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

基本信息

项目摘要

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Jarrod R. Fortwendel其他文献

MOB-mediated regulation of septation initiation network (SIN) signaling is required for echinocandin-induced hyperseptation in emAspergillus fumigatus/em
棘白菌素诱导烟曲霉超分隔需要 MOB 介导的分隔起始网络(SIN)信号调节
  • DOI:
    10.1128/msphere.00695-23
  • 发表时间:
    2024-02-20
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Harrison I. Thorn;Xabier Guruceaga;Adela Martin-Vicente;Ashley V. Nywening;Jinhong Xie;Wenbo Ge;Jarrod R. Fortwendel;Rebecca S. Shapiro
  • 通讯作者:
    Rebecca S. Shapiro
emhapE/em and emhmg1/em Mutations Are Drivers of emcyp51A/em-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical Isolate
emhapE/em 和 emhmg1/em 突变是烟曲霉临床分离株中不依赖于 emcyp51A/em 的泛三唑抗性的驱动因素
  • DOI:
    10.1128/spectrum.05188-22
  • 发表时间:
    2023-05-18
  • 期刊:
  • 影响因子:
    3.800
  • 作者:
    Ana C. O. Souza;Wenbo Ge;Nathan P. Wiederhold;Jeffrey M. Rybak;Jarrod R. Fortwendel;P. David Rogers
  • 通讯作者:
    P. David Rogers

Jarrod R. Fortwendel的其他文献

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{{ truncateString('Jarrod R. Fortwendel', 18)}}的其他基金

Unlocking the cidal activity of echinocandins against Aspergillus fumigatus
解锁棘白菌素对烟曲霉的杀灭活性
  • 批准号:
    10378147
  • 财政年份:
    2021
  • 资助金额:
    $ 23.1万
  • 项目类别:
Unlocking the cidal activity of echinocandins against Aspergillus fumigatus
解锁棘白菌素对烟曲霉的杀灭活性
  • 批准号:
    10179720
  • 财政年份:
    2021
  • 资助金额:
    $ 23.1万
  • 项目类别:
Unlocking the cidal activity of echinocandins against Aspergillus fumigatus
解锁棘白菌素对烟曲霉的杀灭活性
  • 批准号:
    10590730
  • 财政年份:
    2021
  • 资助金额:
    $ 23.1万
  • 项目类别:
Non-cyp51A-mutation Mediated Triazole Resistance in Aspergillus fumigatus
非 cyp51A 突变介导的烟曲霉三唑耐药性
  • 批准号:
    10582526
  • 财政年份:
    2020
  • 资助金额:
    $ 23.1万
  • 项目类别:
Non-cyp51A-mutation Mediated Triazole Resistance in Aspergillus fumigatus
非 cyp51A 突变介导的烟曲霉三唑耐药性
  • 批准号:
    9913275
  • 财政年份:
    2020
  • 资助金额:
    $ 23.1万
  • 项目类别:
Non-cyp51A-mutation Mediated Triazole Resistance in Aspergillus fumigatus
非 cyp51A 突变介导的烟曲霉三唑耐药性
  • 批准号:
    10358515
  • 财政年份:
    2020
  • 资助金额:
    $ 23.1万
  • 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
  • 批准号:
    9282239
  • 财政年份:
    2014
  • 资助金额:
    $ 23.1万
  • 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
  • 批准号:
    8806512
  • 财政年份:
    2014
  • 资助金额:
    $ 23.1万
  • 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
  • 批准号:
    9205482
  • 财政年份:
    2014
  • 资助金额:
    $ 23.1万
  • 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
  • 批准号:
    8696215
  • 财政年份:
    2014
  • 资助金额:
    $ 23.1万
  • 项目类别:

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Is sialic acid recognition receptor a candidate molecule for diagnosis of allergic bronchopulmonary aspergillosis?
唾液酸识别受体是诊断过敏性支气管肺曲霉病的候选分子吗?
  • 批准号:
    20K07183
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开发新的实验模型以了解过敏性支气管肺曲霉病(ABPA)的遗传基础
  • 批准号:
    NC/P002390/1
  • 财政年份:
    2017
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    $ 23.1万
  • 项目类别:
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Airway inflamation in allergic bronchopulmonary aspergillosis and the use of Itraconazole
过敏性支气管肺曲霉病的气道炎症和伊曲康唑的使用
  • 批准号:
    nhmrc : 8201
  • 财政年份:
    2000
  • 资助金额:
    $ 23.1万
  • 项目类别:
    NHMRC Postgraduate Scholarships
ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS
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  • 批准号:
    4688612
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    $ 23.1万
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