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| Status |
Public on Sep 03, 2019 |
| Title |
Host resistance to pulmonary infection with Mycobacterium tuberculosis is mediated by IL-1alpha. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Background: M.tuberculosis is one of the most prevalent and deadly human pathogens. The molecular mechanisms determining the outcomes of an infection with M.tuberculosis, that range from resistance to an active progressive disease, remain incompletely understood. Here we provide the evidence that IL-1alpha plays a critical and non-redundant role in enabling host resistance to pulmonary M.tuberculosis infection in mice that develop functional pathogen-specific adaptive immunity. Mechanistically, IL-1alpha-deficient mice fail to control M.tuberculosis replication in vivo at a level of individual infected cells and succumb to progressive disease at the late phase of infection. Furthermore, we show that IL-1alpha from hematopoietic compartment through IL-1RI operates upstream of TNFRI-signaling pathway and the lack of IL-1alpha leads to the continuous influx of monocytes that acquire a hyper-inflammatory phenotype and contribute to pathology, rather than to a pathogen control. Cell-type-specific restoration of IL-1alpha expression in CD11c+ subsets of lung leukocytes resulted in reduced levels of inflammatory marker expression on lung cells and improved survival IL-1alpha-deficient mice after M.tuberculosis infection. In humans, genetic analysis of single nucleotide polymorphisms in 14 genes implicated in IL-1-IL-1R signaling pathway revealed association of genetic variations in IL-1alpha and IL-1RAP genes with human susceptibility to pulmonary tuberculosis. Our results implicate IL-1alpha as a principal factor of host resistance to M.tuberculosis and IL-1alpha-driven cell-cell crosstalk as a key step in triggering M.tuberculosis control mechanisms that are critical for host survival.
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| Overall design |
Two pools of CD11c+ cells from three mice each were prepared for WT and Il1a-/- experimental groups.
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| Contributor(s) |
Beyer RP, DiPaolo NC, Shafiani S, Day T, Papayannoupoulou T, Iwakura Y, Flavell RA, Bamler TK, Russell DW, Dunstan SJ, Hawn TR, Burt A, Browning B, Jarvik GP, Sherman D, Urdah K, Shayakhmetov DM |
| Citation missing |
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| Submission date |
Oct 04, 2011 |
| Last update date |
Sep 03, 2019 |
| Contact name |
James William MacDonald |
| E-mail(s) |
[email protected]
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| Organization name |
University of Washington
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| Department |
Environmental and Occupational Health Sciences
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| Street address |
4225 Roosevelt Way NE
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| City |
Seattle |
| State/province |
WA |
| ZIP/Postal code |
98105-6099 |
| Country |
USA |
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| Platforms (1) |
| GPL6246 |
[MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [transcript (gene) version] |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA147155 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE32619_RAW.tar |
17.1 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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