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Infection and Immunity, June 2009, p. 2251-2261, Vol. 77, No. 6
0019-9567/09/$08.00+0     doi:10.1128/IAI.00068-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Yersinia pestis Can Reside in Autophagosomes and Avoid Xenophagy in Murine Macrophages by Preventing Vacuole Acidification{triangledown}

Céline Pujol,1,{dagger},{ddagger} Kathryn A. Klein,1,{dagger} Galina A. Romanov,1 Lance E. Palmer,1,§ Carol Cirota,1 Zijiang Zhao,2 and James B. Bliska1*

Center for Infectious Diseases and Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794,1 Department of Pathology and Immunology and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 631102

Received 19 January 2009/ Returned for modification 21 February 2009/ Accepted 10 March 2009

Yersinia pestis survives and replicates in phagosomes of murine macrophages. Previous studies demonstrated that Y. pestis-containing vacuoles (YCVs) acquire markers of late endosomes or lysosomes in naïve macrophages and that this bacterium can survive in macrophages activated with the cytokine gamma interferon. An autophagic process known as xenophagy, which destroys pathogens in acidic autophagolysosomes, can occur in naïve macrophages and is upregulated in activated macrophages. Studies were undertaken here to investigate the mechanism of Y. pestis survival in phagosomes of naïve and activated macrophages and to determine if the pathogen avoids or co-opts autophagy. Colocalization of the YCV with markers of autophagosomes or acidic lysosomes and the pH of the YCV were determined by microscopic imaging of infected macrophages. Some YCVs contained double membranes characteristic of autophagosomes, as determined by electron microscopy. Fluorescence microscopy showed that ~40% of YCVs colocalized with green fluorescent protein (GFP)-LC3, a marker of autophagic membranes, and that YCVs failed to acidify below pH 7 in naïve macrophages. Replication of Y. pestis in naïve macrophages caused accumulation of LC3-II, as determined by immunoblotting. While activation of infected macrophages increased LC3-II accumulation, it decreased the percentage of GFP-LC3-positive YCVs (~30%). A viable count assay showed that Y. pestis survived equally well in macrophages proficient for autophagy and macrophages rendered deficient for this process by Cre-mediated deletion of ATG5, revealing that this pathogen does not require autophagy for intracellular replication. We conclude that although YCVs can acquire an autophagic membrane and accumulate LC3-II, the pathogen avoids xenophagy by preventing vacuole acidification.

* Corresponding author. Mailing address: Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11794-5120. Phone: (631) 632-8782. Fax: (631) 632-4294. E-mail: jbliska{at}ms.cc.sunysb.edu

{triangledown} Published ahead of print on 16 March 2009.

Editor: A. J. Bäumler

{dagger} C.P. and K.A.K. contributed equally to this work.

{ddagger} Present address: UR1282, Infectiologie Animale, Santé Publique (IASP-311), INRA Centre de Tours, F-37380 Nouzilly, France.

§ Present address: Siemens Corporate Research, 755 College Rd. East, Princeton, NJ 08540.

Infection and Immunity, June 2009, p. 2251-2261, Vol. 77, No. 6
0019-9567/09/$08.00+0     doi:10.1128/IAI.00068-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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