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Role of Cathepsins in Mycobacterium tuberculosis Survival in Human Macrophages
David Pires1,2, Joana Marques1, João Palma Pombo1
1Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Portugal.
Abstract:
Cathepsins are proteolytic enzymes that function in the endocytic pathway, especially in lysosomes, where they contribute directly to pathogen killing or indirectly, by their involvement in the antigen presentation pathways. Mycobacterium tuberculosis (MTB) is a facultative intracellular pathogen that survives inside the macrophage phagosomes by inhibiting their maturation to phagolysosomes and thus avoiding a low pH and protease-rich environment. We previously showed that mycobacterial inhibition of the proinflammatory transcription factor NF-κB results in impaired delivery of lysosomal enzymes to phagosomes and reduced pathogen killing. Here, we elucidate how MTB also controls cathepsins and their inhibitors, cystatins, at the level of gene expression and proteolytic activity. MTB induced a general down-regulation of cathepsin expression in infected cells, and inhibited IFNγ-mediated increase of cathepsin mRNA. We further show that a decrease in cathepsins B, S and L favours bacterial survival within human primary macrophages. A siRNA knockdown screen of a large set of cathepsins revealed that almost half of these enzymes have a role in pathogen killing, while only cathepsin F coincided with MTB resilience. Overall, we show that cathepsins are important for the control of MTB infection, and as a response, it manipulates their expression and activity to favour its intracellular survival.
Insights
Mycobacterium tuberculosis (MTB) manipulates cathepsin expression and activity to survive within macrophages. Reducing cathepsin levels aids bacterial survival, highlighting their importance in controlling MTB infection.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Cathepsins are lysosomal proteases crucial for pathogen killing and antigen presentation.
- Mycobacterium tuberculosis (MTB) evades macrophage defenses by blocking phagolysosome maturation.
- MTB's inhibition of NF-κB impairs lysosomal enzyme delivery and pathogen killing.
Purpose of the Study:
- To investigate how MTB controls cathepsin expression and activity.
- To determine the role of specific cathepsins in controlling MTB infection.
- To understand MTB's survival mechanisms involving cathepsin manipulation.
Main Methods:
- Analyzing cathepsin gene expression in MTB-infected macrophages.
- Measuring cathepsin proteolytic activity.
- Utilizing siRNA knockdown to assess cathepsin function in pathogen killing.
- Evaluating the impact of decreased cathepsins B, S, and L on bacterial survival.
Main Results:
- MTB down-regulates cathepsin expression and inhibits IFNγ-induced cathepsin mRNA.
- Reduced levels of cathepsins B, S, and L enhance MTB survival in macrophages.
- Nearly half of screened cathepsins are involved in pathogen killing; only cathepsin F aids MTB resilience.
- MTB actively manipulates cathepsin expression and activity for intracellular survival.
Conclusions:
- Cathepsins play a significant role in controlling MTB infection.
- MTB employs strategies to suppress cathepsin function, promoting its survival.
- Targeting cathepsin pathways could offer new therapeutic strategies against MTB.
