Attenuated Yersinia enterocolitica mutant strains exhibit differential virulence in cytokine-deficient mice: implications for the development of novel live carrier vaccines.
Yersinia enterocolitica mutant strains, including mutants deficient in the chaperone SycH resulting in a functional deficiency in tyrosine phosphatase (YopH), Mn-cofactored superoxide dismutase (SodA), iron-repressive protein 1 (IRP-1), and Yersinia adhesin A (YadA), were demonstrated to be highly attenuated in wild-type C57BL/6 mice. TNFRp55(-/-), IL-12p40(-/-), and IL-18(-/-) mutant mice, in which the Yersinia wild-type strain causes severe systemic infections, were used to investigate whether these Yersinia mutant strains would be attenuated in immunodeficient hosts. A plasmid-cured Yersinia mutant strain was unable to colonize any of the mutant mice tested. A SycH-deficient mutant strain colonized intestinal tissues of these mice but was attenuated for systemic infection in all of the mutant mice. Both YadA- and Irp-1-deficient Yersinia mutants were still attenuated in IL-12(-/-) and IL-18(-/-) mice but were pathogenic in TNFRp55(-/-) mice. By contrast, a Yersinia sodA mutant was highly pathogenic for TNFRp55(-/-) and IL-12p40(-/-) mice while interleukin-18 (IL-18) was dispensable. This finding demonstrates that certain virulence factors enable yersiniae to compete with distinct cytokine-dependent host defense mechanisms. Moreover, while gamma interferon mRNA expression did not reflect protective host responses in cytokine-deficient mice, IL-10 expression coincided with a heavy splenic bacterial load and was associated with progressive infection courses. We can thus segregate minor (SodA), intermediate (YadA and IRP-1), and major (YopH) virulence factors of Y. enterocolitica. Finally, we demonstrate that, even in immunocompromised hosts, Yersinia sycH and, with some restrictions, irp-1 mutants may be suitable for use as live carrier vaccines.
Di Genaro
María S
MS
Max von Pettenkofer Institute for Hygiene and Medical Microbiology, Ludwig Maximilians University Munich, 80336 Munich, Germany.
Waidmann
Marc
M
Kramer
Uwe
U
Hitziger
Niclas
N
Bohn
Erwin
E
Autenrieth
Ingo B
IB
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D001428:Bacterial Vaccines; D016207:Cytokines / Q000172:deficiency* / Q000235:genetics; D004198:Disease Susceptibility; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics; D009154:Mutation; D014613:Vaccines, Attenuated; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics; D015009:Yersinia Infections / Q000276:immunology / Q000382:microbiology; D015008:Yersinia enterocolitica / Q000235:genetics / Q000472:pathogenicity*
D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D016207:Cytokines; D018832:Molecular Chaperones; C090049:SycH protein, Yersinia; D014613:Vaccines, Attenuated; D037521:Virulence Factors