Trained immunity and the regulation of anti-fungal defense

训练有素的免疫力和抗真菌防御的调节

• 批准号: 10557883
• 负责人: Amariliz Rivera
• 金额: $ 63.08万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557883
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Alveolar Macrophages; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Cells; Cessation of life; Clinical; Critical Pathways; Cryptococcosis; Cryptococcus gattii; Cryptococcus neoformans; Data; Defect; Development; Drug resistance; Embryo; Epigenetic Process; Exhibits; Exposure to; Fungal Vaccines; Future; Gene Targeting; Genetic Transcription; Health; Host Defense Mechanism; IFNAR1 gene; Immune; Immunity; Immunization; Immunocompromised Host; Immunosuppression; In Vitro; Infection; Infection Control; Inflammation; Interferons; Intervention; Life; Literature; Lung; Lung infections; Macrophage; Mediator; Medical; Molds; Mus; Mycoses; Natural Immunity; Opportunistic Infections; Pathway interactions; Patient-Focused Outcomes; Patients; Phagocytes; Pharmaceutical Preparations; Population; Predisposition; Publishing; Recording of previous events; Regulation; Role; STAT1 gene; Shapes; Siblings; Signal Transduction; Source; Stimulus; Systems Biology; T-Lymphocyte; Testing; Therapeutic; Tissues; Training; Vaccines; cross immunity; cytokine; fungus; immunogenic; improved; in vivo; insight; loss of function; lung pathogen; monocyte; mortality; neutrophil; novel; pathogen; pathogenic fungus; response; vaccine candidate

Abstract: Although often overlooked as a significant health problem, pulmonary infections with fungal pathogens present a clinical problem of growing concern. Aspergillus fumigatus (Af) and Cryptococcus neoformans (Cn) are two clinically important fungal pathogens that affect immunosuppressed patients worldwide. Both infections are difficult to treat and are associated with high mortality rates. A better understanding of immune mechanisms of host defense against fungi hold the promise of providing the basis for the future development of novel, immune based interventions to improve patient outcomes. Pulmonary macrophages are critical, front-line mediators of host protection against fungi and other pulmonary pathogens. Despite the well-defined role of lung macrophages as crucial initiators of immunity to diverse sets of pathogens, our understanding of how previous infection history shapes subsequent macrophage responses to fungal infection in the lung remain poorly defined. Moreover, an emerging body of literature has now revealed that macrophage populations in the lung are more heterogeneous than originally appreciated and can undergo innate training; an enhanced response to diverse secondary challenges. It is now also understood that alveolar macrophages present in the lung can originate from embryonic precursors (tissue-derived alveolar macrophages-TD-AMs) or from blood monocytes (monocyte-derived alveolar macrophages-Mo-AMs). Whether TD-AM and Mo-AM are equally capable of undergoing innate training is currently unclear. It is also unknown whether innate training is a conserved response to any infectious stimuli or regulated by specific pathways. In preliminary studies, we uncovered that priming with an immunogenic strain of Cn (HK-fbp1) could confer heterologous protection against infection with Af even in the context of drug-induced immunosuppression and in a T cell-independent manner. Preliminary data gathered, suggest that neutrophils and STAT1-dependent signals are important regulators of antifungal monocytes and their differentiation into monocyte-derived cells. Based on our aggregate observations, the central hypothesis of this project is that: CCR2+mo are critical mediators of antifungal immunity and can be instructed by HK-fbp1 into trained mo-AM via the coordinated actions of neutrophils and an interferon (IFN) cascade. We will address two related but independent aims: Aim 1: Investigate the impact of HK-fbp1 immunization to pulmonary innate cell priming and training to promote antifungal immunity; Aim 2: Decipher the contributions of neutrophils in the regulation of antifungal trained immunity.

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