Comparative Immunobiology of the bordetellae

描述(申请人提供)：波氏杆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年代以来一直广泛使用百日咳波氏杆菌疫苗，但它存在着严重的问题；它提供的疾病保护不完整，对感染率没有影响，使细菌能够持续传播。虽然这种肌肉注射疫苗显然不能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的缺乏阻碍了它的改进。在小鼠模型中，B细胞需要清除感染，但过继转移免疫血清对细菌数量影响不大，这意味着B细胞执行除产生抗体之外的其他功能。我们提出了另一种解释：分泌型抗体是对百日咳杆菌保护性免疫的主要机制。这将解释对B细胞的需求和免疫血清缺乏转移效果的原因，因为免疫血清中含有少量的IgA。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，但不影响细菌定植水平，因为它们不会在呼吸道内诱导分泌型IgA。我们最近观察到，与百日咳杆菌不同，血清抗体足以清除小鼠下呼吸道中的支气管败血杆菌。这两个亚种的系统发育关系和基因组序列非常密切，这将使它们的相似和不同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来解释。在这个提案中，我们将确定抗体在控制和清除波尔德氏菌亚种中的作用及其作用机制。目的1.我们将使用缺乏B细胞和过继转移抗体的小鼠，以及特定的同种类型，来确定抗体在细菌控制/清除中的作用。目的2.缺乏特异性抗体效应器功能的小鼠将被用来确定每种抗体对抗体效应的贡献。初步结果表明，这些作用和涉及的机制在不同的呼吸器官和不同的波尔德氏菌亚种中是不同的。目的3.我们已经确定，过继转移的抗体与内源性抗体在应对感染时产生的效果非常不同，这与疫苗诱导的免疫与感染诱导的免疫的观察结果是平行的。我们将使用野生型、B细胞缺陷或IgA缺陷小鼠来比较过继转移抗体和自然产生的抗体，以了解这些差异的基础。这些实验将表征波尔德氏菌亚种与宿主抗体的相互作用，以确定抗体介导的细菌从呼吸道清除的机制。类似的机制可能涉及对其他生物的呼吸道免疫，包括那些被认为是潜在的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.