Functional attribution of LdISP, an endogenous serine protease inhibitor from Leishmania donovani in promoting infection

Alam, Nur; Chakraborti, Sajal; Paik, Dibyendu; Bagchi, Angshuman; Chakraborti, Tapati

doi:10.1016/j.biochi.2018.01.005

Cited by 4 publications

(4 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mass spectrometry analysis of the purified protein matched ISP2 from L. infantum. Immunostaining revealed LdISP close to the flagellar pocket of L. donovani strain AG83 promastigotes, which is compatible with putative secretion of ISP for the inhibition of the NE at the surface of macrophages (25). In another study, recombinant LdISP2 was reported to inhibit the complement-related serine peptidase mannan-binding lectin serine protease (MASP)-2, whereas it did not inhibit MASP-1 or the C1 complex (26).…”

Section: Discussionmentioning

confidence: 81%

“…Recombinant ISP2 also inhibited serine peptidases of the sand fly midgut in vitro, and transgenic lines knocked down to ISP2 were more susceptible to sand fly peptidases and less fit to survive in the midgut (23). Other studies applying treatment of infected RAW cells with recombinant LdISP2 showed slight reduction of infection and of NO production (25). Recombinant LdISP2 was recently shown to inhibit the complement-related serine peptidases and C3c and C5c generation (26).…”

mentioning

confidence: 98%

“…Those observations helped to define ISP2 as a virulence factor required for successful infection by L. major (21, 22), but the potential contribution of ISP2 in modulating NE activity and infection in VL has not been investigated. mRNA to ISP2 was detected in L. donovani (23), and studies in vitro using recombinant ISP2 from this species [ L. donovani inhibitor of serine peptidase 2 (LdISP2)] showed that it can inhibit trypsin and NE (24, 25). Recombinant ISP2 also inhibited serine peptidases of the sand fly midgut in vitro , and transgenic lines knocked down to ISP2 were more susceptible to sand fly peptidases and less fit to survive in the midgut (23).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Neutrophil elastase promotes Leishmania donovani infection via interferon‐β

et al. 2019

View full text Add to dashboard Cite

Visceral leishmaniasis is a deadly illness caused by Leishmania donovani that provokes liver and spleen inflammation and tissue destruction. In cutaneous leishmaniasis, the protein of L. major, named inhibitor of serine peptidases (ISP) 2, inactivates neutrophil elastase (NE) present at the macrophage surface, resulting in blockade of TLR4 activation, prevention of TNF‐α* and IFN‐β production, and parasite survival. We report poor intracellular growth of L. donovani in macrophages from knockout mice for NE (ela−/−), TLR4, or TLR2. NE and TLR4 colocalized with the parasite in the parasitophorous vacuole. Parasite load in the liver and spleen of ela−/− mice were reduced and accompanied by increased NO and decreased TGF‐β production. Expression of ISP2 was not detected in L. donovani, and a transgenic line constitutively expressing ISP2, displayed poor intracellular growth in macrophages and decreased burden in mice. Infected ela−/− macrophages displayed significantly lower IFN‐β mRNA than background mice macrophages, and the intracellular growth was fully restored by exogenous IFN‐β. We propose that L. donovani utilizes the host NE‐TLR machinery to induce IFN‐β necessary for parasite survival and growth during early infection. Low or absent expression of parasite ISP2 in L. donovani is necessary to preserve the activation of the NE‐TLR pathway.—Dias, B. T., Dias‐Teixeira, K. L., Godinho, J. P., Faria, M. S., Calegari‐Silva, T., Mukhtar, M. M., Lopes, U. G., Mottram, J. C., Lima, A. P. C. A. Neutrophil elastase promotes Leishmania donovani infection via interferon‐β. FASEB J. 33,10794–10807 (2019). http://www.fasebj.org

show abstract

Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 98%

mentioning

confidence: 99%

See 1 more Smart Citation

Neutrophil elastase promotes Leishmania donovani infection via interferon‐β

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Reflecting their greater abundance, most work has focused on the roles played by cysteine and metalloproteases (Silva-Almeida et al, 2012;Siqueira-Neto et al, 2018). Although less abundant, serine proteases (SPs) are also key to life cycle progression (Alves et al, 2018), host infection (Alam et al, 2018), and survival (Machado et al, 2019). As SPs possess a canonical well-conserved active site that can be explored with small molecules, they, therefore, represent potential drug targets (Alam et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Discovery of Leishmania Druggable Serine Proteases by Activity-Based Protein Profiling

et al. 2022

View full text Add to dashboard Cite

Leishmaniasis are a group of diseases caused by parasitic protozoa of the genus Leishmania. Current treatments are limited by difficult administration, high cost, poor efficacy, toxicity, and growing resistance. New agents, with new mechanisms of action, are urgently needed to treat the disease. Although extensively studied in other organisms, serine proteases (SPs) have not been widely explored as antileishmanial drug targets. Herein, we report for the first time an activity-based protein profiling (ABPP) strategy to investigate new therapeutic targets within the SPs of the Leishmania parasites. Active-site directed fluorophosphonate probes (rhodamine and biotin-conjugated) were used for the detection and identification of active Leishmania serine hydrolases (SHs). Significant differences were observed in the SHs expression levels throughout the Leishmania life cycle and between different Leishmania species. Using iTRAQ-labelling-based quantitative proteomic mass spectrometry, we identified two targetable SPs in Leishmania mexicana: carboxypeptidase LmxM.18.0450 and prolyl oligopeptidase LmxM.36.6750. Druggability was ascertained by selective inhibition using the commercial serine protease inhibitors chymostatin, lactacystin and ZPP, which represent templates for future anti-leishmanial drug discovery programs. Collectively, the use of ABPP method complements existing genetic methods for target identification and validation in Leishmania.

show abstract