Evolution of Aspergillus fumigatus virulence

烟曲霉毒力的演变

基本信息

批准号：
10753216
负责人：
Robert Andrew Cramer
金额：
$ 57.23万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753216
关键词：
Acute Address Adrenal Cortex Hormones Allergic Bronchopulmonary Aspergillosis Animal Model Antifungal Agents Antifungal Therapy Architecture Aspergillosis Aspergillus Aspergillus fumigatus Biomass Carbon Cell Communication Cells Chronic Clinical Communities Data Development Disease Disease Outcome Disease Progression Dose Drug resistance Environment Ethanol Evolution Exhibits Foundations Funding Gene Cluster Gene Family Genes Genetic Genomics Glucose Goals Gossypium Growth Health Heterogeneity Hour Human Hypoxia Immune Immune system Immunity Infection Knowledge Laboratories Leukocytes Mediating Metabolic Metabolism Microbial Biofilms Modeling Molecular Morphology Mycoses Neutrophil Infiltration Oxygen Pathway interactions Patient Isolation Patients Pattern Phenotype Physiological Physiology Pilot Projects Population Predisposition Property Protein Analysis Proteins Research Role Site Source Study models Suppressor Mutations Tertiary Protein Structure Testing Therapeutic Virulence Virulent Work chemotherapy combat derepression fitness gene function genetic analysis human disease immunoregulation in vivo innovation insight lung injury mouse model neutrophil novel novel diagnostics novel therapeutic intervention pathogenic fungus patient population resistant strain success tool

项目摘要

Project Summary. Fungal mediated disease progression is highlighted by populations of fungal cells that form a community referred to as a biofilm. For therapeutic success, contemporary antifungal therapies must be effective at the site of infection in the context of an established fungal biofilm. Critically, it is now clear that emergent properties arise from fungal biofilms that directly alter virulence, disease progression, and antifungal drug susceptibility. However, the mechanisms through which filamentous fungal biofilm emergent properties impact virulence, disease progression, and antifungal susceptibility remain a significant knowledge gap. The long-term goal of this project is focused on defining the molecular mechanisms of Aspergillus fumigatus biofilm mediated disease progression mechanisms to inform contemporary and novel therapeutic approaches. In the prior funding period, we made important progress that surprisingly revealed heterogeneity in A. fumigatus biofilm morphology across clinical isolates. Differences in biofilm morphology altered virulence and disease progression in vivo in murine models of aspergillosis. We discovered that long term growth in a low oxygen environment gives rise to a biofilm morphology we termed H-MORPH and that a novel fungal specific gene cluster that contains a protein with unknown function was sufficient for H-MOPRH formation. Significantly, we identified H-MORPH clinical isolates from both acute invasive aspergillosis patients and patients with chronic aspergillosis, suggesting H-MORPH can arise in human disease. We observed that H-MOPRH occurs in vivo in a murine model of invasive pulmonary aspergillosis and contributes to worse disease outcomes compared to the contrasting N-MORPH isolates. In aim 1, we will define the genetic pathway(s) that regulate A. fumigatus the development of this unique population level morphotype utilizing the newly discovered biofilm architecture factor (baf) gene family as a tool to dissect the underlying mechanisms. In aim 2, we will define the differences in fungal metabolism that underly N-MORPH and H-MORPH morphotypes and test the hypothesis that H- MORPH biofilms are carbon catabolite de-repressed which leads to increased fitness in vivo. In aim 3, we test the hypothesis that H-MORPH strain metabolism is immune modulatory through alterations in fungal pathogen associated molecular pattern exposure. Taken together, our proposed studies will fill significant knowledge gaps related to the discovery of distinct A. fumigatus morphotypes that directly impact virulence. Advancing our understanding of this knowledge gap is expected to lay the foundation for new diagnostic and therapeutic strategies to combat highly virulent and drug resistant strains of this important human fungal pathogen.

项目摘要。形成真菌细胞群突出了真菌介导的疾病进展称为生物膜的群落。为了治疗成功，现代抗真菌疗法必须在已形成的真菌生物膜的感染部位有效。至关重要的是，现在很清楚真菌生物膜产生的新特性直接改变毒力、疾病进展和抗真菌作用药物敏感性。然而，丝状真菌生物膜出现特性的机制影响毒力、疾病进展和抗真菌药物敏感性仍然是一个重大的知识空白。这该项目的长期目标是确定烟曲霉生物膜的分子机制介导的疾病进展机制为当代和新颖的治疗方法提供信息。在在之前的资助期间，我们取得了重要进展，令人惊讶地揭示了烟曲霉的异质性临床分离株的生物膜形态。生物膜形态的差异改变了毒力和疾病曲霉菌病小鼠模型中的体内进展。我们发现在低氧条件下长期生长环境产生了一种我们称为 H-MORPH 的生物膜形态，并且一种新的真菌特异性基因含有功能未知的蛋白质的簇足以形成 H-MOPRH。值得注意的是，我们从急性侵袭性曲霉病患者和慢性曲霉病患者中鉴定出 H-MORPH 临床分离株曲霉病，表明 H-MORPH 可能出现在人类疾病中。我们观察到 H-MOPRH 在体内发生在侵袭性肺曲霉病的小鼠模型中，与相比，它会导致更糟糕的疾病结果对比 N-MORPH 分离株。在目标 1 中，我们将定义调节烟曲霉的遗传途径利用新发现的生物膜结构开发这种独特的群体水平形态类型因子（baf）基因家族作为剖析潜在机制的工具。在目标 2 中，我们将定义差异真菌代谢中 N-MORPH 和 H-MORPH 形态类型的基础，并检验 H- MORPH 生物膜消除了碳分解代谢物的抑制，从而增强了体内的适应性。在目标 3 中，我们测试 H-MORPH 菌株代谢通过真菌病原体的改变进行免疫调节的假设相关的分子图案曝光。总而言之，我们提出的研究将填补重要的知识与直接影响毒力的不同烟曲霉形态类型的发现相关的空白。推进我们的对这一知识差距的理解有望为新的诊断和治疗奠定基础对抗这种重要的人类真菌病原体的高毒力和耐药菌株的策略。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Is It Time To Kill the Survival Curve? A Case for Disease Progression Factors in Microbial Pathogenesis and Host Defense Research.

DOI：
10.1128/mbio.03483-20
发表时间：
2021-02-09
期刊：
mBio
影响因子：
6.4
作者：
Cramer RA;Kowalski CH
通讯作者：
Kowalski CH

A Fungal Sterylglucosidase at the Intersection of Virulence, Host Immunity, and Therapeutic Development.

DOI：
10.1128/mbio.02425-22
发表时间：
2022-12-20
期刊：
mBio
影响因子：
6.4
作者：
通讯作者：

A novel Sporothrix brasiliensis genomic variant in Midwestern Brazil: evidence for an older and wider sporotrichosis epidemic.

DOI：
10.1080/22221751.2020.1847001
发表时间：
2020-12
期刊：
Emerging microbes & infections
影响因子：
13.2
作者：
Eudes Filho J;Santos IBD;Reis CMS;Patané JSL;Paredes V;Bernardes JPRA;Poggiani SDSC;Castro TCB;Gomez OM;Pereira SA;Schubach EYP;Gomes KP;Mavengere H;Alves LGB;Lucas J;Paes HC;Albuquerque P;Cruz LM;McEwen JG;Stajich JE;Almeida-Paes R;Zancopé-Oliveira RM;Matute DR;Barker BM;Felipe MSS;Teixeira MM;Nicola AM
通讯作者：
Nicola AM