Association between virulence of Yersinia pestis and suppression of gamma interferon and tumor necrosis factor alpha.
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.
Nakajima
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Department of Microbiology, Michigan State University, East Lansing 48824-1101.
Brubaker
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D000818:Animals; D000918:Antibody Specificity; D000942:Antigens, Bacterial / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D007106:Immune Sera / Q000276:immunology; D007110:Immunity, Active; D007116:Immunization, Passive; D007371:Interferon-gamma / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D010930:Plague / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D052899:Pore Forming Cytotoxic Proteins; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014774:Virulence / Q000502:physiology; D015010:Yersinia pestis / Q000472:pathogenicity*
D000942:Antigens, Bacterial; D007106:Immune Sera; C043908:LcrV protein, Yersinia; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma