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Clinical and Vaccine Immunology, October 2009, p. 1457-1466, Vol. 16, No. 10
1071-412X/09/$08.00+0     doi:10.1128/CVI.00172-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Yersinia pestis Can Bypass Protective Antibodies to LcrV and Activation with Gamma Interferon To Survive and Induce Apoptosis in Murine Macrophages {triangledown}

Betty L. Noel,1 Sarit Lilo,1 Daniel Capurso,1,{dagger} Jim Hill,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 Directorate Strategic Technologies, 1-L-20, MOD Main Building, Whitehall, London SWAB 2HB, United Kingdom2

Received 21 April 2009/ Returned for modification 8 June 2009/ Accepted 3 August 2009

Yersinia pestis, the agent of plague, uses a type III secretion injectisome to deliver Yop proteins into macrophages to counteract phagocytosis and induce apoptosis. Additionally, internalized Y. pestis can survive in the phagosomes of naïve or gamma interferon (IFN-{gamma})-activated macrophages by blocking vacuole acidification. The Y. pestis LcrV protein is a target of protective antibodies. The binding of antibodies to LcrV at the injectisome tip results in neutralization of the apoptosis of Y. pestis-infected macrophages and is used as an in vitro correlate of protective immunity. The cytokines IFN-{gamma} and tumor necrosis factor alpha can cooperate with anti-LcrV to promote protection against lethal Y. pestis infection in mice. It is not known if these phagocyte-activating cytokines cooperate with anti-LcrV to increase the killing of the pathogen and decrease apoptosis in macrophages. We investigated how anti-LcrV and IFN-{gamma} impact bacterial survival and apoptosis in cultured murine macrophages infected with Y. pestis KIM5. Y. pestis KIM5 opsonized with polyclonal or monoclonal anti-LcrV was used to infect macrophages treated with or without IFN-{gamma}. The phagocytosis and survival of KIM5 and the apoptosis of macrophages were measured at different time points postinfection. The results show that anti-LcrV reduced apoptosis at an early time point (5 h) but not at a later time point (24 h). Polyclonal anti-LcrV was unable to inhibit apoptosis at either time point in IFN-{gamma}-activated macrophages. Additionally, anti-LcrV was ineffective at promoting the killing of KIM5 in naïve or activated macrophages. We conclude that Y. pestis can bypass protective antibodies to LcrV and activation with IFN-{gamma} to survive and induce apoptosis in murine macrophages.

* 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 26 August 2009.

{dagger} Present address: Division of Biological Sciences, The University of Chicago, Chicago, IL 60637.

Clinical and Vaccine Immunology, October 2009, p. 1457-1466, Vol. 16, No. 10
1071-412X/09/$08.00+0     doi:10.1128/CVI.00172-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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