IFNγ expression by an attenuated strain of Salmonella enterica serovar Typhimurium improves vaccine efficacy in susceptible TLR4-defective C3H/HeJ mice.
C3H/HeJ mice carry a mutated allele of TLR4 gene (TLR4                 (                   d                 )) and thus are hyporesponsive to the lethal effects of lipopolysaccharide (LPS). Characteristically, however, the mice are also hypersusceptible to infections, particularly by Gram-negative bacteria such as Salmonella enterica serovar Typhimurium (S. typhimurium) and are known to be difficult to vaccinate against virulent exposure. This is observed despite the expression of wild-type allele of Nramp1 gene, another important determinant of Salmonella susceptibility. In contrast, C3H/HeN mice (TLR4                 (                   n                 )                 Nramp1                 (                   n                 )) express a functional TLR4 protein and are resistant to infection, even by virulent strains of S. typhimurium. In the present study, we describe the immune system-enhancing properties of an attenuated strain of S. typhimurium engineered to express murine IFN-γ. This strain (designated GIDIFN) was able to modulate immune responses following systemic inoculation by upregulating the production of inflammatory mediators (IL-6 and IL-12) and anti-bacterial effector molecules (nitric oxide; NO). Consequently, this led to a more effective control of bacterial proliferation in systemic target organs in both C3H/HeJ and C3H/HeN mice. Although evidence for the enhancement in immune responses could be observed as early as few hours post-inoculation, sustained improvements required 2-3 days to manifest. Vaccination of C3H/HeJ mice with GIDIFN strain, even at low doses, conferred a significantly higher degree of protection against challenge with virulent Salmonella in susceptible C3H/HeJ mice. Our data demonstrate that IFNγ-expressing Salmonella are immunogenic and confer excellent protection against virulent challenge in susceptible C3H/HeJ mice; in addition they may be used as an effective mucosal delivery vectors against virulent infection and for boosting immune responses in immunodeficient hosts.
Department of Medical Microbiology and Immunology, United Arab Emirates University, Al Ain, United Arab Emirates.
Samia M
SM
Al-Ojali
C B
CB
Tara Moore
Maria J
MJ
Fernandez-Cabezudo
Basel K
BK
Al-Ramadi
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D012481:Salmonella Infections, Animal / Q000517:prevention & control; D022562:Salmonella Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
D000276:Adjuvants, Immunologic; D022562:Salmonella Vaccines; D014613:Vaccines, Attenuated; D007371:Interferon-gamma