Moraxella catarrhalis: virulence-based prevention

卡他莫拉氏菌：基于毒力的预防

• 批准号: 8670720
• 负责人: Timothy F Murphy
• 金额: $ 32.12万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670720
• 关键词: ATP-Binding Cassette Transporters; Accident and Emergency department; Admission activity; Adult; American; Animal Model; Antibiotic Resistance; Antibiotics; Arginine; Bacteria; Bacteria oligopeptide permease; Bacterial Infections; Bacterial Vaccines; Binding; Binding Proteins; Biological Models; Biology; Cause of Death; Cell Culture System; Cell Wall; Cell surface; Cessation of life; Child; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical; Clinical Trials; Conductive hearing loss; Development; Disease; Economic Burden; Epitopes; Family; Genome; Growth; Health Care Costs; Healthcare Systems; Hospitals; Human; Immune response; Infection; Investigation; Knock-out; Knowledge; Laboratories; Language Development; Lower Respiratory Tract Infection; Maintenance; Mediating; Membrane Proteins; Methods; Mining; Modality; Modeling; Molecular Structure; Moraxella (Branhamella) catarrhalis; Morbidity - disease rate; Mus; Nontypable Haemophilus influenza; Organism; Otitis; Otitis Media; Outpatients; Pathogenesis; Peptides; Periplasmic Proteins; Pneumococcal conjugate vaccine; Population; Prevalence; Prevention; Recurrence; Relative (related person); Research; Respiratory Failure; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Role; Speech Development; Streptococcus pneumoniae; Structure; Surface; System; Thinking; Translating; Upper respiratory tract; Vaccine Antigen; Vaccines; Virulence; Virulence Factors; Visit; Work; base; fitness; in vitro Assay; middle ear; mortality; mutant; novel; novel vaccines; pathogen; prevent; social; solute; success; uptake; vaccine candidate; vaccine development

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.

描述（由申请方提供）：卡他莫拉菌是儿童中耳炎和慢性阻塞性肺疾病（COPD）成人下呼吸道感染（加重）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了M.粘膜炎。在M上工作。卡他病已经落后了，因为该生物体以前被认为是一种寄生虫。鉴于其日益增长的重要性，迫切需要M。 粘膜炎疫苗。事实上，世界上只有少数实验室研究这种生物。 M.卡他炎通过栖息在与上呼吸道相邻的环境小生境（包括中耳腔（中耳炎）和患有COPD的成年人的气道）而引起感染。在不同的宿主环境中维持适合性在M.粘膜炎感染。 我们确定寡肽通透酶A（OppA），ABC转运系统的溶质结合蛋白，作为一个有前途的疫苗抗原，也作为一个潜在的毒力因子。M.卡他病对精氨酸有严格的生长要求。我们发现OppA转运含精氨酸的肽。在小鼠模型中，OppA敲除突变体比野生型更快地从呼吸道清除，表明OppA促进了呼吸道感染的持续。 M.呼吸道中的粘膜炎。在目的1中，我们将研究OppA和相关转运蛋白作为毒力因子。我们发现OppA在细菌表面上表达表位，这是对预测的可溶性周质蛋白的令人惊讶的观察。在目标2中，我们将阐明细菌细胞壁中OppA和相关转运蛋白的分子结构，以确定潜在的保护性表位和肽结合区域。目标3将把这些观察结果转化为预防M.卡他炎感染候选疫苗将使用几个互补的模型系统进行评价。 因此，本提案将通过以下方式推动这一领域的发展： * 为未充分研究的病原体确定新的毒力机制 * 阐明了疫苗抗原的结构，我们对该抗原进行了新的观察，挑战了目前对ABC转运蛋白溶质结合蛋白细胞壁结构的认识 * 鉴定和表征新疫苗抗原 虽然对慢性阻塞性肺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新的感染预防模式已经有几十年了。本建议有可能通过鉴定和表征新型疫苗抗原，在预防中耳炎和COPD恶化方面取得根本性进展。由于最近有希望的临床试验，人们对中耳炎疫苗重新产生了热情，为这种方法的可行性创造了动力。