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. 1993 Jan;61(1):23–31. doi: 10.1128/iai.61.1.23-31.1993

Association between virulence of Yersinia pestis and suppression of gamma interferon and tumor necrosis factor alpha.

R Nakajima 1, R R Brubaker 1
PMCID: PMC302683  PMID: 8418045

Abstract

It is established that Yersinia pestis, the causative agent of bubonic plague, and enteropathogenic Yersinia pseudotuberculosis and Yersinia enterocolitica share a ca. 70-kb low-calcium response or Lcr plasmid (Lcr+). The latter is known to encode regulatory functions that restrict growth at 37 degrees C in Ca(2+)-deficient medium and virulence factors that are expressed only in vitro within this environment (e.g., certain Yops and V antigen). In this study, gamma interferon (IFN-gamma) was never detected in mice infected with 10 minimum lethal doses (MLD) of Lcr+ cells of Y. pestis, and significant levels of tumor necrosis factor alpha (TNF-alpha) arose only prior to death. Prompt and marked synthesis of these cytokines was observed upon infection with avirulent Lcr- mutants. Treatment of mice with exogenous IFN-gamma plus TNF-alpha inhibited multiplication of Lcr+ yersiniae in vivo, thereby providing protection against challenge with 10 MLD. Administration of both cytokines was required for absolute survival, suggesting a synergistic rather than cumulative interaction. This protective effect entailed cytokine priming as judged by subsequent detection of substantial levels of endogenous IFN-gamma and TNF-alpha. Monospecific anti-V-antigen, known to provide passive immunity against 10 MLD of Lcr+ Y. pestis, permitted significant synthesis of endogenous IFN-gamma and TNF-alpha. These findings demonstrate that Lcr+ yersiniae suppress synthesis of cytokines and suggest that this effect is mediated by one or more Lcr plasmid-encoded virulence factors.

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Selected References

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