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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 1
(IL-1
), 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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