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| Status |
Public on Oct 31, 2023 |
| Title |
CD38+ Alveolar Macrophages mediate early control of M.tuberculosis proliferation in the lung [CITE-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
Tuberculosis, caused by M.tuberculosis (Mtb), remains an enduring global health challenge, especially given the limited efficacy of current therapeutic interventions. Much of existing research has focused on immune failure as a driver of tuberculosis. However, the crucial role of host macrophage biology in controlling the disease remains underexplored. While we have gained deeper insights into how alveolar macrophages (AMs) interact with Mtb, the precise AM subsets that mediate protection and potentially prevent tuberculosis progression have yet to be identified. In this study, by integrating the use of weighted gene correlation network analysis (WGCNA) modules with our multi-modal scRNA-seq protocol, we were able to evaluate the functional roles of diverse macrophage subpopulations across different infection timepoints, allowing us to delineate the dynamic landscape of controller and permissive AM populations throughout the infection timeline.
Our analyses during specific post-Mtb challenge intervals revealed macrophage populations transitioning between distinct anti- and pro-inflammatory states. Notably, CD38- AMs showed a muted response to early Mtb infection. As infection progressed, we observed a phenotypic shift in AMs, with CD38+ monocyte-derived AMs (moAMs) and a subset of tissue-resident AMs (TR-AMs) emerging as significant controllers of bacterial growth. Interestingly, scATAC-seq analysis of naïve lungs demonstrated that CD38+ TR-AMs possessed a distinct chromatin signature prior to infection, indicative of epigenetic priming, and predisposed them to a pro-inflammatory response. BCG intranasal immunization increased the numbers of CD38+ macrophages, substantially enhancing their capability to restrict Mtb growth.
Collectively, our findings emphasize the pivotal, dynamic roles of different macrophage subsets in TB infection and reveal rational pathways for the development of improved vaccines and immunotherapeutic strategies, with implications for the broader field of infectious diseases.
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| Overall design |
Mice were intranasally inoculated with 1500 CFUs of the Erdman strains (smyc′::mCherry, hspx′::GFP/smyc′::mCherry, or hsp60′::GFP). At 2, 4, and 6 weeks post-infection (w.p.i.), mice were euthanized. Cells from infected mice were then sorted. Sorted cells were resuspended in cell staining buffer and an ADT plus HTO antibody cocktail mix. The samples were then fixed in methanol overnight, rehydrated and then processed for scRNA-seq.
Infected samples: M.tuberculosis-infected cells from the lungs of BL/6 mice.
Bystander samples: Uninfected cells from the lungs of M.tuberculosis-infected BL/6 mice.
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| Contributor(s) |
Pisu D, Mattila JT, Russell DG |
| Citation(s) |
39070650, 39358361 |
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| Submission date |
Oct 20, 2023 |
| Last update date |
Oct 15, 2024 |
| Contact name |
Davide Pisu |
| E-mail(s) |
[email protected]
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| Phone |
6072620103
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| Organization name |
Cornell University
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| Department |
Microbiology and Immunology
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| Lab |
David G. Russell
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| Street address |
930 Campus Road
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| City |
Ithaca |
| State/province |
NY |
| ZIP/Postal code |
14853 |
| Country |
USA |
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| Platforms (2) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
| GPL30172 |
NextSeq 2000 (Mus musculus) |
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| Samples (17)
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| GSM7851843 |
4 Weeks Infected, mRNA |
| GSM7851844 |
6 Weeks Bystander, mRNA |
| GSM7851845 |
6 Weeks Infected, mRNA |
| GSM7851846 |
2 Weeks BCG-vaccinated, mRNA |
| GSM7851847 |
2 Weeks Bystander, ADT |
| GSM7851848 |
2 Weeks Infected, ADT |
| GSM7851849 |
2 Weeks Infected, HTO |
| GSM7851850 |
4 Weeks Bystander, ADT |
| GSM7851851 |
4 Weeks Infected, ADT |
| GSM7851852 |
4 Weeks Infected, HTO |
| GSM7851853 |
6 Weeks Bystander, ADT |
| GSM7851854 |
6 Weeks Infected, ADT |
| GSM7851855 |
6 Weeks Infected, HTO |
| GSM7851856 |
2 Weeks BCG-vaccinated, HTO |
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| Relations |
| BioProject |
PRJNA1030427 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE245950_ADT_HTO_details_README.txt |
1.3 Kb |
(ftp)(http) |
TXT |
| GSE245950_RAW.tar |
183.4 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
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