Role of Peroxidoxins in Leishmania chagasiSurvival

The mechanisms by which Leishmaniaparasites survive exposure to highly reactive oxygen (ROS) and nitrogen (RNS) species within phagosomes of macrophages are not well known. Recently it has been shown that RNS alone is sufficient and necessary to control Leishmania donovani infection in mice (Murray, H. W., and Nathan, C. F. (1999) J. Exp. Med. 189, 741–746). No enzymatic defense against RNS has been discovered inLeishmania to date. We have previously isolated two peroxidoxins (LcPxn1 and LcPxn2) from Leishmania chagasiand showed that recombinant LcPxn1 protein was capable of detoxifying hydrogen peroxide, hydroperoxide, and hydroxyl radicals (Barr, S. D., and Gedamu, L. (2001) J. Biol. Chem. 276, 34279–34287). In further characterizing the physiological role of peroxidoxins in Leishmania survival, we show here that recombinant LcPxn1 protein can detoxify RNS in addition to ROS, whereas recombinant LcPxn2 protein can only detoxify hydrogen peroxide. LcPxn1 and LcPxn2 are localized to the cytoplasm, and overexpression of LcPxn1 in L. chagasi parasites enhanced survival when exposed to exogenous ROS and RNS and enhanced survival within U937 macrophage cells. Site-directed mutagenesis studies revealed that the conserved Cys-52 residue is essential for detoxifying hydrogen peroxide, t-butyl hydroperoxide, and hydroxyl radicals, whereas the conserved Cys-173 residue is essential for detoxifying t-butyl hydroperoxide and peroxynitrite. This is the first report of an enzymatic defense against RNS in Leishmania. The mechanisms by which Leishmaniaparasites survive exposure to highly reactive oxygen (ROS) and nitrogen (RNS) species within phagosomes of macrophages are not well known. Recently it has been shown that RNS alone is sufficient and necessary to control Leishmania donovani infection in mice (Murray, H. W., and Nathan, C. F. (1999) J. Exp. Med. 189, 741–746). No enzymatic defense against RNS has been discovered inLeishmania to date. We have previously isolated two peroxidoxins (LcPxn1 and LcPxn2) from Leishmania chagasiand showed that recombinant LcPxn1 protein was capable of detoxifying hydrogen peroxide, hydroperoxide, and hydroxyl radicals (Barr, S. D., and Gedamu, L. (2001) J. Biol. Chem. 276, 34279–34287). In further characterizing the physiological role of peroxidoxins in Leishmania survival, we show here that recombinant LcPxn1 protein can detoxify RNS in addition to ROS, whereas recombinant LcPxn2 protein can only detoxify hydrogen peroxide. LcPxn1 and LcPxn2 are localized to the cytoplasm, and overexpression of LcPxn1 in L. chagasi parasites enhanced survival when exposed to exogenous ROS and RNS and enhanced survival within U937 macrophage cells. Site-directed mutagenesis studies revealed that the conserved Cys-52 residue is essential for detoxifying hydrogen peroxide, t-butyl hydroperoxide, and hydroxyl radicals, whereas the conserved Cys-173 residue is essential for detoxifying t-butyl hydroperoxide and peroxynitrite. This is the first report of an enzymatic defense against RNS in Leishmania. nitric oxide peroxynitrite hydroxyl radicals hydroperoxide tert-butyl hydroperoxide reactive nitrogen species reactive oxygen species glutathione S-transferase green fluorescent protein dithioerythritol Pyrogallol Red bovine serum albumin phosphate-buffered saline 2,2′-azinobis(3-ethylbenzthiazoline-6-sulfonic acid 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide Leishmania is a protozoan parasite that affects over 12 million people worldwide with an estimated 2 million new cases each year. Depending on the species involved, symptoms range from the self-healing cutaneous form (e.g. Leishmania major) to the fatal visceral form (e.g. Leishmania chagasi). The parasites are transmitted as promastigotes from the gut of its sandfly vector to mammalian host macrophages wherein they transform into amastigotes and proliferate. As a macrophage defense mechanism, nitric oxide (⋅NO),1 peroxynitrite (ONOO−), hydroxyl radicals (⋅OH), hydrogen peroxide (H2O2), hydroperoxide (ROOH), and superoxide radicals ( O2⋅→) are produced in an attempt to destroy the parasites. These reactive nitrogen species (RNS) and oxygen species (ROS) readily react with proteins, DNA, and lipids and have been implicated in a wide variety of cell functions such as signal transduction, redox homeostasis, apoptosis, aging, activation of T lymphocytes, control of blood pressure, tumor progression, protection of eye tissue, and pathogen infection/defense (1Droge W. Physiol. Rev. 2002; 82: 47-95Crossref PubMed Scopus (7426) Google Scholar, 2Peshenko I.V. Singh A.K. Shichi H. J. Ocul. Pharmacol. Ther. 2001; 17: 93-99Crossref PubMed Scopus (37) Google Scholar, 3Butterfield L.H. Merino A. Golub S.H. Shau H. Antioxid. Redox Signal. 1999; 1: 385-402Crossref PubMed Scopus (121) Google Scholar, 4Nathan C. Shiloh M.U. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 8841-8848Crossref PubMed Scopus (1148) Google Scholar). Numerous reports have shown that Leishmania parasites are susceptible to ROS-mediated killing (5Zarley J.H. Britigan B.E. Wilson M.E. J. Clin. Invest. 1991; 88: 1511-1521Crossref PubMed Scopus (95) Google Scholar, 6Wilson M.E. Andersen K.A. Britigan B.E. Infect. Immun. 1994; 62: 5133-5141Crossref PubMed Google Scholar, 7Pearson R.D. Harcus J.L. Roberts D. Donowitz G.R. J. Immunol. 1983; 131: 1994-1999PubMed Google Scholar, 8Channon J.Y. Blackwell J.M. Parasitology. 1985; 91: 197-206Crossref PubMed Scopus (34) Google Scholar, 9Murray H.W. J. Immunol. 1982; 129: 351-357PubMed Google Scholar) and RNS-mediated killing (10Roach T.I. Kiderlen A.F. Blackwell J.M. Infect. Immun. 1991; 59: 3935-3944Crossref PubMed Google Scholar, 11Bhattacharyya S. Ghosh S. Dasgupta B. Mazumder D. Roy S. Majumdar S. J. Infect. Dis. 2002; 185: 1704-1708Crossref PubMed Scopus (66) Google Scholar, 12Green S.J. Meltzer M.S. Hibbs Jr., J.B. Nacy C.A. J. Immunol. 1990; 144: 278-283PubMed Google Scholar, 13Mauel J. Ransijn A. Buchmuller-Rouiller Y. J. Leukoc. Biol. 1991; 49: 73-82Crossref PubMed Scopus (141) Google Scholar, 14Liew F.Y. Millott S. Parkinson C. Palmer R.M. Moncada S. J. Immunol. 1990; 144: 4794-4797PubMed Google Scholar, 15Evans T.G. Thai L. Granger D.L. Hibbs Jr., J.B. J. Immunol. 1993; 151: 907-915PubMed Google Scholar, 16Vouldoukis I. Riveros-Moreno V. Dugas B. Ouaaz F. Becherel P. Debre P. Moncada S. Mossalayi M.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7804-7808Crossref PubMed Scopus (252) Google Scholar, 17Murray H.W. Nathan C.F. J. Exp. Med. 1999; 189: 741-746Crossref PubMed Scopus (356) Google Scholar). It has been shown that RNS alone is both necessary and sufficient to control Leishmania donovani infection in mice (17Murray H.W. Nathan C.F. J. Exp. Med. 1999; 189: 741-746Crossref PubMed Scopus (356) Google Scholar) and more recently that both ROS and RNS produced by macrophages act together early to control infection by L. chagasi (18Gantt K.R. Goldman T.L. McCormick M.L. Miller M.A. Jeronimo S.M. Nascimento E.T. Britigan B.E. Wilson M.E. J. Immunol. 2001; 167: 893-901Crossref PubMed Scopus (227) Google Scholar) and L. donovani (11Bhattacharyya S. Ghosh S. Dasgupta B. Mazumder D. Roy S. Majumdar S. J. Infect. Dis. 2002; 185: 1704-1708Crossref PubMed Scopus (66) Google Scholar, 17Murray H.W. Nathan C.F. J. Exp. Med. 1999; 189: 741-746Crossref PubMed Scopus (356) Google Scholar). These studies suggest that further characterization of antioxidant molecules within Leishmaniaand the role that they play in parasite survival in the promastigote and amastigote stages could lead to the development of novel strategies to compromise parasite survival. Despite the ability of ROS and RNS to control Leishmaniainfection within macrophages, strains causing cutaneous and visceral leishmaniasis persist long enough within macrophages to produce skin lesions or death. The molecular mechanisms by whichLeishmania circumvent the toxic effects of these reactive species is not fully understood. Some Leishmania molecules implicated in antioxidant defense against ROS include intracellular thiols (19Channon J.Y. Blackwell J.M. Parasitology. 1985; 91: 207-217Crossref PubMed Scopus (24) Google Scholar), lipophosphoglycan (20Chan J. Fujiwara T. Brennan P. McNeil M. Turco S.J. Sibille J.C. Snapper M. Aisen P. Bloom B.R. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 2453-2457Crossref PubMed Scopus (204) Google Scholar, 21Sacks D.L. Brodin T.N. Turco S.J. Mol. Biochem. Parasitol. 1990; 42: 225-233Crossref PubMed Scopus (88) Google Scholar), iron superoxide dismutase (22Paramchuk W.J. Ismail S.O. Bhatia A. Gedamu L. Mol. Biochem. Parasitol. 1997; 90: 203-221Crossref PubMed Scopus (90) Google Scholar), HSP70 (23Miller M.A. McGowan S.E. Gantt K.R. Champion M. Novick S.L. Andersen K.A. Bacchi C.J. Yarlett N. Britigan B.E. Wilson M.E. J. Biol. Chem. 2000; 275: 33883-33889Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar), ovothiol and Mol. Biochem. Parasitol. 2001; PubMed Scopus Google Scholar), and peroxidoxins Gedamu L. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (66) Google Scholar, Blackwell J.M. Mol. Biochem. Parasitol. PubMed Scopus Google Scholar, H. C. M. A. L. Biol. Med. 2002; PubMed Scopus (88) Google Scholar, A. T.I. Infect. Immun. PubMed Google Scholar). The mechanisms by whichLeishmania the toxic effects of RNS is has recently been implicated in L. from S.H. Parasitology. 1999; PubMed Scopus Google Scholar). an enzymatic defense against RNS has not been are highly conserved in from to are by two conserved to and and in as molecular have been Gedamu L. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (66) Google Scholar, N. 2000; Full Text Full Text PDF Scopus Google Scholar, C. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, M.S. J. Mol. Biol. 2000; PubMed Scopus (141) Google Scholar). as to detoxify ROS, and S. Parasitol. Full Text Full Text PDF PubMed Scopus Google Scholar), recently to the Gedamu L. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (66) Google Scholar). have been implicated in detoxifying RNS in and L. Nathan C. Mol. 1: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, P. Nathan C. 2000; PubMed Scopus Google Scholar). We have previously isolated two from L. chagasi that are LcPxn1 are highly in the amastigote and LcPxn2 are highly in the promastigote Gedamu L. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (66) Google Scholar). LcPxn1 protein was shown to detoxify and the of its and the role that L. chagasi peroxidoxins play in detoxifying RNS and in parasite survival has not been In we that recombinant LcPxn1 not can detoxify RNS in addition to ROS and show that LcPxn1 L. chagasi parasites from and RNS-mediated in and survival within we have the of LcPxn1 in detoxifying both ROS and which from peroxidoxins isolated from LcPxn1 and by mutagenesis as previously J. T. Scholar). into the vector and by in for which was to the and by and over a as by The with and further and protein was on a the protein was as previously J. Biochem. PubMed Scopus Google Scholar). the dithioerythritol or t-butyl hydroperoxide, and protein with for The was with the addition of of acid of and of and the peroxide of peroxide as a The of and the of as previously B. J.M. PubMed Scopus Google Scholar). was to the to the as and protein in for was and the for of acid and of acid to the and the was for was in a a with well and to react for to as previously Biochem. 1993; PubMed Scopus Google Scholar). protein with for was to the and for 2 of was to each and the was for The was on a a peroxynitrite was from hydrogen peroxide and the PubMed Google Scholar) and over as previously R.M. PubMed Google Scholar). The was as previously Biochem. 2001; PubMed Scopus Google Scholar). The Pyrogallol Red and of peroxynitrite was to the for which the was of DNA, and was as previously Biochem. 1995; PubMed Scopus Google Scholar). was to the and for The was on a a as previously J.C. D. PubMed Google Scholar). and protein in phosphate-buffered saline for was to the and the of to was by the in vector by S. M. in was to and in L. The a and a with The vector and the with and for the LcPxn1 and LcPxn2 as the of was a and a The of was from to The was with and and The of LcPxn1 was a and a The of LcPxn2 was a and a The of LcPxn1 and LcPxn2 each and and of and LcPxn1 or LcPxn2 and and into and of the vector by S. M. by the of proteins, parasites by and in in of and on for was and for a further of the was in for and on a and to was and an enhanced the overexpression of LcPxn1 and LcPxn1 parasites of each in and in for a to as with to was from of The was as previously (5Zarley J.H. Britigan B.E. Wilson M.E. J. Clin. Invest. 1991; 88: 1511-1521Crossref PubMed Scopus (95) Google Scholar, J. Fujiwara T. Brennan P. McNeil M. Turco S.J. Sibille J.C. Snapper M. Aisen P. Bloom B.R. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 2453-2457Crossref PubMed Scopus (204) Google Scholar, D.L. Turco S.J. Mol. Biochem. Parasitol. PubMed Scopus Google Scholar). of 2 promastigotes or promastigotes with and in of exposed for 2 to t-butyl hydroperoxide or the was as previously (20Chan J. Fujiwara T. Brennan P. McNeil M. Turco S.J. Sibille J.C. Snapper M. Aisen P. Bloom B.R. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 2453-2457Crossref PubMed Scopus (204) Google Scholar). and for The parasites for 2 in the of 2 of for of The parasites in 2 of for on of acid was to the and they on for to and with of acid and with of a in 2 of and for for of U937 from was as previously Wilson M.E. Infect. Immun. PubMed Google Scholar). U937 a of in and into macrophages by with of of with 2 and for to with by with L. chagasi parasites a parasite to U937 cell of for parasites to with and in The of infection in U937 was and by of cell A. M. M. B. Exp. 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PubMed Google Scholar). to the LcPxn1 protein and the from with LcPxn1 and was in protection LcPxn2 protein and LcPxn2 or As further of and and superoxide not from not the suggest that recombinant LcPxn1 protein is capable of detoxifying RNS whereas LcPxn2 not to detoxify The two to and in peroxidoxins are highly conserved The has been implicated as the residue in the of Proc. Natl. Acad. Sci. U. S. A. 1994; 91: PubMed Scopus Google Scholar, 1997; PubMed Scopus Google Scholar) and peroxynitrite P. Nathan C. 2000; PubMed Scopus Google Scholar). the in Leishmania we mutagenesis of the conserved Cys-52 and Cys-173 and recombinant LcPxn1 protein to and In the acid in detoxifying ROS, we that protein to detoxify t-butyl hydroperoxide and in each with LcPxn1 protein In protein to from was by with LcPxn1 or Cys-52 to essential for detoxifying ROS, which is with with was in the ability of to detoxify with LcPxn1 and from In not with LcPxn1 and these suggest that the Cys-173 residue is not essential for detoxifying or is essential in detoxifying protein not against with LcPxn1 and and not from LcPxn2 protein was to detoxify only It not or it with In the acid in detoxifying we that protein of in detoxifying and from with LcPxn1 protein that Cys-52 is not essential for detoxifying protein not a in detoxifying with LcPxn1 or and could not from that Cys-173 is the residue and is essential for detoxifying and LcPxn2 not detoxify and could not of and to with and protein more protection with LcPxn1 these suggest that the Cys-52 residue is essential for detoxifying and Cys-173 is essential for detoxifying and and Cys-52 Cys-173 are essential for detoxifying in of the antioxidant of recombinant LcPxn1 and LcPxn1 and LcPxn2 in a new LcPxn1 protein can chagasi parasites from exposure to an in ROS and we LcPxn1 protein in the parasites to they enhanced survival. with the vector the of LcPxn1 and the of the not and and showed that each of the early and more a in the of LcPxn1 protein with the control which the vector alone early and parasites LcPxn1 protein a in each enhanced survival exposure to and with control parasites the vector alone with (5Zarley J.H. Britigan B.E. Wilson M.E. J. Clin. Invest. 1991; 88: 1511-1521Crossref PubMed Scopus (95) Google Scholar), we that the control parasites more to early parasites We that the control parasites more to and In of that Cys-52 is essential in detoxifying and and that Cys-173 is essential in detoxifying and parasites not an enhanced survival exposure to or enhanced survival exposure to with control parasites an enhanced survival exposure to and not exposure to or which is with with recombinant protein to with recombinant LcPxn1 proteins, parasites and not enhanced survival exposure to not enhanced survival exposure to of the ROS or further the functions of LcPxn1 and LcPxn2 in parasite survival, we the of these within L. The acid of LcPxn1 not to a signal which that it localized to the The the of LcPxn2 are and the signal of the signal in showed that signal is highly of the signal to was not sufficient to to the J.M. Mol. Biol. PubMed Scopus Google Scholar). We and protein and in L. chagasi parasites. and of each parasite with revealed the of a protein of that both the and No to the protein alone in of the isolated from parasites the showed that both the and are localized the the to the with the control parasites the protein alone The for both LcPxn1 and LcPxn2 are from the of not These suggest that both LcPxn1 and LcPxn2 are localized to the the stages of infection with a an in macrophages H.W. J. Immunol. 1982; 129: 351-357PubMed Google Scholar, K.R. Goldman T.L. McCormick M.L. Miller M.A. Jeronimo S.M. Nascimento E.T. Britigan B.E. Wilson M.E. J. Immunol. 2001; 167: 893-901Crossref PubMed Scopus (227) Google Scholar, J.Y. Roberts Blackwell J.M. Google Scholar, R.D. Harcus J.L. Donowitz G.R. J. Immunol. 1982; 129: Google Scholar), U937 J.H. PubMed Scopus Google Scholar, J. Immunol. 1983; Google Scholar, T. M. 1993; PubMed Scopus Google Scholar) in which ROS is produced in to macrophages, U937 have been shown to produce RNS infection is (18Gantt K.R. Goldman T.L. McCormick M.L. Miller M.A. Jeronimo S.M. Nascimento E.T. Britigan B.E. Wilson M.E. J. Immunol. 2001; 167: 893-901Crossref PubMed Scopus (227) Google Scholar, C. Jr., PubMed Scopus Google Scholar, P. M. M. M. Infect. Immun. 1999; PubMed Google Scholar). We have previously shown that the of LcPxn1 the amastigote with early parasites Gedamu L. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (66) Google Scholar). into the role that LcPxn1 in intracellular survival within macrophages, we the ability of L. chagasi parasites LcPxn1 to survive within the macrophage cell The of amastigotes LcPxn1 macrophage and infection was and These are control parasites the with and 12 parasites a of amastigotes macrophage of with for the control parasites. and was in the parasites and the control parasites. or not a in parasite with the control parasites No in the of U937 was not reports have shown that both ROS and RNS to the early control of Leishmania infection and that RNS alone is necessary and sufficient to control Leishmania infection (11Bhattacharyya S. Ghosh S. Dasgupta B. Mazumder D. Roy S. Majumdar S. J. Infect. Dis. 2002; 185: 1704-1708Crossref PubMed Scopus (66) Google Scholar, 17Murray H.W. Nathan C.F. J. Exp. Med. 1999; 189: 741-746Crossref PubMed Scopus (356) Google Scholar, K.R. Goldman T.L. McCormick M.L. Miller M.A. Jeronimo S.M. Nascimento E.T. Britigan B.E. Wilson M.E. J. Immunol. 2001; 167: 893-901Crossref PubMed Scopus (227) Google Scholar). the of an antioxidant defense against ROS and more RNS intracellular Leishmania a for survival. In further characterizing the role of peroxidoxins chagasi survival, we have shown that recombinant LcPxn1 protein can detoxify RNS in addition to ROS, whereas recombinant LcPxn2 protein to play a more role by only to detoxify LcPxn1 chagasi parasites enhanced parasite survival within macrophage and exposure to ROS and In we have implicated the Cys-52 residue as essential in detoxifying and Cys-173 as essential for detoxifying and with studies on peroxidoxins from the Cys-52 residue of LcPxn1 is essential for detoxifying and is with the of for which the of the residue by peroxide to form a acid residue This can react with the Cys-173 residue a such as or in inLeishmania to form a 1997; PubMed Scopus Google Scholar, S.J. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). The of for the of has not been previously to the of for detoxifying studies revealed that the Cys-52 residue is essential for detoxifying which with a of a can a hydrogen from the Cys-52 to form a This can by to form a acid residue and react with the Cys-173 residue a It is can in with of in and as such a of peroxidoxins have to to with peroxidoxins have been shown to highly in such as of the and peroxidoxins are the protein in Biochem. 1994; PubMed Scopus (81) Google Scholar, Proc. Natl. Acad. Sci. U. S. A. 1989; 86: PubMed Scopus Google Scholar). have been shown to to such as from by Gedamu L. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (66) Google Scholar, Biochem. 1993; PubMed Scopus Google Scholar). we have shown here that LcPxn1 is which its of into with and that its overexpression can parasites from an exogenous Numerous studies have as for peroxidoxins as in that can from and from parasites glutathione which are of in We previously that recombinant LcPxn1 protein can detoxify and have these studies to show that LcPxn1 can L. chagasi from and we that both the conserved Cys-52 and Cys-173 are essential for detoxifying which an for the of with the of and studies have the of the the of peroxidoxins 1997; PubMed Scopus Google Scholar, 2002; PubMed Scopus Google Scholar). It is that the Cys-173 residue of LcPxn1 essential for the into a more for a to the and more The of an could the acid that on the to further into which has been to lead to J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). we could not with recombinant LcPxn2 which is to LcPxn1 has been a report Blackwell J.M. Mol. Biochem. Parasitol. PubMed Scopus Google Scholar) of a from L. that is highly to LcPxn2 and is of detoxifying studies with the from has revealed that and the of in the is for of the protein 2002; PubMed Scopus Google Scholar). The LcPxn1 and LcPxn2 is the of a acid the of It is that the the into that is not for or is more to as of the of LcPxn1 and LcPxn2 more into and peroxidoxins have been previously shown to from and L. Nathan C. Mol. 1: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, P. Nathan C. 2000; PubMed Scopus Google Scholar). show that LcPxn1 can detoxify and and Leishmania from the by which inLeishmania from the by which peroxidoxins detoxify The conserved residue of the was to essential for P. Nathan C. 2000; PubMed Scopus Google Scholar), whereas we that the residue of LcPxn1 is essential for This for studies with Leishmania peroxidoxins that the ability of peroxidoxins to detoxify of is the Cys-173 residue can the in in the of oxygen to the Cys-173 and the of the of Cys-173 it into and peroxidoxins have been shown to and from the toxic effects by L. Nathan C. Mol. 1: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), has been of a recombinant protein capable of detoxifying We that overexpression of LcPxn1 protein in parasites from both and we that recombinant LcPxn1 protein can mutagenesis of LcPxn1 protein revealed that of the conserved or essential for and the of both to This that LcPxn1 a for detoxifying which we are the overexpression of LcPxn1 not the within the parasites protection to the parasites when exposed to It is that of and LcPxn1 within the parasites to an is that overexpression of LcPxn1 inLeishmania parasites enhanced survival within macrophages Despite the that ROS and RNS act together early to control Leishmania infection and that RNS alone is sufficient to control L. chagasi long enough to a fatal show chagasi parasites a enzymatic defense against ROS and against overexpression of the Cys-173 in the which we to only and not enhanced survival early in infection when ROS are produced in when infection is and when and protein are the parasites Cys-173 to enhanced survival. The Cys-52 which is only not enhanced survival early in infection and to survival stages of These that ROS are early in infection and that RNS alone to sufficient to control suggest that LcPxn1 parasite survival in and within macrophages by a of defense against the ROS and LcPxn1 is in the amastigote it could protection from the ROS and RNS that are produced within the macrophages that are to into the parasites. LcPxn2 is in the early of the and that LcPxn2 to to only detoxify that LcPxn2 a more in parasite survival in the promastigote in the gut of the sandfly which not as in ROS and RNS as within the of the macrophages of the The of an enzymatic defense against RNS in addition to ROS chagasi is it a within the parasites that can detoxify molecules produced by the host that have been previously shown to It to a to LcPxn1 is in Leishmania strains that the self-healing cutaneous form of peroxidoxins isolated from L. Blackwell J.M. Mol. Biochem. Parasitol. PubMed Scopus Google Scholar) H. C. M. A. L. Biol. Med. 2002; PubMed Scopus (88) Google Scholar, H. H. L. B. H. J. Biol. Med. 2002; PubMed Scopus Google Scholar) have not been shown to the ability to detoxify It is that LcPxn2 is an to LcPxn1 that a in the This could have the of the the conserved in the of functions such as to detoxify and which to a for L. chagasi survival. It to the of the functions of LcPxn1 to the of L. a of the mechanisms for intracellular survival and the role that peroxidoxins play in Leishmania survival. We are and and infection to a of the role that peroxidoxins play in the of

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