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Infect Immun, May 1998, p. 1910-1917, Vol. 66, No. 5
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Genetic Control of Immune Response to Recombinant Antigens Carried by an Attenuated Salmonella typhimurium Vaccine Strain: Nramp1 Influences T-Helper Subset Responses and Protection against Leishmanial Challenge

Shiu-Shing Soo,1,2 Bernardo Villarreal-Ramos,3 C. M. Anjam Khan,4 Carlos E. Hormaeche,4 and Jenefer M. Blackwell1,2,*

Department of Pathology, University of Cambridge, Cambridge CB2 1QP,1 Institute of Animal Health, Compton Near Newbury RG16 0NN,3 Department of Microbiology, The Medical School, University of Newcastle, Newcastle upon Type NE2 4HH,4 and Department of Medicine, University of Cambridge Clinical School, Cambridge CB2 2QQ,2 United Kingdom

Received 1 July 1997/Returned for modification 9 September 1997/Accepted 23 January 1998

Attenuated strains of Salmonella typhimurium have been widely used as vehicles for delivery and expression of vaccine antigens in murine models of infectious disease. In mice, early bacterial replication following infection with S. typhimurium is controlled by the gene (Nramp1, formerly Ity/Lsh/Bcg) encoding the natural-resistance-associated macrophage protein (Nramp1). Nramp1 regulates macrophage activation and has multiple pleiotropic effects, including regulation of tumor necrosis factor alpha, interleukin 1beta (IL-1beta ), and major histocompatibility complex class II molecules, all of which influence antigen processing and presentation. Nramp1 also has a direct effect on antigen processing, possibly by regulating the activity of proteases in the late endosomal compartment. Hence, there are multiple ways (regulation of bacterial load or recombinant antigen dose, class II molecule expression, costimulatory or adjuvant activity, and antigen processing) that Nramp1 might influence responses to recombinant salmonella vaccines. To test the hypothesis that Nramp1 influences responses to vaccination, congenic mouse strains have been used to analyze immune responses to recombinant antigens (tetanus toxoid antigen and leishmanial gp63) carried by live attenuated S. typhimurium aroA aroD mutants. Results show that congenic mice carrying the wild-type (S. typhimurium resistance) Nramp1 allele mount a predominantly T-helper-1 (IL-2 and gamma interferon) response to vaccination and show enhanced resolution of lesions following challenge infection with Leishmania major. In contrast, mice carrying mutant (S. typhimurium susceptibility) Nramp1 mount a T-helper-2 (immunoglobulin E and IL-4) response and show exacerbated lesion growth upon challenge.

* Corresponding author. Mailing address: Department of Medicine, University of Cambridge Clinical School, Level 5, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom. Phone: 01223 336947. Fax: 01223 336846. E-mail: JMB37{at}CUS.CAM.AC.UK.

Infect Immun, May 1998, p. 1910-1917, Vol. 66, No. 5
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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