title: Association between virulence of Yersinia pestis and suppression of gamma interferon and tumor necrosis factor alpha.
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.
authors.affiliation: Department of Microbiology, Michigan State University, East Lansing 48824-1101.
authors.forename: R
authors.initials: R
authors.lastname: Nakajima
authors.forename: R R
authors.initials: RR
authors.lastname: Brubaker
mesh_terms: 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*
chemical_list: D000942:Antigens, Bacterial; D007106:Immune Sera; C043908:LcrV protein, Yersinia; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma