Activation of innate immune responses by IL-2-expressing Salmonella typhimurium is independent of Toll-like receptor 4.
We previously demonstrated that an attenuated strain of Salmonella enterica serovar Typhimurium, engineered to express IL-2 (strain GIDIL2), is cleared more rapidly than its parental, non-cytokine-expressing, strain (designated BRD509) from the reticuloendothelial system of susceptible BALB/c mice. This early clearance correlated with the induction of a strong innate immune response within a few hours of administration of GIDIL2 organisms. In the present study, we wished to assess the contribution of LPS recognition to GIDIL2-induced immune responses using Toll-like receptor 4 (TLR4) mutant C3H/HeJ mice. In contrast to LPS responder mice, both BRD509 and GIDIL2 strains persisted at higher levels in LPS non-responder animals. However, the GIDIL2 bacterial loads in the peritoneal cavity and spleen, recovered over a period of 21 days post infection, were consistently lower than the corresponding CFUs of the BRD509 strain. Direct evidence for the induction of innate immunity was shown by demonstrating increased NK cell cytotoxicity, NOS2 gene expression, and nitric oxide synthesis by peritoneal cells obtained as early as 2h after infection with GIDIL2, but not BRD509, organisms. Unlike BALB/c mice, however, these responses failed to afford any protection against virulent challenge in C3H/HeJ mice. Taken together, our data demonstrate that despite the induction of innate immune responses by IL2-expressing organisms, this was not sufficient to induce protection in TLR4 mutant mice.
al-Ramadi
Basel K
BK
Department of Medical Microbiology, Faculty of Medicine and Health Sciences, UAE University, PO Box 17666, Al Ain, United Arab Emirates. ramadi.b@uaeu.ac.ae
Fernandez-Cabezudo
Maria J
MJ
Mustafa
Nada
N
Xu
Damo
D
D000818:Animals; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression; D007113:Immunity, Innate; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D012481:Salmonella Infections, Animal / Q000235:genetics / Q000276:immunology; D012486:Salmonella typhimurium / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D013154:Spleen / Q000276:immunology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014774:Virulence
D018076:DNA, Complementary; D007376:Interleukin-2; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D009569:Nitric Oxide; D007371:Interferon-gamma