INVASIVE NONCAPSULATED H. INFLUENZAE

描述(改编自申请人的摘要)：一小部分 侵袭性流感嗜血杆菌疾病是(很可能是)由于不可分型 (即无包膜的)菌株。随着H. 流感病毒结合衣壳疫苗侵袭性的相对比例 由不可分型生物引起的疾病有所增加：在某些地区，这是 大多数人，在其他人中，只有它的流行率增加了。因为人们的担忧 此类病例的流行率将继续增加(因为 接种疫苗对b型菌株施加的选择性压力)， 了解无囊化流感嗜血杆菌的作用机制很重要(S) 侵入并引起菌血症(和菌血症相关疾病) 免疫能力较强的儿童。我们的初步数据显示 毒力决定簇由一种新的噬菌体(HP2)携带，并且 细菌通过逃避补体系统在血液中复制。补语是 被认为对宿主防御入侵的流感嗜血杆菌很重要 对人类的感染。负责毒力的基因已被确定为 人血清抗性1(Hsr1)基因，目前尚无同源基因 数据库。仅某些非分型流感嗜血杆菌的溶原性转化 转化为毒力的结果表明“辅助”基因 为了充分表现出毒力，这是必要的。 这项拟议中的研究试图定义负责的额外基因(S) 异常的毒力适当，决定了这些毒力的流行程度 侵袭性非分型流感嗜血杆菌的基因定义了其机制 通过HP2减轻补体活性，并识别辅助基因 使用无毒实验室表达这种毒力特性所需的 流感嗜血杆菌Rd.KW20。了解这种毒力机制，这是 对于未被包裹的流感嗜血杆菌来说是不同寻常的，将允许识别新的 表面成分，这是潜在的疫苗原。猪瘟病毒的抗原性表位 在这种机制中工作的基因产物可以用来产生一种新的H. 流感病毒结合疫苗对侵袭性分离株具有活性。

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.