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Infection and Immunity, December 2008, p. 5488-5499, Vol. 76, No. 12
0019-9567/08/$08.00+0     doi:10.1128/IAI.00682-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Early Phagosomal Stage of Francisella tularensis Determines Optimal Phagosomal Escape and Francisella Pathogenicity Island Protein Expression{triangledown}

Audrey Chong,1 Tara D. Wehrly,1 Vinod Nair,2 Elizabeth R. Fischer,2 Jeffrey R. Barker,3 Karl E. Klose,3 and Jean Celli1*

Tularemia Pathogenesis Section, Laboratory of Intracellular Parasites,1 Electron Microscopy Unit, Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840,2 South Texas Center for Emerging Infectious Diseases and Department of Biology, University of Texas at San Antonio, San Antonio, Texas 782493

Received 30 May 2008/ Returned for modification 28 July 2008/ Accepted 2 October 2008

Francisella tularensis is an intracellular pathogen that can survive and replicate within macrophages. Following phagocytosis and transient interactions with the endocytic pathway, F. tularensis rapidly escapes from its original phagosome into the macrophage cytoplasm, where it eventually replicates. To examine the importance of the nascent phagosome for the Francisella intracellular cycle, we have characterized early trafficking events of the F. tularensis subsp. tularensis strain Schu S4 in a murine bone marrow-derived macrophage model. Here we show that early phagosomes containing Schu S4 transiently interact with early and late endosomes and become acidified before the onset of phagosomal disruption. Inhibition of endosomal acidification with the vacuolar ATPase inhibitor bafilomycin A1 or concanamycin A prior to infection significantly delayed but did not block phagosomal escape and cytosolic replication, indicating that maturation of the early Francisella-containing phagosome (FCP) is important for optimal phagosomal escape and subsequent intracellular growth. Further, Francisella pathogenicity island (FPI) protein expression was induced during early intracellular trafficking events. Although inhibition of endosomal acidification mimicked the early phagosomal escape defects caused by mutation of the FPI-encoded IglCD proteins, it did not inhibit the intracellular induction of FPI proteins, demonstrating that this response is independent of phagosomal pH. Altogether, these results demonstrate that early phagosomal maturation is required for optimal phagosomal escape and that the early FCP provides cues other than intravacuolar pH that determine intracellular induction of FPI proteins.

* Corresponding author. Mailing address: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, 903 South 4th Street, Hamilton, MT 59840. Phone: (406) 375 9713. Fax: (406) 375 9640. E-mail: jcelli{at}niaid.nih.gov

{triangledown} Published ahead of print on 13 October 2008.

Editor: A. J. Bäumler

Infection and Immunity, December 2008, p. 5488-5499, Vol. 76, No. 12
0019-9567/08/$08.00+0     doi:10.1128/IAI.00682-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Clemens, D. L., Lee, B.-Y., Horwitz, M. A. (2009). Francisella tularensis Phagosomal Escape Does Not Require Acidification of the Phagosome. Infect. Immun. 77: 1757-1773 [Abstract] [Full Text]  
  • Schmerk, C. L., Duplantis, B. N., Howard, P. L., Nano, F. E. (2009). A Francisella novicida pdpA mutant exhibits limited intracellular replication and remains associated with the lysosomal marker LAMP-1. Microbiology 155: 1498-1504 [Abstract] [Full Text]  


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