Comparative Immunobiology of the bordetellae

性状（由申请方提供）：博德特氏菌属包括重要的人类和动物呼吸道病原体。尽管自20世纪40年代以来广泛使用，但百日咳杆菌疫苗存在重大问题;它提供了不完全的疾病保护，对感染率没有影响，允许细菌持续传播。虽然很明显，这种肌内疫苗不会产生与呼吸道粘膜感染相同的保护作用，但对保护性免疫机制缺乏了解阻碍了其改进。在小鼠模型中，需要B细胞来清除感染，但过继转移免疫血清对细菌数量几乎没有影响，这意味着B细胞除了产生抗体外还具有某些功能。我们提出了另一种解释：分泌性抗体是对B的保护性免疫的主要机制。百日咳。这可以解释对B细胞的需求和缺乏免疫血清（其含有很少的伊加）的转移效果。它还表明，疫苗通过血清抗体介导的毒素中和来预防严重疾病，但不影响细菌定殖水平，因为它们不诱导呼吸道内的分泌伊加。我们最近观察到，与B不同。百日咳时，血清抗体足以清除B。支气管败血症从小鼠的下呼吸道。这两个亚种非常密切的系统发育关系和基因组序列将允许相似性和差异都与它们引起的疾病有关，并根据它们的比较基因组学和最近出现的人类病原体进行解释。在本提案中，我们将确定抗体在控制和清除博德特氏菌亚种中的作用及其作用机制。目标1.我们将使用缺乏B细胞和抗体过继转移的小鼠，以及特定的同种型，以确定抗体在细菌控制/清除中的作用。目标2.将使用缺乏特异性抗体效应子功能的小鼠来确定每种对抗体效应的贡献。初步结果表明，这些影响，并涉及的机制，不同的呼吸器官和不同的博德特氏菌亚种。目标3。我们已经确定，过继转移的抗体与那些响应感染而内源性产生的抗体具有非常不同的效果，这与疫苗诱导的观察结果相一致，而不是感染诱导的免疫力。我们将使用野生型、B细胞缺陷型或IgA缺陷型小鼠比较过继转移和天然产生的抗体，以了解这些差异的基础。这些实验将表征博德特氏菌亚种与宿主抗体的相互作用，以确定抗体介导的呼吸道细菌清除机制。类似的机制可能涉及对其他生物体的呼吸免疫，包括那些被认为具有潜在生物恐怖主义威胁的生物。

DESCRIPTION (provided by applicant): The genus Bordetella includes important human and animal respiratory pathogens. Despite its extensive use since the 1940s, the Bordetella pertussis vaccine has substantial problems; it provides incomplete protection from disease and has no effect on the infection rate, allowing bacteria to circulate on an ongoing basis. Although it is clear that this intramuscular vaccine does not generate the same protection as infection of the respiratory mucosa, lack of understanding of the mechanisms of protective immunity hampers its improvement. In the mouse model, B cells are required to clear infection but adoptive transfer of immune serum had little effect on bacterial numbers, interpreted to mean B cells perform some function other than antibody production. We propose an alternative interpretation; secretory antibodies are the primary mechanism of protective immunity to B. pertussis. This would explain the requirement for B cells and the lack of effect of transfer of immune serum, which contains little IgA. It also suggests that vaccines prevent severe disease via serum antibody-mediated neutralization of toxins, but do not affect bacterial colonization levels because they do not induce secretory IgA within the respiratory tract. We have recently observed that, unlike B. pertussis, serum antibodies are sufficient to clear B. bronchiseptica from the lower respiratory tract of mice. The extraordinarily close phylogenetic relatedness and the genomic sequences of these two subspecies will allow both similarities and differences to be both related to the diseases they cause and interpreted in light of their comparative genomics and the recent emergence of the human pathogen. In this proposal we will determine the roles of antibodies, and their mechanisms of action, in control and clearance of Bordetella subspecies. Aim 1. We will use mice lacking B cells and adoptive transfer of antibodies, and specific isotypes, to determine the role of antibodies in bacterial control/clearance. Aim 2. Mice lacking specific antibody effector functions will be used to determine the contribution of each to the antibody effects. Preliminary results indicate these effects, and the mechanisms involved, differ in various respiratory organs and with different Bordetella subspecies. Aim 3. We have determined that adoptively transferred antibodies have very different effects than do those endogenously produced in response to infection, paralleling observations of vaccine-induced, as opposed to infection-induced, immunity. We will compare adoptively transferred and naturally produced antibodies using wild type, B cell deficient or IgA-deficient mice to understand the basis for these differences. These experiments will characterize the interactions of Bordetella subspecies with host antibodies to determine the mechanisms of antibody-mediated bacterial clearance from the respiratory tract. Similar mechanisms are likely to be involved in respiratory immunity to other organisms, including those considered potential bioterrorism threats.