Ontogeny and metabolism of lung alveolar macrophages in tuberculosis
Active Project Grant Awarded Last action
- Award ID
- R01AI184960
- Recipient
-
Trustees Of Boston University UEI FBYMGMHW4X95
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $2,237,218
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 45% complete
- Place of performance
- Roxbury, MA 02118, USA
Award details come from USAspending.gov.
Description
- Abstract
- Our current vaccine development strategies against tuberculosis (TB) focus on the induction of adaptive immune responses, but that may not be sufficient to mount effective immunity. Mycobacterium tuberculosis (MTB) resides in heterogenous lung macrophages with various levels of permissiveness in the presence of the same immune pressure. Among them, lung alveolar macrophages (AMS) are highly permissive cells, which facilitate rapid growth of MTB and promote disease dissemination at the early stage of infection. However, the underlying mechanism that determines this permissive nature of AMS during MTB infection remains elusive. Identifying determinants regulating the response of AMS to MTB is thus essential for the development of new therapeutics and novel vaccine platforms. While AMS are derived from embryonic precursors in naïve mice, they can be replaced by bone marrow-derived monocytes during infection. IT is unknown whether the origin of AMS change and how the altered ontogeny impacts the permissiveness and functions of AMS during MTB infection. In addition to ontogeny, our previous work has demonstrated that lung macrophage metabolism plays a critical role in promoting or controlling the progression of TB. AMS consume fatty acids and engage in fatty acid oxidation (FAO), a pathway that has been associated with the optimal growth of MTB. Given that both ontogeny and metabolism play pivotal roles in modulating how macrophages respond to MTB infection, we hypothesize that ontogeny and metabolism are intrinsic features that regulate the permissiveness of AMS during MTB infection. We further propose that harnessing these two features will allow the reprogramming of AMS for better control of MTB at the early stage of infection. We will test this hypothesis with three aims: aim 1. Determine how ontogeny contributes to the response of AMS during MTB infection. Aim 2. Delineate how glycolysis and FAO differentially regulate the permissiveness of AMS during MTB infection. Aim 3. Reprogramming AMS by leveraging their ontogeny and metabolism against MTB infection. To address these aims, we will exploit multi-disciplinary approaches, including immunology, metabolism, genomics, microbiology, novel mouse models and human primary AMS to directly probe how ontogeny and major metabolic pathways regulate the permissiveness of AMS during MTB infection. Knowledge gained from these studies is expected to provide a better understanding of the mechanism regulating am response to MTB, which opens the gate for reprogramming AMS for enhanced control of MTB at the early stage of infection as well as aiding in development of host-directed therapies against TB.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $733,869 | |
| Amendment | $0 | |
| Amendment | $733,424 | |
| Original award | $769,925 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Trustees Of Tufts College | $102,160 | |
| Arkansas Children's Research Institute | $67,239 | |
| Syracuse University | $0 | |
| Trustees Of Tufts College | $0 | |
| Trustees Of Tufts College | $102,161 | |
| Syracuse University | $67,220 | |
| Syracuse University | $65,044 | |
| Trustees Of Tufts College | $102,161 |
Quick answers
Who received award R01AI184960?
R01AI184960 was awarded to Trustees Of Boston University by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on August 13, 2024.
How much is award R01AI184960 worth?
$2,237,218 has been obligated on R01AI184960.
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