One-carbon metabolism and immune cell function in tuberculosis

结核病中的一碳代谢和免疫细胞功能

基本信息

  • 批准号:
    10719273
  • 负责人:
  • 金额:
    $ 78.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-02 至 2027-07-31
  • 项目状态:
    未结题

项目摘要

Abstract The immunometabolism of tuberculosis (TB) offers new opportunities for controlling this deadly infectious disease. We and others have characterized the immunometabolic changes in multiple animal models of TB and found that metabolic remodeling to the HIF-1-mediated Warburg effect is a general response to infection by Mycobacterium tuberculosis, the causative agent of TB. Recently, using multiple approaches that include metabolomics and transcriptomic profiling, we identified novel core metabolic pathways that are found in both Mtb-infected M1-like macrophages and in mouse lungs. These include glutaminolysis and one-carbon metabolism. One-carbon metabolism catabolizes the transfer of serine-derived one-carbon (1C) units to generate methyl-tetrahydrofolate (THF) intermediates that are then utilized for nucleotide synthesis and for methylation reactions through the methionine cycle. One-carbon metabolism is also involved in redox balancing through the generation of NADH/NADPH and of glycine and cysteine for glutathione (GSH) synthesis. We also found that inhibition of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) leads to diminished M1-like polarization that includes dysregulated mitochondrial function and dampened mTORC1/ATF4 signaling in M1- like macrophages. MTHFD2 is a key mitochondrial enzyme of one-carbon metabolism that is encoded by Mthfd2, which is highly induced in Mtb infected M-like macrophages and mouse lungs. Based on these observations, we hypothesize that mitochondrial MTHFD2-mediated, one-carbon metabolism contributes to metabolic remodeling programs of activating immune cells by generating 1C units for nucleotide synthesis and methylation reactions, as well as reducing equivalents and GSH for redox homeostasis. Since TB is often associated with a deficiency of folic acid, the precursor of the 1C carrier THF, we also hypothesize that folic acid deficiency during Mtb infection dampens one-carbon metabolism, leading to diminished activation, differentiation, and effector function of host immune cells. Moreover, since elevated MTHFD2 in vivo is associated with inflammatory disease severity, we further hypothesize that prolonged and elevated expression of one-carbon metabolism contributes to lung pathology at the chronic stage of Mtb infection. To test our hypothesis, in Aim 1, we will delineate how MTHFD2- mediated, one-carbon metabolism regulates immunometabolic properties of M1-like macrophages, mitochondrial biology, serine metabolic pathways, and the mechanism of Mthfd2 upregulation. In Aim 2, we will generate conditional KO mouse strains lacking Mthfd2 in myeloid cells and T cell lineage to delineate the impact of Mthfd2 deficiency on disease progression and immunometabolic properties of immune cells and/or subsets. With Aim 3, we will use a susceptible mouse model of TB to evaluate the effects of folic acid dietary intake on the expression of host immunity to control Mtb infection. We will also define the therapeutic role of inhibitors targeting one-carbon metabolism during anti-TB treatment at chronic stages of the infection. Our study is expected to advance the development of urgently needed host-directed therapies (HDTs) to enhance the ability of immune cells to clear Mtb infection and/or to prevent the development of pathology.
摘要结核病(TB)的免疫代谢为控制这一致命疾病提供了新的机会

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Padmini Salgame其他文献

Padmini Salgame的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Padmini Salgame', 18)}}的其他基金

Animal models and related services (AMRS) core
动物模型和相关服务(AMRS)核心
  • 批准号:
    10793866
  • 财政年份:
    2023
  • 资助金额:
    $ 78.42万
  • 项目类别:
Immune Determinants of the Course of Mycobacterium tuberculosis infection and Disease
结核分枝杆菌感染和疾病过程的免疫决定因素
  • 批准号:
    10493277
  • 财政年份:
    2021
  • 资助金额:
    $ 78.42万
  • 项目类别:
Immune Determinants of the Course of Mycobacterium tuberculosis infection and Disease
结核分枝杆菌感染和疾病过程的免疫决定因素
  • 批准号:
    10271649
  • 财政年份:
    2021
  • 资助金额:
    $ 78.42万
  • 项目类别:
Immune Determinants of the Course of Mycobacterium tuberculosis infection and Disease
结核分枝杆菌感染和疾病过程的免疫决定因素
  • 批准号:
    10665030
  • 财政年份:
    2021
  • 资助金额:
    $ 78.42万
  • 项目类别:
Program in Infection, Immunity and Inflammation
感染、免疫和炎症项目
  • 批准号:
    9924471
  • 财政年份:
    2016
  • 资助金额:
    $ 78.42万
  • 项目类别:
TLR2 and the Tubercle Granuloma
TLR2 和结节肉芽肿
  • 批准号:
    8231291
  • 财政年份:
    2011
  • 资助金额:
    $ 78.42万
  • 项目类别:
TLR2 and the Tubercle Granuloma
TLR2 和结节肉芽肿
  • 批准号:
    8433535
  • 财政年份:
    2011
  • 资助金额:
    $ 78.42万
  • 项目类别:
TLR2 and the Tubercle Granuloma
TLR2 和结节肉芽肿
  • 批准号:
    8714524
  • 财政年份:
    2011
  • 资助金额:
    $ 78.42万
  • 项目类别:
TLR2 and the Tubercle Granuloma
TLR2 和结节肉芽肿
  • 批准号:
    8616331
  • 财政年份:
    2011
  • 资助金额:
    $ 78.42万
  • 项目类别:
TLR2 and the Tubercle Granuloma
TLR2 和结节肉芽肿
  • 批准号:
    8032716
  • 财政年份:
    2011
  • 资助金额:
    $ 78.42万
  • 项目类别:

相似海外基金

ADVANCED DEVELOPMENT OF LQ A LIPOSOME-BASED SAPONIN-CONTAINING ADJUVANT FOR USE IN PANSARBECOVIRUS VACCINES
用于 Pansarbecovirus 疫苗的 LQ A 脂质体含皂苷佐剂的先进开发
  • 批准号:
    10935820
  • 财政年份:
    2023
  • 资助金额:
    $ 78.42万
  • 项目类别:
ADVANCED DEVELOPMENT OF BBT-059 AS A RADIATION MEDICAL COUNTERMEASURE FOR DOSING UP TO 48H POST EXPOSURE"
BBT-059 的先进开发,作为辐射医学对策,可在暴露后 48 小时内进行给药”
  • 批准号:
    10932514
  • 财政年份:
    2023
  • 资助金额:
    $ 78.42万
  • 项目类别:
Advanced Development of a Combined Shigella-ETEC Vaccine
志贺氏菌-ETEC 联合疫苗的先进开发
  • 批准号:
    10704845
  • 财政年份:
    2023
  • 资助金额:
    $ 78.42万
  • 项目类别:
Advanced development of composite gene delivery and CAR engineering systems
复合基因递送和CAR工程系统的先进开发
  • 批准号:
    10709085
  • 财政年份:
    2023
  • 资助金额:
    $ 78.42万
  • 项目类别:
Advanced Development of Gemini-DHAP
Gemini-DHAP的高级开发
  • 批准号:
    10760050
  • 财政年份:
    2023
  • 资助金额:
    $ 78.42万
  • 项目类别:
Advanced development and validation of an in vitro platform to phenotype brain metastatic tumor cells using artificial intelligence
使用人工智能对脑转移肿瘤细胞进行表型分析的体外平台的高级开发和验证
  • 批准号:
    10409385
  • 财政年份:
    2022
  • 资助金额:
    $ 78.42万
  • 项目类别:
ADVANCED DEVELOPMENT OF A VACCINE FOR PANDEMIC AND PRE-EMERGENT CORONAVIRUSES
针对大流行和突发冠状病毒的疫苗的高级开发
  • 批准号:
    10710595
  • 财政年份:
    2022
  • 资助金额:
    $ 78.42万
  • 项目类别:
Advanced development and validation of an in vitro platform to phenotype brain metastatic tumor cells using artificial intelligence
使用人工智能对脑转移肿瘤细胞进行表型分析的体外平台的高级开发和验证
  • 批准号:
    10630975
  • 财政年份:
    2022
  • 资助金额:
    $ 78.42万
  • 项目类别:
ADVANCED DEVELOPMENT OF A VACCINE CANDIDATE FOR STAPHYLOCOCCUS AUREUS INFECTION
金黄色葡萄球菌感染候选疫苗的高级开发
  • 批准号:
    10710588
  • 财政年份:
    2022
  • 资助金额:
    $ 78.42万
  • 项目类别:
ADVANCED DEVELOPMENT OF A VACCINE FOR PANDEMIC AND PRE-EMERGENT CORONAVIRUSES
针对大流行和突发冠状病毒的疫苗的高级开发
  • 批准号:
    10788051
  • 财政年份:
    2022
  • 资助金额:
    $ 78.42万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了