung. Following infection and replication in multiple pulmonary cell types, Schu4 failed to induce the production of proinflammatory cytokines or increase the expression of MHCII or CD86 on the surface of resident DC within the first few days of disease. However, Schu4 did induce early and transient production of TGF-
, a potent immunosuppressive cytokine. The absence of DC activation following infection could not be attributed to the apoptosis of pulmonary cells, because there were minimal differences in either annexin or cleaved caspase-3 staining in infected mice compared with that in uninfected controls. Rather, we demonstrate that Schu4 actively suppressed in vivo responses to secondary stimuli (LPS), e.g., failure to recruit granulocytes/monocytes and stimulate resident DC. Thus, unlike attenuated strains of F. tularensis, Schu4 induced broad immunosuppression within the first few days after aerosol infection. This difference may explain the increased virulence of type A strains compared with their more attenuated counterparts.
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 a grant form the Colorado State University College Research Council and by Rocky Mountain Regional Center of Excellence National Institutes of Health Grant U01 AI056487-01.
2 Address correspondence and reprint requests to Dr. Catharine M. Bosio at the current address: National Institutes of Health/National Institute of Allergy and Infectious Diseases/Rocky Mountain Laboratories, 903 South 4th Street, Hamilton, MT 59840. E-mail address: bosioc{at}niaid.nih.gov
3 Abbreviations used in this paper: LVS, live vaccine strain; BAL, bronchoalveolar lavage; BHI, brain-heart infusion; DC, dendritic cell; IHC, immunohistochemistry; MHCII, MHC class II; MLN, mediastinal lymph node.
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