Nakajima R, Motin V L, Brubaker R R
Exploratory Research Laboratories I, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Infect Immun. 1995 Aug;63(8):3021-9. doi: 10.1128/iai.63.8.3021-3029.1995.
It is established that an approximately 70-kb Lcr plasmid enables Yersinia pestis, the causative agent of bubonic plague, to multiply in focal necrotic lesions within visceral organs of mice by preventing net synthesis of the cytokines tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma), thereby minimizing inflammation (Lcr+). Rabbit antiserum raised against cloned staphylococcal protein A-V antigen fusion peptide (PAV) is known to passively immunize mice against 10 minimum lethal doses of intravenously injected Lcr+ cells of Y. pestis. In this study, injected PAV suppressed TNF-alpha and IFN-gamma in mice challenged with avirulent V antigen-deficient Y. pestis (lcrV or Lcr-) and promoted survival in vivo of these isolates as well as salmonellae and Listeria monocytogenes (with which the outcome was lethal). Active immunization of mice with PAV protected against 1,000 minimum lethal doses of intravenously injected Lcr+ cells of Y. pestis and Yersinia pseudotuberculosis but not Yersinia enterocolitica. The progressive necrosis provoked by Lcr+ cells of Y. pestis in visceral organs of nonimmunized mice was replaced after active immunization with PAV by massive infiltration of neutrophils and mononuclear cells (which generated protective granulomas indistinguishable from those formed against avirulent Lcr- mutants in nonimmunized mice). Distinct multiple abscesses typical of Lcr+ cells of Y. pseudotuberculosis were prevented by similar immunization. Significant synthesis of TNF-alpha and IFN-gamma occurred in spleens of mice actively immunized with PAV after challenge with Lcr+ cells of Y. pestis. These findings suggest that V antigen contributes to disease by suppressing the normal inflammatory response.
已确定一个约70 kb的Lcr质粒能使腺鼠疫的病原体鼠疫耶尔森菌通过阻止细胞因子肿瘤坏死因子α（TNF-α）和γ干扰素（IFN-γ）的净合成，在内脏器官的局灶性坏死病变中增殖，从而将炎症降至最低（Lcr+）。已知针对克隆的葡萄球菌蛋白A-V抗原融合肽（PAV）产生的兔抗血清能被动免疫小鼠，使其抵抗静脉注射的10个最小致死剂量的鼠疫耶尔森菌Lcr+细胞。在本研究中，注射的PAV抑制了用无毒V抗原缺陷型鼠疫耶尔森菌（lcrV或Lcr-）攻击的小鼠体内的TNF-α和IFN-γ，并促进了这些分离株以及沙门氏菌和单核细胞增生李斯特菌在体内的存活（对后两者的结果是致死性的）。用PAV对小鼠进行主动免疫可保护其抵抗静脉注射的1000个最小致死剂量的鼠疫耶尔森菌Lcr+细胞和假结核耶尔森菌，但不能抵抗小肠结肠炎耶尔森菌。在未免疫小鼠的内脏器官中，鼠疫耶尔森菌Lcr+细胞引发的进行性坏死，在用PAV进行主动免疫后，被中性粒细胞和单核细胞的大量浸润所取代（这些细胞形成了与未免疫小鼠中针对无毒Lcr-突变体形成的保护性肉芽肿无法区分的保护性肉芽肿）。类似的免疫可预防假结核耶尔森菌Lcr+细胞典型的明显多发性脓肿。在用鼠疫耶尔森菌Lcr+细胞攻击后，用PAV主动免疫的小鼠脾脏中发生了TNF-α和IFN-γ的显著合成。这些发现表明，V抗原通过抑制正常的炎症反应而促进疾病发展。
