CVI Accepts, published online ahead of print on 14 October 2009

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Clin. Vaccine Immunol. doi:10.1128/CVI.00333-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Dual function antibodies to Y. pestis LcrV required for pulmonary clearance of plague

Nicholas A. Eisele and Deborah M. Anderson^*

Departments of Veterinary Pathobiology and Molecular Microbiology & Immunology, University of Missouri, Columbia, MO

^* To whom correspondence should be addressed. Email: andersondeb{at}missouri.edu.

Yersinia pestis causes pneumonic plague, a necrotic pneumonia which rapidly progresses to death without early treatment. Antibodies to protective antigen LcrV are thought to neutralize its essential function in the Type III Secretion System (TTSS) and by themselves are capable of inducing immunity to plague in mouse models. To develop multi-valent LcrV antibodies as a therapeutic treatment option, we screened for monoclonal antibodies (MAbs) to LcrV which could prevent its function in the TTSS. Though we were able to identify single and combination MAbs which provided high level inhibition of the TTSS, these did not promote phagocytosis in vitro and were only weakly protective in a mouse pneumonic plague model. Only one MAb, BA5, was able to protect mice from pneumonic plague. In vitro, MAb BA5 blocked the TTSS with equal or even less efficiency as other MAbs in single or in combination but its activity led to increased phagocytic uptake. Polyclonal anti-LcrV was superior to BA5 in promoting phagocytosis and was also more efficient in protecting mice from pneumonic plague. Together the data support a hypothesis whereby pulmonary clearance of Y. pestis by antibodies requires both the neutralization of the Type III Secretion System and simultaneous stimulation of innate signaling pathways used by phagocytic cells to destroy pathogens.