Cathepsin L maturation and activity is impaired in macrophages harboring M. avium and M. tuberculosis

Nepal, Rajeev M.; Mampe, Stephanie; Shaffer, Brian C.; Erickson, Ann H.; Bryant, Paula Wolf

doi:10.1093/intimm/dxl029

Cited by 23 publications

(16 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…No significant protein reduction was detected for CtsL in our experiments. Yet, a reduction in cathepsin L protein levels was described by Nepal and colleagues52 in response to infection of IFNγ-stimulated mouse bone marrow macrophages with live or heat-killed MTB. Therefore, enhanced differences may be attributed to the type of host cells used.…”

Section: Discussionmentioning

confidence: 92%

Role of Cathepsins in Mycobacterium tuberculosis Survival in Human Macrophages

Pires

Marques

Pombo

et al. 2016

Sci Rep

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 92%

Role of Cathepsins in Mycobacterium tuberculosis Survival in Human Macrophages

Pires

Marques

Pombo

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…7). Cathepsin L-like proteins have been described in other invertebrate hemocytes (60,61) and are modulated by colonization in both pathogenic (62,63) and beneficial associations (Ref. 64 and this study).…”

Section: Discussionmentioning

confidence: 58%

Colonization State Influences the Hemocyte Proteome in a Beneficial Squid–Vibrio Symbiosis

Schleicher

VerBerkmoes

Shah

et al. 2014

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

The squid Euprymna scolopes and the luminescent bacterium Vibrio fischeri form a highly specific beneficial light organ symbiosis. Not only does the host have to select V. fischeri from the environment, but it must also prevent subsequent colonization by non-symbiotic microorganisms. Host macrophage-like hemocytes are believed to play a role in mediating the symbiosis with V. fischeri. Previous studies have shown that the colonization state of the light organ influences the host's hemocyte response to the symbiont. To further understand the molecular mechanisms behind this process, we used two quantitative mass-spectrometry-based proteomic techniques, isobaric tags for relative and absolute quantification (iTRAQ) and label-free spectral counting, to compare and quantify the adult hemocyte proteomes from colonized (sym) and uncolonized (antibiotic-treated/cured) squid. Overall, iTRAQ allowed for the quantification of 1,024 proteins with two or more peptides. Thirty-seven unique proteins were determined to be significantly different between sym and cured hemocytes (p value < 0.05), with 20 more abundant proteins and 17 less abundant in sym hemocytes. The label-free approach resulted in 1,241 proteins that were identified in all replicates. Of 185 unique proteins present at significantly different amounts in sym hemocytes (as determined by spectral counting), 92 were more abundant and 93 were less abundant. Comparisons between iTRAQ and spectral counting revealed that 30 of the 37 proteins quantified via iTRAQ exhibited trends similar to those identified by the label-free method. Both proteomic techniques mutually identified 16 proteins that were significantly different between the two groups of hemocytes (p value < 0.05). The presence of V. fischeri in the host light organ influenced the abundance of proteins associated with the cytoskeleton, adhesion, lysosomes, proteolysis, and the innate immune response. These data provide evidence that colonization by V. fischeri alters the hemocyte proteome and reveals proteins that may be important for maintaining host-symbiont specificity. Molecular & Cellular Proteomics

show abstract

“…Similarly, cathepsin B accumulates in delayed-type hypersensitivity reactions induced by M. tuberculosis (26). Cathepsin L maturation and activity is impaired in macrophages harboring M. tuberculosis, indicating that M. tuberculosis modulates the cathepsin response to its advantage (27). A cathepsin Z haplotype was implicated as a genetic marker for tuberculosis susceptibility in a Ugandan household contact study (28); however, in a casecontrol study in Iran, the cathepsin Z rs34069356 polymorphism (29) was not associated with pulmonary tuberculosis.…”

Section: Discussionmentioning

confidence: 96%

Cathepsin G in Experimental Tuberculosis: Relevance for Antibacterial Protection and Potential for Immunotherapy

Walter

Steinwede

Aly

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Neutrophil serine proteases, such as cathepsin G (CG) and neutrophil elastase (NE), have been implicated in the protective response against infections, including experimental mycobacterial infections. The goal of this study was to explore the role of CG in immunocompetent mice challenged aerogenically with Mycobacterium tuberculosis. We used genetically CG- or CG/NE-deficient mice to define the importance of these neutrophil serine proteases for antibacterial protection, granulomatous response, and survival. In addition, we explored the effect of intratracheally delivered liposomally encapsulated CG/NE as a therapeutic approach early during M. tuberculosis infection. Our data show that the presence of CG or CG/NE prolongs survival in M. tuberculosis–infected mice. However, CG is not directly involved in antibacterial defenses, and exogenous intratracheal administration of CG combined with NE does not reduce bacterial loads in the lungs of M. tuberculosis–infected mice.

show abstract

Cathepsin L maturation and activity is impaired in macrophages harboring M. avium and M. tuberculosis

Cited by 23 publications

References 71 publications

Role of Cathepsins in Mycobacterium tuberculosis Survival in Human Macrophages

Role of Cathepsins in Mycobacterium tuberculosis Survival in Human Macrophages

Colonization State Influences the Hemocyte Proteome in a Beneficial Squid–Vibrio Symbiosis

Cathepsin G in Experimental Tuberculosis: Relevance for Antibacterial Protection and Potential for Immunotherapy

Contact Info

Product

Resources

About