Role of cathepsins in mycobacterium tuberculosis survival in human macrophages

David Pires, Joana Marques, João Palma Pombo, Nuno Carmo, Paulo Bettencourt, Olivier Neyrolles, Geanncarlo Lugo-Villarino, Elsa Anes*

*Autor correspondente para este trabalho

Resultado de pesquisarevisão de pares

58 Citações (Scopus)

Resumo

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-Iκ B 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 IFNÎ 3-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.
Idioma originalEnglish
Número do artigo32247
Número de páginas13
RevistaScientific Reports
Volume6
DOIs
Estado da publicaçãoPublicado - 30 ago. 2016
Publicado externamenteSim

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