Defining the State of CD8+ and CD4+ T cells and the Effect of Antibiotic Treatment on Chronic States of Coccidioidomycosis Disease

定义 CD8 和 CD4 T 细胞的状态以及抗生素治疗对球孢子菌病慢性状态的影响

• 批准号: 10316113
• 负责人: Susana Tejeda-Garibay
• 金额: $ 3.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, MERCED
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-31 至 2023-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316113
• 关键词: 16S ribosomal RNA sequencing; AIDS/HIV problem; Acute Disease; Aerosols; Affect; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antifungal Agents; Asthma; Bacteria; Bacterial Pneumonia; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Etiology; Cell Differentiation process; Cells; Centers for Disease Control and Prevention (U.S.); Central America; Chronic; Chronic Disease; Clinical; Clostridium difficile; Coccidioides; Coccidioides immitis; Coccidioides posadasii; Coccidioidomycosis; Communication; Communities; Cryptococcus; Development; Diagnosis; Disease; Disease Marker; Disease Outcome; Disease Progression; Exhibits; Filipino; Firmicutes; Germ-Free; Global Warming; Goals; Immune; Immune response; Immunity; Immunologic Tests; Immunosuppression; Infection; Influenza A Virus, H1N1 Subtype; Inhalation; Invaded; Lead; Liquid substance; Lung; Lung diseases; Lung infections; Mediating; Modeling; Mucous Membrane; Mus; Mycoses; Outcome; Pathway interactions; Patients; Persons; Play; Population; Predisposition; Regulatory T-Lymphocyte; Reproduction spores; Respiratory distress; Role; Salmonella; Shigella flexneri; Soil; South America; Streptococcus pneumoniae; Symptoms; T-Cell Activation; T-Lymphocyte; Testing; United States; Up-Regulation; accurate diagnosis; aerosolized; bacterial resistance; chronic infection; community acquired pneumonia; desert fever; diabetic; effector T cell; exhaust; exhaustion; experience; flu; fungus; high risk; lung microbiome; lung microbiota; microbiome; microbiome alteration; novel therapeutics; pathogen; pathogenic fungus; predictive marker; prevent; receptor; receptor expression; response

PROJECT SUMMARY Coccidioidomycosis, also known as Valley fever, is a fungal infection caused by inhalation of Coccidioides immitis and Coccidioides posadasii upon soil disturbance and aerosolization of the pathogen spores. Coccidioides is endemic to Southwest United States, Central America, and South America and is found in hot, dry regions. It is considered an emerging disease as it is spreading into non-endemic regions and is expected to double in endemic region this century due to global warming. Valley fever can be a fatal fungal infection that is often misdiagnosed as community acquired pneumonia and treated with several rounds of antibiotics prior to accurate diagnosis. This contributes to a growing problem of antibiotic resistance and may also alter immune responses to Coccidioides. We know that antibiotic treatment significantly shifts the lung microbiota repertoire to being less diverse, with an increase in resistant bacteria, but it is unknown how antibiotics affect the interrelationship between the host lung microbiome, the invading fungal pathogen, and the immune response. The factors contributing to the development of Valley fever as either an acute or chronic disease are unknown. Chronic infections often elicit CD4+ and CD8+ T cell exhaustion, characterized by an upregulation of inhibitory pathways and a decrease in effector function. Suppression of T cell effector function by exhaustion could promote chronic disease and serve as predictive markers of disease state. Thus, the goal of this proposal is to: 1) analyze the exhaustion state of CD4+ and CD8+ T cells in infected mice as a means of understanding the host response; and 2) determine the impact antibiotic treatment has on disease outcome. I hypothesize that CD4+ and CD8+ T cells develop an exhausted state, directly contributing to chronic fungal infection, and that an altered microbiome through antibiotic treatment negatively impacts effective fungal clearance and potentially enhances the rate of exhaustion.

项目摘要 球孢子菌病，也被称为山谷热，是一种真菌感染引起的吸入球孢子菌 对土壤扰动和病原菌孢子气溶胶化的影响。 球孢子菌属是美国西南部、中美洲和南美洲特有的， 干旱地区。它被认为是一种新出现的疾病，因为它正在向非流行地区蔓延， 在这个世纪，由于全球变暖，山谷热可能是一种致命的真菌感染， 经常被误诊为社区获得性肺炎，并在感染前接受几轮抗生素治疗。 准确的诊断。这导致抗生素耐药性问题日益严重，也可能改变免疫系统。 对Coccidioides的回应我们知道抗生素治疗显著改变了肺部微生物群的组成 随着耐药细菌的增加，抗生素的多样性减少，但目前尚不清楚抗生素如何影响 宿主肺微生物组、入侵的真菌病原体和免疫应答之间的相互关系。 导致山谷热发展为急性或慢性疾病的因素尚不清楚。 慢性感染通常引起CD 4+和CD 8 + T细胞耗竭，其特征在于抑制性T细胞增殖的上调。 途径和效应器功能的降低。通过耗竭抑制T细胞效应子功能， 促进慢性疾病，并作为疾病状态的预测标志物。因此，本提案的目标是： 1)分析感染小鼠中CD 4+和CD 8 + T细胞的耗竭状态，作为了解 宿主反应; 2）确定抗生素治疗对疾病结果的影响。我假设 CD 4+和CD 8 + T细胞发展为衰竭状态，直接导致慢性真菌感染， 通过抗生素治疗改变的微生物组负面影响有效的真菌清除， 潜在地提高了耗尽的速率。