INVASIVE NONCAPSULATED H. INFLUENZAE

描述（改编自申请人的摘要）：一小部分 入侵H.流感疾病是（可能已经）由于不可分型 (i.e.未包囊的）菌株。随着儿童H. 流感结合疫苗，侵袭性 由于不可分型的生物体引起的疾病增加了：在某些地区， 在大多数情况下，只有在其他情况下，其流行率有所增加。因为担心 这种情况将继续增加流行（因为 通过针对B型菌株的疫苗接种施加的选择压力）， 重要的是要了解未封装的H使用的机制。流感 侵入并引起菌血症（和菌血症相关疾病）， 免疫能力强的免疫儿童。我们的初步数据表明， 毒力决定簇是由一种新的噬菌体（HP2）携带的， 细菌通过逃避补体系统在血液中复制。补语是 被认为是重要的主机防御入侵H.流感 人类感染。负责毒性的基因已经被指定为 人血清耐药1（hsr1）基因，目前没有同源物， 数据库。仅某些不可分型的H的溶原性转化。流感 结果转化为毒力，表明“辅助”基因 为了充分表达毒力。 这项拟议中的研究旨在确定负责 不寻常的毒力适当，确定这些毒力的流行 基因组中的一组侵袭性不可分型的H。流感病毒，确定机制 HP2通过其减轻补体活性，并鉴定辅助基因， 使用无毒力实验室表达该毒力性状所需的 菌株H.流感路KW 20。了解这种毒力机制， 不寻常的未封装的H.流感，将允许识别新的 表面成分是潜在的疫苗原。的抗原表位 在该机制中起作用的基因产物可用于产生新的H. 对侵袭性分离株有活性的流感结合疫苗。

Description (Adapted from the applicant's abstract): A small percentage of invasive H. influenzae disease is (and probably has been) due to nontypable (i.e. unencapsulated) strains. With increasing immunization of children with H. influenzae conjugate capsular vaccines, the relative proportion of invasive disease due to nontypable organisms has increased: in certain locales it is the majority, in others only its prevalence has increased. Because of the concern that such cases will continue to increase in prevalence (because of the selective pressure exerted by vaccination against type b strains), it is important to understand the mechanism(s) used by unencapsulated H. influenzae to invade and cause bacteremia (and bacteremia-associated diseases) in immunocompetent immunized children. Our preliminary data indicate that the virulence determinant is carried by a novel bacteriophage (HP2) and the bacterium to replicate in blood by evading the complement system. Complement is recognized to be important in host defense against invasive H. influenzae infections in humans. The gene responsible for virulence has been designated the Human Serum Resistance 1 (hsr1) gene, and has no homolog in the current databases. Lysogenic conversion of only certain nontypeable H. influenzae results in conversion to virulence suggesting that "accessory" genes are necessary, for full expression of virulence. The proposed research seeks to define the additional gene(s) responsible for the unusual virulence properly, determine the prevalence of these virulence genes in a panel on invasive nontypeable H. influenzae, define the mechanisms by which HP2 mitigates complement activity, and identify the accessory genes needed for expression of this virulence trait using the avirulent laboratory strain H. influenzae Rd. KW20. Understanding this virulence mechanism, which is unusual for unencapsulated H. influenzae, will permit identification of new surface components, which are potential vaccinogens. Antigenic epitopes of the gene products operative in this mechanism can be used to produce a new H. influenzae conjugate vaccine active against invasive isolates.