Genetic Determinants of Aspergillus host-pathogen interactions

曲霉菌宿主-病原体相互作用的遗传决定因素

• 批准号: 10724816
• 负责人: Jarrod R. Fortwendel
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-23 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724816
• 关键词: Address; Allergic Bronchopulmonary Aspergillosis; Anabolism; Aspergillosis; Aspergillus; Aspergillus fumigatus; Asthma; Automobile Driving; Caspase; Cell Line; ChIP-seq; Chronic; Clinical; Coculture Techniques; Complex; Cystic Fibrosis; Development; Fungal Components; Future; Gene Deletion; Gene Expression Profile; Gene Expression Profiling; Genetic Determinism; Genetic Epistasis; Genetic Transcription; Goals; Human; Immune response; Immunity; Immunocompetent; Immunocompromised Host; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory Response; Interleukin-1 beta; Libraries; Macrophage; Masks; Measures; Mediating; Molecular; Morbidity - disease rate; Organism; Pathogen detection; Pathogenicity; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phagocytosis; Process; Protein Kinase; Proteins; Regulation; Research; Research Design; Role; Screening Result; Severities; Signal Transduction; Stimulus; Stress Response Signaling; Syndrome; Tissue-Specific Gene Expression; Virulence; Work; biological adaptation to stress; chronic infection; diagnostic criteria; fungus; gene complementation; immunological status; immunopathology; improved outcome; in vivo; molecular assembly/self assembly; monocyte; mortality; mouse model; mutant; new therapeutic target; novel; novel therapeutic intervention; pathogen; pathogenic fungus; protein-histidine kinase; respiratory; response; sensor histidine kinase; therapeutic target; tool; transcription factor; transcriptome sequencing

The long-term goal of our work is to reduce the morbidity and mortality associated with Aspergillus infections by improving outcomes of host-pathogen interactions. Aspergillus fumigatus is the major airborne fungal pathogen and is responsible for a range of clinical syndromes, the severity of which is dependent on host immune status. Invasive pulmonary aspergillosis and disseminated infections can occur in severely immunocompromised hosts and are often associated with mortality rates of up to 90%. In immune competent hosts, A. fumigatus colonization can lead to chronic pulmonary aspergillosis (CPA), a clinical manifestation with recently defined diagnostic criteria that impacts upwards of 1.6 million individuals per year. Many individuals with CPA have underlying respiratory conditions, such as asthma or cystic fibrosis, that are further exacerbated by the presence of the fungus. Although multiple Pathogen-Associated Molecular Patterns (PAMPs) driving host recognition and response are known, uncovering novel fungal molecular pathways that could serve as therapeutic targets to enhance or mask PAMP display and/or biosynthesis could prove useful therapeutic targets to modulate host response for improved outcomes. To address this, we utilized activation of the inflammasome, a multiprotein intracellular complex that detects pathogenic organisms to initiate inflammatory responses, as a tool to uncover Aspergillus mutants with altered abilities to activate host response. We have completed a preliminary screen to measure IL-1β secretion from a macrophage differentiated human monocyte cell line employing an A. fumigatus protein kinase disruption library recently generated in our lab. Of 118 protein kinase disruption mutants screened, we identified seven A. fumigatus protein kinases that either significantly increased (n=2) or decreased (n=5) inflammasome-dependent IL-1β secretion upon disruption. Strikingly, both of the protein kinase disruption mutants that induced increased IL-1β release encode phospho-relay sensor histidine kinases (phkA and fhk3), a sub-class of protein kinases that directly sense environmental and intracellular changes and subsequently activate stress response signaling. The molecular pathways controlled by PhkA and Fhk3 are unknown, as both HKs are largely uncharacterized. Although a major consequence of HK signaling is activation of stress responses pathways that upregulate transcription factor activity to respond to environmental stimuli, the downstream transcriptional effectors for all A. fumigatus HKs remain undescribed. Our work will delineate A. fumigatus histidine kinase (HK)-dependent mechanisms of host response (Aim 1) and identify A. fumigatus transcriptional regulators of inflammasome activation (Aim 2). Through completion of the proposed Aims, we will delineate fungal molecular pathways mediating Aspergillus-induced host response. This work is essential for future development of novel therapeutic approaches targeted towards activating protection against invasive infections or mitigating harmful host-response during chronic infections.

我们的工作的长期目标是减少发病率和死亡率与曲霉感染通过