Immunity to plague infections

对鼠疫感染的免疫力

• 批准号: 8233342
• 负责人: Olaf Schneewind
• 金额: $ 42.55万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233342
• 关键词: Address; Adverse effects; Animals; Antibodies; Antigens; Attenuated; Bacteria; Biological; Bubonic Plague; CD14 gene; Cells; Development; Event; FDA approved; Funding; Generations; Goals; Human; Immune; Immune response; Immunity; Immunization; Infection; Injection of therapeutic agent; Interleukin-10; Intervention; Knockout Mice; Life; Mediating; Molecular; Mus; Natural Immunity; Nature; Needles; Pathogenesis; Phagocytes; Phagocytosis; Pilum; Plague; Plague Vaccine; Pneumonic Plague; Positioning Attribute; Property; Proteins; Research; Research Project Grants; Role; Signal Transduction; Specific qualifier value; Subunit Vaccines; Surface; TLR2 gene; TLR6 gene; Vaccines; Variant; Virulence; Virulent; Whole Cell Vaccine; Work; Yersinia; Yersinia pestis; base; biodefense; cytokine; immunoregulation; in vivo; mutant; nonhuman primate; pathogen; prevent; programs; weapons

Yersinia pestis, the highly virulent agent of plague, is a biological weapon. Strategies to prevent plague have been sought for centuries, however neither an FDA approved vaccine nor the molecular basis of plague immunity are established. Immunization of animals or humans with live-attenuated (non-pigmented) Y. pestis strains raises protective immunity, however associated side effects prohibit the use of whole cell vaccines in humans. Previous efforts to develop subunit vaccines combined two protein antigens, F1 and LcrV, to prevent bubonic and pneumonic plague. This GLRCE funded research program addresses the need for plague vaccines and also seeks to understand the molecular basis of plague immunity. Our work demonstrated that Y. pestis F1 pili are dispensable for the pathogenesis of bubonic or pneumonic plague. During infection, breakthrough mutants emerge that henceforth escape plague immunity derived from either F1 subunit vaccines or live-attenuated strains. Breakthrough mutants carry IS1541 insertions in cafIA (which specifies the usher for pilus assembly), indicating that F1 pili are not a suitable vaccine component. LcrV subunit vaccines were shown to protect mice and non-human primates against bubonic and pneumonic plague. LcrV displays immune modulatory effects. A variant, V10, lacks these properties, but retains the ability to raise protective immunity. LcrV is positioned at the tip of type III needles and antibodies against LcrV protect immune cells from Yersinia type III injection of effector Yops, a virulence mechanism that blocks bacterial phagocytosis and NF-KB activation by host immune cells. Plague bacteria preferentially inject phagocytes and this target selection requires CD14 and TLR6 on the surface of immune cells. LcrVmediated engagement of CD14/TLR2/TLR6 triggers signal transduction cascades, IL-10 release as well as suppression of proinflammatory cytokines. Goals of this renewal application are to develop subunit vaccines for plague protection and to appreciate plague immunity at a molecular level by determining the nature of protective antibodies and Y. pestis escape variants. Other work will determine the contributions of TLR2, TLR6 and CD14 towards Y. pestis selection of targets for type III injection and unravel the mechanisms whereby the pathogen evades the development of immunity during plague infections.

鼠疫耶尔森氏菌是一种生物武器，是鼠疫的高毒力病原体。预防鼠疫的策略