Abstract
Leishmaniasis is one of the most assorted and intricate of all vector borne diseases caused by the genus Leishmania. Survival of Leishmania parasites inside the mammalian host needs a set of virulence factors, among them, Leishmania proteases have paramount importance. Several of these proteases have been identified as potential virulence factors for their crucial roles in the invasion of the host via parasite migration through tissue barriers, degradation of host proteins for nutrition purpose, immune evasion and activation of inflammation. Hence, the investigation on proteases in Leishmania is proposed as a valuable approach to enhance our knowledge on host-parasite interaction. Through various studies, a number of metalloproteases and cysteine proteases have been implicated as major components in host invasion by modulating host cell signaling for the establishment and continuation of infection by Leishmania. But, the roles of serine proteases in leishmaniasis have not been investigated adequately. In this review, we will discuss the significance of Leishmania proteases in parasite lifecycle and their possible accountability as a new drug target with special emphasis on Leishmania serine proteases.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Alvar J, Velez ID, Bern C et al (2012) Leishmaniasis worldwide and global estimates of its incidence. PLoS One 7:e35671–e356712
Okwor I, Uzonna JE (2013) The immunology of Leishmania/HIV co-infection. Immunol Res 56:163–171. doi:10.1007/s12026-013-8389-8
Bogdan C, Rollinghoff M (1999) How do protozoan parasites survive inside macrophages? Parasitol Today 15:22–28
Denkers EY, Butcher BA (2005) Sabotage and exploitation in macrophages parasitized by intracellular protozoans. Trends Parasitol 21:35–41
Stager S, Joshi T, Bankoti R (2010) Immune evasive mechanisms contributing to persistent Leishmania donovani infection. Immunol Res 47:14–24
Sacks D, Sher A (2002) Evasion of innate immunity by parasitic protozoa. Nat Immunol 3:1041–1047
Cunningham AC (2002) Parasitic adaptive mechanisms in infection by Leishmania. Exp Mol Pathol 72:132–141
Kaye P, Scott P (2011) Leishmaniasis: complexity at the host-pathogen interface. Nat Rev Microbiol 9:604–615
Favali C, Tavares N, Clarencio J et al (2007) Leishmania amazonensis infection impairs differentiation and function of human dendritic cells. J Leukoc Biol 82:1401–1406
Sharma U, Singh S (2012) Immunobiology of leishmaniasis. Indian J Exp Biol 47:412–423
Proudfoot L, Nikolaev AV, Feng GJ et al (1996) Regulation of the expression of nitric oxide synthase and leishmanicidal activity by glycoconjugates of Leishmania lipophosphoglycan in murine macrophages. Proc Natl Acad Sci 93:10984–10989
Moradin N, Descoteaux A (2012) Leishmania promastigotes: building a safe niche within macrophages. Front Cell Infect Microbiol 2:1–7
Goto H, Prianti MG (2009) Immunoactivation and immunopathogeny during active visceral leishmaniasis. Rev Inst Med Trop Sao Paulo 51:241–246
Olivier M, Gregory DJ, Forget G (2005) Subversion mechanisms by which Leishmania parasites escape the host immune response: a signaling point of view. Clin Microbiol Rev 18:293–305
Shio MT, Hassani K, Isnard A et al (2012) Host cell signalling and Leishmania mechanisms of evasion. J Trop Med 2012:1–14
Shadab M, Ali N (2011) Evasion of host defence by Leishmania donovani: subversion of signaling pathways. Mol Biol Int 2011:1–14
Bhardwaj S, Srivastava N, Sudan R et al (2010) Leishmania interferes with host cell signaling to devise a survival strategy. J Biomed Biotechnol 2010:1–13
Shio MT, Olivier M (2010) Leishmania survival mechanisms: the role of host phosphatases. J Leuko Biol 88:1–3
Blanchette J, Racette N, Faure R, Siminovitch KA, Olivier M (1999) Leishmania-induced increases in activation of macrophage SHP-1 tyrosine phosphatase are associated with impaired IFN-gamma-triggered JAK2 activation. Eur J Immunol 29:3737–3744
Ghosh S, Bhattacharyya S, Sirkar M et al (2002) Leishmania donovani suppresses activated protein 1 and NF-κB activation in host macrophages via ceramide generation: involvement of extracellular signal-regulated kinase. Infect Immun 70:6828–6838
Matlashewski G (2001) Leishmania infection and virulence. Med Microbiol Immunol 190:37–42
Olivier M, Atayde VD, Isnard A et al (2012) Leishmania virulence factors: focus on the metalloprotease GP63. Microbes Infect 14:1–13
Franco LH, Beverley SM, Dario S et al (2011) Innate immune activation and subversion of mammalian functions by Leishmania lipophosphoglycan. J Parasitol Res 2012:1–11
Lacerda DI, Cysne-Finkelstein L, Nunes MP et al (2012) Kinetoplastid membrane protein-11 exacerbates infection with Leishmania amazonensis in murine macrophages. Mem Inst Oswaldo Cruz 107:238–245
Vermelho AB, Branquinha MH, D’Ávila-Levy CM et al (2010) Biological roles of peptidases in Trypanosomatids. Open Parasitol J 4:5–23
Zucca M, Savoia D (2011) Current developments in the therapy of protozoan infections. Open Med Chem J 5:4–10
Singh N, Kumar M, Singh RK (2012) Leishmaniasis: current status of available drugs and new potential drug targets. Asin Pac J Trop Med 5:485–497
Armstrong PB (2006) Proteases and protease inhibitors: a balance of activities in host–pathogen interaction. Immunobiology 211:263–281
Rosenthal PJ (1999) Proteases of protozoan parasites. Adv Parasitol 43:106–159
Carruthers VB, Blackman MJ (2005) A new release on life: emerging concepts in proteolysis and parasite invasion. Mol Microbiol 55:1617–1630
Klemba M, Goldberg DE (2002) Biological roles of protease in parasitic protozoa. Annu Rev Biochem 71:275–305
McKerrow JH, Caffrey C, Kelly B et al (2006) Proteases in parasitic diseases. Annu Rev Pathol 1:497–536
Piña-Vázquez C, Reyes-López M, Ortíz-Estrada G et al (2012) Host-parasite interaction: parasite-derived and -induced proteases that degrade human extracellular matrix. J Parasitol Res 2012:1–24
Besteiro S, Williams RAM, Coombs GH et al (2007) Protein turnover and differentiation in Leishmania. Int J Parasitol 37:1063–1075
Sajid M, McKerrow JH (2002) Cysteine proteases of parasitic organisms. Mol Biochem Parasitol 120:1–21
Mottram JC, Coombs GH, Alexander J (2004) Cysteine peptidases as virulence factors of Leishmania. Curr Opin Microbiol 7:375–381
Yao C (2010) Major surface protease of trypanosomatids: one size fits all? Infect Immun 78:22–31
Isnard A, Hassani K, Shio MT (2012) Impact of Leishmania metalloproteases GP63 on macrophage signaling. Front Cell Infect Microbiol 2:1–9
Chang KP, McGwire BS (2002) Molecular determinants and regulation of Leishmania virulence. Kinetoplastid Biol Dis 1:1–7
Olivier M, Hassani K (2010) Protease inhibitors as prophylaxis against leishmaniasis: new hope from the major surface protease gp63. Future Med Chem 2:539–542
Burleigh BA, Andrews NW (1995) A 120 kDa alkaline peptidase from T. cruzi is involved in the generation of a novel Ca2+-signalling factor for mammalian cells. J Biol Chem 270:5172–5180
Burleigh BA, Caler EV, Webster P et al (1997) A cytosolic serine endopeptidase from Trypanosoma cruzi is required for the generation of Ca2+ signaling in mammalian cells. J Cell Biol 136:609–620
Alvarez VE, Niemirowicz GT, Cazzulo JJ (2012) The peptidases of Trypanosoma cruzi: digestive enzymes, virulence factors, and mediators of autophagy and programmed cell death. Biochim Biophys Acta 1824:195–206
Cai H, Kuang R, Gu J, Wang Y (2011) Proteases in malaria parasites - a phylogenomic perspective. Curr Genomics 12:417–427
Schneider P, Rosat JP, Bouvier J, Louis J, Bordier C (1992) Leishmania major-differential regulation of the surface metalloprotease in amastigote and promastigote stages. Exp Parasitol 75:196–206
Voth BR, Kelly BL, Joshi PB et al (1998) Differentially expressed Leishmania major gp63 genes encode cell surface leishmanolysin with distinct signals for glycosylphosphatidylinositol attachment. Mol Biochem Parasitol 93:31–41
McMaster WR, Morrison CJ, MacDonald MH, Joshi PB (1994) Mutational and functional analysis of the Leishmania surface metalloproteinase GP63: similarities to matrix metalloproteinases. Parasitology 108(Suppl):S29–S36
Bahr V, Stierhof YD, Ilg T et al (1993) Expression of lipophosphoglycan, high- molecular weight phosphoglycan and glycoprotein 63 in promastigotes and amastigotes of Leishmania mexicana. Mol Biochem Parasitol 58:107–121
Ilg T, Harbecke D, Wiese M et al (1993) Monoclonal antibodies directed against Leishmania secreted acid phosphatase and lipophosphoglycan. Partial characterization of private and public epitopes. Eur J Biochem 217:603–615
Roberts SC, Swihart KG, Agey MW et al (1993) Sequence diversity and organization of the msp gene family encoding gp63 of Leishmania chagasi. Mol Biochem Parasitol 62:157–171
Ramamoorthy R, Donelson JE, Paetz KE et al (1992) Three distinct RNAs for the surface protease gp63 are differentially expressed during development of Leishmania donovani chagasi promastigotes to an infectious form. J Biol Chem 267:1888–1895
Ma L, Meng Q, Cheng W et al (2011) Involvement of the GP63 protease in infection of Trichomonas vaginalis. Parasitol Res 109:71–79
Yao C, Donelson JE, Wilson ME et al (2003) The major surface protease (MSP or GP63) of Leishmania sp. Biosynthesis, regulation of expression, and function. Mol Biochem Parasitol 132:1–16
McGwire BS, Chang KP, Engman DM (2003) Migration through the by the parasitic protozoan Leishmania is enhanced by surface metalloprotease gp63. Infect Immun 71:1008–1010
Theander TG, Hviid L et al (1994) The major surface glycoprotein [gp63] from Leishmania major and Leishmania donovani cleaves CD4 molecules on human T cells. J Immunol 152:4542–4548
Garcia MR, Graham S, Harris RA et al (1997) Epitope cleavage by Leishmania endopeptidases [s] limits the efficiency of the exogenous pathway of major histocompatibility complex class I-associated antigen presentation. Eur J Immunol 27:1005–1013
Kulkarni MM, McMaster WR, Kamysz E et al (2006) The major surface-metalloprotease of the parasitic protozoan, Leishmania, protects against antimicrobial peptide-induced apoptotic killing. Mol Microbiol 62:1484–1497
Corradin S, Ransijn A, Corradin G et al (1999) MARCKS-related protein [MRP] is a substrate for the Leishmania major surface protease leishmanolysin [gp63]. J Biol Chem 274:25411–25418
Gomez MA, Contreras I, Hallé M et al (2009) Leishmania GP63 alters host signaling through cleavage-activated protein tyrosine phosphatases. Sci Signal 2:ra58
Contreras I, Gómez MA, Nguyen O (2010) Leishmania-induced inactivation of the macrophage transcription factor AP-1 is mediated by the parasite metalloprotease GP63. PLoS Pathog 6:e1001148
Gregory DJ, Godbout M, Contreras I et al (2008) A novel form of NF-kappa B is induced by Leishmania infection: involvement in macrophage gene expression. Eur J Immunol 38:1071–1081
Cameron P, McGachy A, Anderson M et al (2004) Inhibition of lipopolysaccharide induced macrophage IL-12 production by Leishmania mexicana amastigotes: the role of cysteine peptidases and the NF-kappaB signaling pathway. J Immunol 173:3297–3304
LiekeT NS, Eidsmo L et al (2008) Leishmania surface protein GP63 binds directly to human natural killer cells and inhibits proliferation. Clin Exp Immunol 153:221–230
Jaramillo M, Gomez MA, Larsson O et al (2011) Leishmania repression of host translation through mTOR cleavage is required for parasite survival small antimicrobial peptides with leishmanicidal activity. J Biol Chem 280:984–990
Choudhury R, Das P, De T et al (2010) Immunolocalization and characterization of two novel proteases in Leishmania donovani: putative roles in host invasion and parasite development. Biochimie 92:1274–1286
Ivens AC, Peacock CS, Worthey EA et al (2005) The genome of the kinetoplastid parasite, Leishmania major. Science 309:436–442
Caffrey CR, Steverding D (2009) Kinetiplastid papain-like cysteine peptidases. Mol Biochem Parasitol 167:12–19
Williams RA, Tetley L, Mottram JC et al (2006) Cysteine peptidases CPA and CPB are vital for autophagy and differentiation in Leishmania mexicana. Mol Microbiol 61:655–674
Mahmoudzadeh-Niknam H, McKerrow JH (2004) Leishmania tropica: cysteine proteases are essential for growth and pathogenicity. Exp Parasitol 106:158–163
Selzer PM, Pingel S, Hsieh I et al (1999) Cysteine protease inhibitors as chemotherapy: lessons from a parasite target. Proc Natl Acad Sci U S A 96:11015–11022
McKerrow JH, Rosenthal PJ, Swenerton R et al (2008) Development of protease. Inhibitors for protozoan infections. Curr Opin Infect Dis 21:668–672
Alexander J, Coombs GH, Mottram JC (1998) Leishmania Mexicana cysteine proteinase-deficient mutants have attenuated virulence for mice and potentiate a Th1 response. J Immunol 161:6794–6801
Buxbaum LU, Denise H, Coombs GH et al (2003) Cysteine protease B of Leishmania mexicana inhibits host Th1 responses and protective immunity. J Immunol 171:3711–3717
Denise H, McNeil K, Brooks DR et al (2003) Expression of multiple CPB genes encoding cysteine proteases is required for Leishmania mexicana virulence in vivo. Infect Immun 71:3190–3195
Somanna A, Mundodi V, Gedamu L (2002) Functional analysis of cathepsin B-like cysteine proteases from Leishmania donovani complex. Evidence for the activation of latent transforming growth factor beta. J Biol Chem 277:25305–25312
Mottram JC, Brooks DR, Coombs GH (1998) Roles of cysteine proteinases of trypanosomes and Leishmania in host-parasite interactions. Curr Opin Microbiol 1:455–460
Denise H, Poot J, Jiménez M et al (2006) Studies on the CPA cysteine peptidase in the Leishmania infantum genome strain JPCM5. BMC Mol Biol 13:42
Duboise SM, Vannier-Santos MA, Costa-Pinto D et al (1994) The biosynthesis, processing, and immunolocalization of Leishmania pifanoi amastigote cysteine proteinases. Mol Biochem Parasitol 68:119–132
Pollock KG, McNeil KS, Mottram JC et al (2003) The Leishmania mexicana cysteine protease, CPB2.8, induces potent Th2 responses. J Immunol 170:1746–1753
Mottram JC, Souza AE, Hutchison JE et al (1996) Evidence from disruption of the lmcpb gene array of Leishmania mexicana that cysteine proteinases are virulence factors. Proc Natl Acad Sci U S A 93:6008–6013
Alves CR, Pontes de Carvalho LC, Souza ALA et al (2001) A strategy for the differentiation of T-cell epitopes on Leishmania cysteine proteinases. Cytobios 104:33–41
Alves CR, Benévolo-De-Andrade TC, Alves JL et al (2004) Th1 and Th2 immunological profile induced by cysteine proteinase in murine leishmaniasis. Parasite Immunol 26: 127–135
Saffari B, Mohabatkar H (2009) Computational analysis of cysteine proteases (Clan CA, Family Cl) of Leishmania major to find potential epitopic regions. Genom Proteom Bioinformatic 7:87–95
Nagill R, Kaur S (2011) Vaccine candidates for leishmaniasis: a review. Int Immunopharmacol 11:1464–1488
Doroud D, Zahedifard F, Vatanara A et al (2011) Cysteine proteinase type I, encapsulated in solid lipid nanoparticles induces substantial protection against Leishmania major infection in C57BL/6 mice. Parasite Immunol 33:335–348
Fedeli CE, Ferreira JH, Mussalem JS et al (2010) Partial protective responses induced by a recombinant cysteine proteinase from Leishmania (Leishmania) amazonensis in a murine model of cutaneous leishmaniasis. Exp Parasitol 124:153–158
Khoshgoo N, Zahedifard F, Azizi H et al (2008) Cysteine proteinase type III is protective against Leishmania infantum infection in BALB/c mice and highly antigenic in visceral leishmaniasis individuals. Vaccine 26:5822–5829
Bryson K, Besteiro S, McGachy HA et al (2009) Overexpression of the natural inhibitor of cysteine peptidases in Leishmania mexicana leads to reduced virulence and a Th1 response. Infect Immun 77:2971–2978
Bates PA, Robertson CD, Coombs GH (1994) Expression of cysteine proteinases by metacyclic promastigotes of Leishmania mexicana. J Eukaryot Microbiol 41:199–203
Frame MJ, Mottram JC, Coombs GH (2000) Analysis of the roles of cysteine proteinases of Leishmania mexicana in the host-parasite interaction. Parasitology 121:367–377
Bart G, Frame MJ, Carter R et al (1997) Cathepsin B-like cysteine proteinase-deficient mutants of Leishmania mexicana. Mol Biochem Parasitol 88:53–61
Das L, Datta N, Bandyopadhyay S et al (2001) Successful therapy of lethal murine visceral leishmaniasis with cystatin involves up-regulation of nitric oxide and a favorable T cell response. J Immunol 166:4020–4028
Mukherjee S, Ukil A, Das PK (2007) Immunomodulatory peptide from cystatin, a natural cysteine protease inhibitor, against leishmaniasis as a model macrophage disease. Antimicrob Agents Chemother 51:1700–1707
Mundodi V, Kucknoor AS, Gedamu L (2005) Role of Leishmania [Leishmania] chagasi amastigote cysteine protease in intracellular parasite survival: studies by gene disruption and antisense mRNA inhibition. BMC Mol Biol 6:3
De Souza LS, Lang T, Prina E et al (1995) Intracellular Leishmania amazonensis amastigotes internalize and degrade MHC class II molecules of their host cells. J Cell Sci 108:3219–3231
Abu-Dayyeh I, Hassani K, Westra ER et al (2010) Comparative study of the ability of Leishmania mexicana promastigotes and amastigotes to alter macrophage signaling and functions. Infect Immun 78:2438–2445
Mottram JC, Souza AE, Hutchison JE et al (1996) Evidence from disruption of the lmCPB gene array of Leishmania mexicana that cysteine proteinases are virulence factors. Proc Natl Acad Sci 93:6008–6013
Di Cera E (2009) Serine proteases. IUBMB Life 61:510–515
Davies BJ, Pickard BS, Steel M et al (1998) Serine proteases in rodent hippocampus. J Biol Chem 273:23004–23011
Hedstrom L (2002) Serine protease mechanism and specificity. Chem Rev 102:4501–4524
Blow DM, Birktoft JJ, Hartley BS (1969) Role of a buried acid group in the mechanism of action of chymotrypsin. Nature 221:337–340
Almonte AG, Sweatt JD (2011) Serine proteases, serine protease inhibitors, and protease activated receptors: roles in synaptic function and behavior. Brain Res 1407:107–122
Leger AJ, Covic L, Kuliopulos A (2006) Protease-activated receptors in cardiovascular diseases. Circulation 114:1070–1077
Macfarlane SR, Seatter MJ, Kanke T et al (2001) Proteinase-activated receptors. Pharmacol Rev 53:245–282
Wang Y, Luo W, Reiser G (2008) Trypsin and trypsin-like proteases in the brain: proteolysis and cellular functions. Cell Mol Life Sci 65:237–252
Barrett AJ, Rawlings ND (1992) Oligopeptidases, and the emergence of prolyl oligopeptidase family. Biol Chem Hoppe Seyler 373:353–360
Caler EV, de Avalos SV, Haynes PA et al (1998) Oligopeptidase B-dependent signaling mediates host cell invasion by Trypanosoma cruzi. EMBO J 17:4975–4986
Bastos IM, Grellier P, Martins NF et al (2005) Molecular, functional and structural properties of the prolyl oligopeptidase of Trypanosoma cruzi (POP Tc80), which is required for parasite entry into mammalian cells. Biochem J 388:29–38
Bal G, Van der Veken P, Antonov D et al (2003) Prolylisoxazoles: potent inhibitors of prolyloligopeptidase with antitrypanosomal activity. Bioorg Med Chem Lett 13:2875–2878
Grellier P, Vendeville S, Joyeau R (2001) Trypanosoma cruzi prolyl oligopeptidase Tc80 is involved in nonphagocytic mammalian cell invasion by trypomastigotes. J Biol Chem 276:47078–47086
McLuskey K, Paterson NG, Bland ND et al (2010) Crystal structure of Leishmania major oligopeptidase B gives insight into the enzymatic properties of a trypanosomatid virulence factor. J Biol Chem 285:39249–39259
Li H, Child MA, Bogyo M (2012) Proteases as regulators of pathogenesis: examples from the Apicomplexa. Biochim Biophys Acta 1824:177–185
Toubarro D, Lucena-Robles M, Nascimento G et al (2009) An apoptosis-inducing serine protease secreted by the entomopathogenic nematode Steinernema carpocapsae. Int J Parasitol 39:1319–1330
Hasnain SZ, McGuckin MA, Grencis RK et al (2012) Serine protease(s) secreted by the nematode Trichuris muris degrade the mucus barrier. PLoS Negl Trop Dis 6:e1856
Toubarro D, Lucena-Robles M, Nascimento G et al (2010) Serine protease-mediated host invasion by the parasitic nematode Steinernema carpocapsae. J Biol Chem 285:30666–30675
Kim K (2004) Role of proteases in host cell invasion by Toxoplasma gondii and other Apicomplexa. Acta Trop 91:69–81
Montero E, Rafiqa S, Heckb S et al (2007) Inhibition of human erythrocyte invasion by Babesia divergens using serine protease inhibitors. Mol Biochem Parasitol 153:80–84
Xue Q, Waldrop GL, Schey KL et al (2006) A novel slow-tight binding serine protease inhibitor from eastern oyster (Crassostrea virginica) plasma inhibits perkinsin, the major extracellular protease of the oyster protozoan parasite Perkinsus marinus. Comp Biochem Physiol B Biochem Mol Biol 145:16–26
Andrade AS, Santoro MM, de Melo MN et al (1998) Leishmania (Leishmania) amazonensis: purification and enzymatic characterization of a soluble serine oligopeptidase from promastigotes. Exp Parasitol 89:153–160
Morty RE, Authie E, Troeberg L et al (1999) Purification and characterisation of a trypsin-like serine oligopeptidase from Trypanosoma congolense. Mol Biochem Parasitol 102:145–155
Swenerton RK, Zhang S, Sajid M et al (2011) The oligopeptidase B of Leishmania regulates parasite enolase and immune evasion. J Biol Chem 286:429–440
Guedes HL, Duarte Carneiro MP, de Oliveira Gomes DC et al (2007) Oligopeptidase B from Leishmania amazonensis: molecular cloning, gene expression analysis and molecular model. Parasitol Res 101:865–875
Silva-López RE, Morgado-Díaz JA, dos Santos PT et al (2008) Purification and subcellular localization of a secreted 75 kDa Trypanosoma cruzi serine oligopeptidase. Acta Trop 107:159–167
Alvarez VE, Niemirowicz GT, Cazzulo JJ (2011) The peptidases of Trypanosoma cruzi: digestive enzymes, virulence factors, and mediators of autophagy and programmed cell death. Biochim Biophys Acta 1824:195–206
Silva Lopez RE, De Simone SG (2004) A serine protease from a detergent-soluble extract of Leishmania (Leishmania) amazonensis. Z Naturforsch C 59:590–598
Silva-Lopez RE, Giovanni-De-Simone S (2004) Leishmania (Leishmania) amazonensis: purification and characterization of a promastigote serine protease. Exp Parasitol 107:173–182
Silva-Lopez RE, Coelho MG, De Simone SG (2005) Characterization of an extracellular serine protease of Leishmania (Leishmania) amazonensis. Parasitology 131:85–96
Guedes HL, Rezende JM, Fonseca MA et al (2007) Identification of serine proteases from Leishmania braziliensis. Z Naturforsch C 62:373–381
Silva-López RE, Santos TR, Morgado-Díaz JA et al (2010) Serine protease activities in Leishmania (Leishmania) chagasi promastigotes. Parasitol Res 107:1151–1162
Choudhury R, Bhaumik SK, De T et al (2009) Identification, purification and characterization of a secretory serine protease in an Indian strain of Leishmania donovani. Mol Cell Biochem 320:1–14
Alves CR, Corte-Real S, Bourguignon SC et al (2005) Leishmania amazonensis: early proteinase activities during promastigote-amastigote differentiation in vitro. Exp Parasitol 109:38–48
Morgado-Diaz JA, Silva-Lopez RE, Alves CR et al (2005) Subcellular localization of an intracellular serine protease of 68 kDa in Leishmania (Leishmania) amazonensis promastigotes. Mem Inst Oswaldo Cruz 100:377–383
Silva-Lopez RE, Morgado-Díaz JA, Alves CR et al (2004) Subcellular localization of an extracellular serine protease in Leishmania (Leishmania) amazonensis. Parasitol Res 93:328–331
Choudhury R, Das P, Bhaumik SK et al (2010) In situ immunolocalization and stage-dependent expression of a secretory serine protease in Leishmania donovani and its role as a vaccine candidate. Clin Vac Immunol 17:660–667
Bañuls AL, Hide M, Prugnolle F (2007) Leishmania and the Leishmaniases: a parasite genetic update and advances in taxonomy, epidemiology and pathogenicity in humans. Adv Parasitol 64:1–113
Swenerton RK, Knudsen GM, Sajid M et al (2010) Leishmania subtilisin is a maturase for the trypanothione reductase system and contributes to disease pathology. J Biol Chem 285:31120–31129
Munday JC, McLuskey K, Brown E et al (2011) Oligopeptidase B deficient mutants of Leishmania major. Mol Biochem Parasitol 175:49–57
Guedes HL, Pinheiro RO, Chaves SP et al (2010) Serine proteases of Leishmania amazonensis as immunomodulatory and disease-aggravating components of the crude LaAg. Vaccine 28:5491–5496
Silva VM, Larangeira DF, Oliveira PR et al (2011) Enhancement of experimental cutaneous leishmaniasis by Leishmania molecules is dependent on interleukin-4, serine protease/esterase activity, and parasite and host genetic backgrounds. Infect Immun 79:1236–1243
Choudhury R, Das P, De T et al (2013) 115 kDa serine protease confers sustained protection to visceral leishmaniasis caused by Leishmania donovani via IFN-γ induced down-regulation of TNF-α mediated MMP-9 activity. Immunobiology 218:114–126
Valdivieso E, Dagger F, Rascón A (2007) Leishmania mexicana: identification and characterization of an aspartyl proteinase activity. Exp Parasitol 116:77–82
Perteguer MJ, Gómez-Puertas P, Cañavate C et al (2013) Ddi1-like protein from Leishmania major is an active aspartyl proteinase. Cell Stress Chaperones 18:171–181
Savoia D, Allice T, Tovo PA (2005) Antileishmanial activity of HIV protease inhibitors. Int J Antimicrob Agents 26:92–94
Trudel N, Garg R, Messier N et al (2008) Intracellular survival of Leishmania species that cause visceral leishmaniasis is significantly reduced by HIV-1 protease inhibitors. J Infect Dis 198:1292–1299
Kumar P, Lodge R, Trudel N et al (2010) Nelfinavir, an HIV-1 protease inhibitor, induces oxidative stress-mediated, caspase-independent apoptosis in Leishmania amastigotes. PLoS Negl Trop Dis 4:e642
Valdivieso E, Rangel A, Moreno J et al (2010) Effects of HIV aspartyl-proteinase inhibitors on Leishmania sp. Exp Parasitol 126:557–563
Santos LO, Marinho FA, Altoé EF et al (2009) HIV aspartyl peptidase inhibitors interfere with cellular proliferation, ultrastructure and macrophage infection of Leishmania amazonensis. PLoS One 4:4918
Zhang T, Maekawa Y, Yasutomo K et al (2000) Pepstatin A-sensitive aspartic proteases in lysosome are involved in degradation of the invariant chain and antigen-processing in antigen presenting cells of mice infected with Leishmania major. Biochem Biophys Res Commun 276:693–701
Giudice P, Mary-Krause M, Pradier C et al (2002) Impact of highly active antiretroviral therapy on the incidence of visceral leishmaniasis in a French cohort of patients infected with human immunodeficiency virus. J Infect Dis 186:1366–1370
Rosa R, Pineda JA, Delgado J et al (2002) Incidence of and risk factors for symptomatic visceral leishmaniasis among human immunodeficiency virus type 1-infected patients from Spain in the era of highly active antiretroviral therapy. J Clin Microbiol 40:762–776
Chawla B, Madhubala R (2010) Drug targets in Leishmania. J Parasit Dis 34:1–13
Silva-López RE (2010) Leishmania proteases: new targets for rational drug development. Quim Nova 33:1541–1548
Armstrong PB (2006) Proteases and protease inhibitors: a balance of activities in host pathogen interaction. Immunobiology 21:263–281
Sabotič J, Kos J (2012) Microbial and fungal protease inhibitors—current and potential applications. Appl Microbiol Biotechnol 93:1351–1375
Cazzulo JJ (2002) Proteinases of Trypanosoma cruzi: potential targets for the chemotherapy of Chagas disease. Curr Top Med Chem 2:1261–1271
Fear G, Komarnytsky S, Raskin I (2007) Protease inhibitors and their peptidomimetic derivatives as potential drugs. Pharmacol Ther 113:354–368
Turk B (2006) Targeting proteases: successes, failures and future prospects. Nat Rev Drug Discov 5:785–799
Drag M, Salvesen GS (2010) Emerging principles in protease-based drug discovery. Nat Rev Drug Discov 9:690–701
Santos ALS (2011) Protease expressions by microorganisms and its relevance to crucial physiological/pathological events. World J Biol Chem 2:48–58
Safavi E, Rostami A (2012) Role of serine proteases in inflammation: Bowman–Birk protease inhibitor (BBI) as a potential therapy for autoimmune diseases. Exp Mol Pathol 93:428–433
Besterio S, Coombs GH, Mottram JC (2004) A potential role of ICP, a Leishmanial inhibitor of cysteine peptidases, in the interaction between host and parasite. Mol Microbial 54:1224–1236
Rosenthal PJ, Lee GK, Smith RE (1993) Inhibition of a Plasmodium vinckei cysteine proteinase cures murine malaria. J Clin Invest 91:1052–1056
Doyle PS, Zhou YM, Engel JC et al (2007) A cysteine protease inhibitor cures Chagas’ disease in an immunodeficient-mouse model of infection. Antimicrob Agents Chemother 51:3932–3939
Croft SL (2008) Kinetoplastida: new therapeutic strategies. Parasite 15:522–527
Robertson CD (1999) The Leishmania mexicana proteasome. Mol Biochem Parasitol 103:49–60
Steert K, Berg M, Mottram JC et al (2010) α-ketoheterocycles as inhibitors of Leishmania mexicana cysteine protease CPB. Chem Med Chem 5:1734–1748
Gontijo VS, Judice WAS, Codonho B et al (2012) Leishmanicidal, antiproteolytic and antioxidant evaluation of natural biflavonoids isolated from Garcinia brasiliensis and their semisynthetic derivatives. Euro J Med Chem 58:613–623
Gantt KR, Schultz-Cherry S, Rodriguez N et al (2003) Activation of TGF-β by Leishmania chagasi: importance for parasite survival in macrophages. J Immunol 170:2613–2620
Lima AK, Elias CG, Souza JE et al (2009) Dissimilar peptidase production by avirulent and virulent promastigotes of Leishmania braziliensis: inference on the parasite proliferation and interaction with macrophages. Parasitology 136:1179–1191
Bangs JD, Ransom DA, Nimick M et al (2001) In vitro cytocidal effects on Trypanosoma brucei and inhibition of Leishmania major GP63 by peptidomimetic metalloproteases inhibitors. Mol Biochem Parasitol 114:111–117
Das A, Ali N (2012) Vaccine development against Leishmania donovani. Front Immunol 3:99
White RE, Powell DJ, Berry C (2011) HIV proteinase inhibitors target the Ddi1-like protein of Leishmania parasites. FASEB J 25:1729–1736
Santos LO, Vitorio BS, Branquinha MH et al (2013) Nelfinavir is effective in inhibiting the multiplication and aspartic peptidase activity of Leishmania species, including strains obtained from HIV-positive patients. J Antimicrob Chemother 68:348–353. doi:10.1093/jac/dks410
Demarchi IG, Silveira TG, Ferreira IC, Lonardoni MV (2012) Effect of HIV protease inhibitors on new world Leishmania. Parasitol Int 61:538–544
Griensven J, Diro E, Lopez-Velez R et al (2013) HIV-1 protease inhibitors for treatment of visceral leishmaniasis in HIV-co-infected individuals. Lancet Infect Dis 13:251–259
Pimentel IAS, de Siqueira PC, Katz S et al (2012) In vitro and in vivo activity of an organic tellurium compound on Leishmania (Leishmania) chagasi. PLoS One 7:e48780. doi:10.1371/journal.pone.0048780
Siqueira Paladi C, Pimentel IAS, Katz S et al (2012) In vitro and in vivo activity of palladacycle complex on Leishmania (Leishmania) amazonensis. PLoS Negl Trop Dis 6:e1626. doi:10.1371/journal.pntd.0001626
Lima AP, Reis FC, Costa TF (2013) Cysteine peptidase inhibitors in trypanosomatid parasites. Curr Med Chem 20:3152–3173
Gemma S, Giovani S, Brindisi M, Tripaldi P (2012) Quinolylhydrazones as novel inhibitors of plasmodium falciparum serine protease PfSUB1. Bioorg Med Chem Lett 22:5317–5321
Witheres-Martinez C, Jean L, Blackman MJ (2004) Subtilisin like proteases of the malaria parasite. Mol Microbiol 53:55–63
Krowarsch D, Cierpicki T, Jelen F et al (2003) Canonical protein inhibitors of serine proteases. Cell Mol Life Sci 60:2427–2444
Lee DH, Goldberg AL (1998) Proteasome inhibitors: valuable new tools for cell biologists. Trends Cell Biol 8:397–403
McKerrow JH, Engel JC, Caffrey CR (1999) Cysteine protease inhibitors as chemotherapy for parasitic infections. Bioorg Med Chem 74:639–644
Roggwiller E, Bétoulle ME, Blisnick T et al (1996) A role for erythrocyte band 3 degradation by the parasite gp76 serine protease in the formation of the parasitophorous vacuole during invasion of erythrocytes by Plasmodium falciparum. Mol Biochem Parasitol 82:13–24
Ehmke V, Heindl C, Rottmann M, Freymond C, Schweizer WB, Brun R, Stich A, Schirmeister T, Diederich F (2011) Potent and selective inhibition of cysteine proteases from Plasmodium falciparum and Trypanosoma brucei. Chem Med Chem 6:273–278
Conseil V, Soete M, Dubremetz JF (1999) Serine protease inhibitors block invasion of host cells by Toxoplasma gondii. Antimicrob Agents Chemother 46:1358–1361
Peyre JE, Xue Q, Itoh N et al (2010) Cooper Serine protease inhibitor cvSI-1 potential role in the eastern oyster host defense against the protozoan parasite Perkinsus marinus. Develop Comp Immunol 34:84–92
Motta FN, Bastos IMD, Faudry E et al (2012) The Trypanosoma cruzi virulence factor oligopeptidase B (OPBTc) assembles into an active and stable dimer. PLoS One 7:e30431
Morty RE, Troeberg L, Pike RN et al (1998) A trypanosome oligopeptidase as a target for the trypanocidal agents pentamidine, diminazene and suramin. FEBS Lett 433:251–256
Silva-Lopez RE, Morgado-Díaz JA, Chávez MA et al (2007) Effects of serine protease inhibitors on viability and morphology of Leishmania (Leishmania) amazonensis promastigotes. Parasitol Res 101:1627–1635
Pereira IO, Assis DM, Juliano MA et al (2011) Natural products from Garcinia brasiliensis as Leishmania protease inhibitors. J Med Food 14:557–562
Bastos IM, Motta FN, Grellier P et al (2013) Parasite prolyl oligopeptidases and the challenge of designing chemotherapeuticals for chagas disease, leishmaniasis and African trypanosomiasis. Curr Med Chem 20:3103–3115
Coetzer THT, Goldring JPD, Huson LEJ (2008) Oligopeptidase B: a processing peptidase involved in pathogenesis. Biochimie 90:336–344
Acknowledgements
Thanks are also due to the University Grant Commission (New Delhi) and the Council of Scientific & Industrial Research (New Delhi), Govt. of India for financing this work.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Das, P., Alam, M.N., De, T., Chakraborti, T. (2013). Proteases as Virulence Factors in Leishmania: Focus on Serine Proteases as Possible Therapeutic Targets. In: Chakraborti, S., Dhalla, N. (eds) Proteases in Health and Disease. Advances in Biochemistry in Health and Disease, vol 7. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9233-7_9
Download citation
DOI: https://doi.org/10.1007/978-1-4614-9233-7_9
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-9232-0
Online ISBN: 978-1-4614-9233-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)