Improved Therapeutics and Diagnostics for Pneumocystis Pneumonia

改进肺孢子虫肺炎的治疗和诊断

• 批准号: 9210593
• 负责人: JAY K KOLLS
• 金额: $ 24.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9210593
• 关键词: Acquired Immunodeficiency Syndrome; Antibodies; Antibody Response; Antifungal Agents; Antigen Targeting; Antigens; Antimicrobial Resistance; Binding; Biological Assay; Bronchoscopy; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Carbohydrates; Chimeric Proteins; Clinical; Complement; Complication; Cyst; Data; Death Rate; Dendritic Cells; Detection; Diagnosis; Diagnostic; Drug Interactions; Electron Transport; Engineering; Epitopes; Extracellular Domain; Fungal Proteins; Genes; Glucans; Grant; HIV; HIV Infections; Health Care Costs; Histology; Hospitalization; Host Defense Mechanism; Host resistance; Housing; Human; Humoral Immunities; IgG1; Imagery; Immune; Immunity; Immunization; Immunize; Immunocompromised Host; Immunoglobulin G; Immunological Models; In Vitro; Infection; Length of Stay; Life Cycle Stages; Ligase; Lung; Lung Inflammation; Mediating; Methodology; Mitochondria; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Neutrophilia; Organism; Passive Immunization; Patients; Phagocytosis; Pharmaceutical Preparations; Pneumocystis; Pneumocystis Infections; Pneumocystis carinii Pneumonia; Pneumonia; Predictive Value; Prevalence; Prophylactic treatment; Proteins; Proteomics; Resistance to infection; Resolution; Risk; Sampling; Serine Protease; Severities; Staining method; Stains; Sterols; Surface; Surface Antigens; Syndrome; Testing; Therapeutic; Treatment Efficacy; Treatment outcome; Trimethoprim-Sulfamethoxazole; Vaccinated; Vaccines; base; clinical Diagnosis; cost; dectin 1; immunogenicity; improved; killings; molecular diagnostics; mortality; novel; pneumocyte; polyclonal antibody; pre-clinical; prevent; public health relevance; reconstitution; therapeutic evaluation; transcriptome sequencing; transmission process

 DESCRIPTION (provided by applicant): Pneumocystis (PC) pneumonia remains a serious complication of HIV infection and other immunocompromised states. Recent ICD9 data show that since 2008 there are consistently 14-15,000 hospitalizations per year with an average cost of close to $1B per annum in the US alone. Moreover treatment for PCP has not changed in 20 years and there is concern of anti-microbial resistance and drug:drug interactions with TMP-SMX (the frontline therapy for PCP). We have shown that passive immunization with polyclonal antibodies or monoclonal antibodies or immmunoadhesins to surface antigens reduce the severity of PCP as ameliorate immune reconstitution syndrome. To date most of these therapies have been directed against the ascus form of the organism which is the environmental form. However RNAs-seq analyses shows that the troph is the replicative form and these data now open up to new avenues for therapeutics and diagnostics. First targeting antigens expressed on the surface of the trophozoite (and perhaps on the ascus as well) with therapeutic immunization or antibodies should abort the infection. Secondly as the trophozoite is the replicative form of infection a trophozoite- specific molecular diagnostic would improve sensitivity of clinical diagnosis which currently is still based on subjective histology. We will test these two hypotheses with the following specific aims: Specific Aim 1. Determine the immunogenicity and efficacy of a dual life cycle vaccine for PCP. Specific Aim 2. Determine the efficacy of dual life cycle antibodies to treat PCP and immune reconstitution syndrome (IRIS). Specific Aim 3. Determine the positive predictive value of a troph specific molecular diagnostic compared to current methodology. The above aims will advance therapeutic and diagnostic options to reduce the morbidity and mortality of PJP.

 描述（由申请人提供）：肺孢子虫（PC）肺炎仍然是HIV感染和其他免疫功能低下状态的严重并发症。最近的ICD 9数据显示，自2008年以来，每年有14000 - 15000例住院治疗，仅在美国每年的平均费用就接近10亿美元。此外，五氯苯酚的治疗在20年内没有改变，人们担心抗微生物耐药性和与TMP-SMX（五氯苯酚的一线治疗）的药物相互作用。我们已经证明，用多克隆抗体或单克隆抗体或针对表面抗原的免疫粘附素进行被动免疫，可以减轻PCP的严重程度，同时改善免疫重建综合征。迄今为止，这些疗法中的大多数都是针对作为环境形式的生物体的寄生虫形式。然而，RNAs-seq分析表明，troph是复制形式，这些数据现在为治疗和诊断开辟了新的途径。首先用治疗性免疫或抗体靶向滋养体表面（可能也包括滋养体表面）表达的抗原，应能中止感染。其次，由于滋养体是感染的复制形式，滋养体特异性分子诊断将提高目前仍基于主观组织学的临床诊断的敏感性。我们将测试这两个假设与以下具体目标：具体目标1.确定PCP双生命周期疫苗的免疫原性和有效性。具体目标2。确定双生命周期抗体治疗PCP和免疫重建综合征（IRIS）的疗效。具体目标3。与目前的方法相比，确定营养体特异性分子诊断的阳性预测值。上述目标将促进治疗和诊断选择，以降低PJP的发病率和死亡率。