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Infection and Immunity, December 1999, p. 6572-6582, Vol. 67, No. 12
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Leptospiral Outer Membrane Proteins OmpL1 and LipL41 Exhibit Synergistic Immunoprotection

David A. Haake,1,2,* Mary K. Mazel,1 Adam M. McCoy,1,dagger Frank Milward,3 Garlo Chao,1 James Matsunaga,1 and Elizabeth A. Wagar4

Division of Infectious Diseases, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 900731; Department of Medicine2 and Department of Pathology and Laboratory Medicine,4 UCLA School of Medicine, Los Angeles, California 90095; and Predéveloppement, Merial Biodivision, 69342 Lyon Cédex 07, France3

Received 27 May 1999/Returned for modification 23 July 1999/Accepted 2 September 1999

New vaccine strategies are needed for prevention of leptospirosis, a widespread human and veterinary disease caused by invasive spirochetes belonging to the genus Leptospira. We have examined the immunoprotective capacity of the leptospiral porin OmpL1 and the leptospiral outer membrane lipoprotein LipL41 in the Golden Syrian hamster model of leptospirosis. Specialized expression plasmids were developed to facilitate expression of leptospiral proteins in Escherichia coli as the membrane-associated proteins OmpL1-M and LipL41-M. Although OmpL1-M expression is highly toxic in E. coli, this was accomplished by using plasmid pMMB66-OmpL1, which has undetectable background expression without induction. LipL41-M expression and processing were enhanced by altering its lipoprotein signal peptidase cleavage site to mimic that of the murein lipoprotein. Active immunization of hamsters with E. coli membrane fractions containing a combination of OmpL1-M and LipL41-M was found to provide significant protection against homologous challenge with Leptospira kirschneri serovar grippotyphosa. At 28 days after intraperitoneal inoculation, survival in animals vaccinated with both proteins was 71% (95% confidence interval [CI], 53 to 89%), compared with only 25% (95% CI, 8 to 42%) in the control group (P < 0.001). On the basis of serological, histological, and microbiological assays, no evidence of infection was found in the vaccinated survivors. The protective effects of immunization with OmpL1-M and LipL41-M were synergistic, since significant levels of protection were not observed in animals immunized with either OmpL1-M or LipL41-M alone. In contrast to immunization with the membrane-associated forms of leptospiral proteins, hamsters immunized with His6-OmpL1 and His6-LipL41 fusion proteins, either alone or in combination, were not protected. These data indicate that the manner in which OmpL1 and LipL41 associates with membranes is an important determinant of immunoprotection.

* Corresponding author. Mailing address: Division of Infectious Diseases, 111F, VA Greater LA Healthcare System, Los Angeles, CA 90073. Phone: (310) 478-3711, ext. 40267. Fax: (310) 268-4928. E-mail: dhaake{at}ucla.edu.

dagger Present address: Harvard University, The Biological Laboratories, Cambridge, MA 02138.

Infection and Immunity, December 1999, p. 6572-6582, Vol. 67, No. 12
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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