Moraxella catarrhalis: virulence-based prevention

描述(申请人提供)：卡他莫拉菌是儿童中耳炎和成人慢性阻塞性肺疾病(COPD)下呼吸道感染(恶化)的重要原因。自2000年以来，肺炎球菌结合疫苗在儿童中的广泛使用导致卡他毛虫定殖化和感染的流行增加。对卡氏支原体的研究一直滞后，因为这种有机体以前被认为是共生体。鉴于其日益增长的重要性，迫切需要卡他分支杆菌疫苗。事实上，世界上只有少数几个实验室研究这种有机体。 卡特氏支原体通过栖息在与上呼吸道相连的环境中，包括中耳间隙(中耳炎)和患有COPD的成年人的呼吸道而引起感染。在卡氏支原体感染的发病机制中，在不同的寄主环境中保持适合性是至关重要的。 我们发现寡肽渗透酶A(Oppa)是ABC转运蛋白系统的一种溶质结合蛋白，是一种很有前途的疫苗抗原，也是一种潜在的毒力因子。卡氏微囊藻对精氨酸有严格的生长要求。我们发现OPPA可以运输含精氨酸的多肽。在小鼠模型中，oppa基因敲除突变体比野生型更快地从呼吸道中清除，表明oppa有助于持续 呼吸道中的卡特氏支原体。在目标1中，我们将研究oppa及其相关转运蛋白作为毒力因子。我们发现oppa在细菌表面表达表位，对于预测的可溶性周质蛋白来说，这是一个令人惊讶的观察结果。在目标2中，我们将阐明OPPA的分子结构和细菌细胞壁中相关的转运蛋白，以确定潜在的保护性表位和多肽结合区。AIM 3将把这些观察结果转化为预防卡他毛虫感染的疫苗的开发。将使用几个互补的模型系统对候选疫苗进行评估。 因此，本提案将通过以下方式推进这一领域： *为研究不足的病原体确定新的毒力机制 *阐明疫苗抗原的结构，我们在该抗原上有新的观察结果，挑战了目前关于ABC转运蛋白溶质结合蛋白细胞壁结构的想法 *确定和表征新的疫苗抗原 虽然对慢性阻塞性肺疾病中耳炎和细菌感染的生物学知识正在进步，但在这些临床环境中开发真正的新的感染预防方法已经有几十年了。本提案有可能通过鉴定和表征新的疫苗抗原，在预防中耳炎和COPD加重方面取得根本性进展。鉴于最近前景看好的临床试验，人们对中耳炎疫苗的热情重新高涨，为这种方法创造了可行性的势头。

DESCRIPTION (provided by applicant): Moraxella catarrhalis is an important cause of otitis media in children, and lower respiratory tract infections (exacerbations) in adults with chronic obstructive pulmonary disease (COPD). The widespread use of pneumococcal conjugate vaccines in children since 2000 has caused an increased prevalence of colonization and infection by M. catarrhalis. Work on M. catarrhalis has lagged behind because the organism was previously regarded as a commensal. Given its growing importance, there is an urgent need for M. catarrhalis vaccines. Indeed, only a handful of laboratories in world study the organism. M. catarrhalis causes infection by inhabiting environmental niches contiguous with the upper respiratory tract, including the middle ear space (otitis media) and the airways in adults with COPD. The maintenance of fitness in different host milieus is of central importance in the pathogenesis of M. catarrhalis infections. We identified oligopeptide permease A (OppA), a solute binding protein of an ABC transporter system, as a promising vaccine antigen and also as a potential virulence factor. M. catarrhalis has a strict growth requirement for arginine. We showed that OppA transports arginine-containing peptides. An OppA knockout mutant is cleared more quickly from the respiratory tract than wild type in a murine model, indicating that OppA facilitates persistence of M. catarrhalis in the respiratory tract. In Aim 1, we will investigate OppA and related transporter as virulence factors. We showed that OppA expresses epitopes on the bacterial surface, a surprising observation for a predicted soluble periplasmic protein. In Aim 2 we will elucidate the molecular structure of OppA and related transporters in the bacterial cell wall to identify potentially protective epitopes and peptide binding regions. Aim 3 will translate these observations to the development of vaccines to prevent M. catarrhalis infection. Vaccine candidates will be evaluated using several complementary model systems. Thus the present proposal will advance the field by: * identifying new virulence mechanisms for an understudied pathogen * elucidating structure of a vaccine antigen on which we have novel observations that challenge current thinking about cell wall structure of solute binding proteins of ABC transporter * identifying and characterizing new vaccine antigens While knowledge of the biology of otitis media and bacterial infection in COPD is advancing, it has been decades since the development of truly new prevention modalities for infection in these clinical settings. The present proposal has the potential to make fundamental advances in prevention of otitis media and exacerbations of COPD through identification and characterization of novel vaccine antigens. There is a renewed enthusiasm for vaccines for otitis media given recent promising clinical trials, creating a momentum of feasibility for this approach.