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.

项目总结 球孢子菌病，也称为谷热，是一种因吸入球孢子菌素而引起的真菌感染 球孢子虫和球孢子虫对土壤扰动和病原菌孢子气雾化的影响。 球孢子虫是美国西南部、中美洲和南美洲的特有种，在炎热的 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扩散，预计 由于全球变暖，本世纪地方病流行地区的人口将增加一倍。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，并在治疗前接受了几轮抗生素治疗 准确的诊断。这导致了日益严重的抗生素耐药性问题，并可能改变免疫系统 对球孢子虫的反应。我们知道抗生素治疗显著改变了肺部微生物区系。 变得不那么多样化，耐药细菌增加，但尚不清楚抗生素是如何影响 宿主肺微生物群、入侵真菌病原体和免疫反应之间的相互关系。 谷热发展为一种急性或慢性疾病的因素尚不清楚。 慢性感染通常导致CD4+和CD8+T细胞耗尽，其特征是抑制性上调 途径和效应器功能的下降。衰竭对T细胞效应器功能的抑制可能 促进慢性疾病，并作为疾病状态的预测标志。因此，这项提议的目标是： 1)分析感染小鼠外周血中CD4+和CD8+T细胞的耗竭状态，以了解 宿主反应；以及2)确定抗生素治疗对疾病结局的影响。我假设 CD4+和CD8+T细胞进入衰竭状态，直接导致慢性真菌感染， 通过抗生素治疗而改变的微生物群对有效的真菌清除和 可能会增加精疲力竭的速度。