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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
Reduced expression of CD45 protein-tyrosine phosphatase provides protection against anthrax pathogenesis
Rekha G Panchal1, Ricky L Ulrich, Steven B Bradfute
1United States Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702-5011, USA. rekha.panchal@amedd.army.mil
Abstract:
The modulation of cellular processes by small molecule inhibitors, gene inactivation, or targeted knockdown strategies combined with phenotypic screens are powerful approaches to delineate complex cellular pathways and to identify key players involved in disease pathogenesis. Using chemical genetic screening, we tested a library of known phosphatase inhibitors and identified several compounds that protected Bacillus anthracis infected macrophages from cell death. The most potent compound was assayed against a panel of sixteen different phosphatases of which CD45 was found to be most sensitive to inhibition. Testing of a known CD45 inhibitor and antisense phosphorodiamidate morpholino oligomers targeting CD45 also protected B. anthracis-infected macrophages from cell death. However, reduced CD45 expression did not protect anthrax lethal toxin (LT) treated macrophages, suggesting that the pathogen and independently added LT may signal through distinct pathways. Subsequent, in vivo studies with both gene-targeted knockdown of CD45 and genetically engineered mice expressing reduced levels of CD45 resulted in protection of mice after infection with the virulent Ames B. anthracis. Intermediate levels of CD45 expression were critical for the protection, as mice expressing normal levels of CD45 or disrupted CD45 phosphatase activity or no CD45 all succumbed to this pathogen. Mechanism-based studies suggest that the protection provided by reduced CD45 levels results from regulated immune cell homeostasis that may diminish the impact of apoptosis during the infection. To date, this is the first report demonstrating that reduced levels of host phosphatase CD45 modulate anthrax pathogenesis.
Insights
Targeting the host phosphatase CD45 with inhibitors or reduced expression protected mice against Bacillus anthracis infection. Intermediate CD45 levels were crucial for this immune defense, highlighting a novel therapeutic strategy.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Cellular processes are modulated by small molecule inhibitors and gene manipulation to understand disease pathways.
- Chemical genetic screening is a powerful tool for identifying key players in pathogenesis.
Purpose of the Study:
- To identify host factors that modulate Bacillus anthracis infection using chemical genetic screening.
- To investigate the role of host phosphatase CD45 in anthrax pathogenesis.
Main Methods:
- Chemical genetic screening of phosphatase inhibitors against B. anthracis-infected macrophages.
- Assaying compound sensitivity against a panel of phosphatases, focusing on CD45.
- Utilizing CD45 inhibitors and antisense phosphorodiamidate morpholino oligomers (PMOs).
- Conducting in vivo studies with gene-targeted knockdown and genetically engineered mice.
- Mechanism-based studies to elucidate protective effects.
Main Results:
- Several phosphatase inhibitors protected B. anthracis-infected macrophages; CD45 was the most sensitive target.
- CD45 inhibition and reduced expression protected macrophages and mice from virulent B. anthracis infection.
- Protection required intermediate CD45 levels; normal, absent, or inhibited phosphatase activity led to susceptibility.
- Reduced CD45 expression did not protect against anthrax lethal toxin (LT), suggesting distinct signaling pathways.
- Protection is linked to regulated immune cell homeostasis and reduced apoptosis during infection.
Conclusions:
- Reduced host phosphatase CD45 levels modulate anthrax pathogenesis, offering a novel therapeutic target.
- Host-directed therapies targeting CD45 may be effective against B. anthracis infections.
- Distinct signaling pathways are involved in pathogen-induced cell death versus lethal toxin-induced effects.
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