Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols

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dc.contributor.authorCorrêa Soares, Juliana B R
dc.contributor.authorMenezes, Diego
dc.contributor.authorVannier-Santos, Marcos A
dc.contributor.authorFerreira-Pereira, Antonio
dc.contributor.authorAlmeida, Giulliana T
dc.contributor.authorVenancio, Thiago M
dc.contributor.authorVerjovski-Almeida, Sergio
dc.contributor.authorZishiri, Vincent K
dc.contributor.authorKuter, David
dc.contributor.authorHunter, Roger
dc.contributor.authorEgan, Timothy J
dc.contributor.authorOliveira, Marcus F
dc.date.accessioned2021-10-08T07:15:53Z
dc.date.available2021-10-08T07:15:53Z
dc.date.issued2009
dc.description.abstractBackgroundThe parasitic trematode Schistosoma mansoni is one of the major causative agents of human schistosomiasis, which afflicts 200 million people worldwide. Praziquantel remains the main drug used for schistosomiasis treatment, and reliance on the single therapy has been prompting the search for new therapeutic compounds against this disease. Our group has demonstrated that heme crystallization into hemozoin (Hz) within the S. mansoni gut is a major heme detoxification route with lipid droplets involved in this process and acting as a potential chemotherapeutical target. In the present work, we investigated the effects of three antimalarial compounds, quinine (QN), quinidine (QND) and quinacrine (QCR) in a murine schistosomiasis model by using a combination of biochemical, cell biology and molecular biology approaches.Methodology/Principal FindingsTreatment of S. mansoni-infected female Swiss mice with daily intraperitoneal injections of QN, and QND (75 mg/kg/day) from the 11th to 17th day after infection caused significant decreases in worm burden (39%–61%) and egg production (42%–98%). Hz formation was significantly inhibited (40%–65%) in female worms recovered from QN- and QND-treated mice and correlated with reduction in the female worm burden. We also observed that QN treatment promoted remarkable ultrastructural changes in male and female worms, particularly in the gut epithelium and reduced the granulomatous reaction to parasite eggs trapped in the liver. Microarray gene expression analysis indicated that QN treatment increased the expression of transcripts related to musculature, protein synthesis and repair mechanisms.ConclusionsThe overall significant reduction in several disease burden parameters by the antimalarial quinoline methanols indicates that interference with Hz formation in S. mansoni represents an important mechanism of schistosomicidal action of these compounds and points out the heme crystallization process as a valid chemotherapeutic target to treat schistosomiasis.Author SummaryHeme is an essential molecule to most living organisms, but once in a free state it exerts toxic effects. Blood-feeding organisms evolved efficient ways to detoxify free heme derived from hemoglobin digestion. A key mechanism present in some hematophagous organisms consists of the crystallization of heme into a pigment named hemozoin. Schistosoma mansoni is one of the etiologic agents of human schistosomiasis, a parasitic disease that affects over 200 million people in tropical and subtropical areas. Hemozoin formation represents the main heme detoxification pathway in S. mansoni. Here, we report that the antimalarial quinoline methanols quinine and quinidine exert schistosomicidal effects notably due to their capacity to interfere with hemozoin formation. When quinine or quinidine were administered intraperitoneally during seven days to S. mansoni-infected mice (75 mg/kg/day), both worm and eggs burden were significantly reduced. Interestingly, hemozoin content in female worms was drastically affected after treatment with either compound. We also found that quinine caused important changes in the cellular organization of worm gastrodermis and increased expression of genes related to musculature, protein synthesis and repair mechanisms. Together, our results indicate that interference with hemozoin formation is a valid chemotherapeutic target for development of new schistosomicidal agents.
dc.identifier.apacitationCorrêa Soares, J. B. R., Menezes, D., Vannier-Santos, M. A., Ferreira-Pereira, A., Almeida, G. T., Venancio, T. M., ... Oliveira, M. F. (2009). Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols. <i>PLoS Neglected Tropical Diseases</i>, 3(7), e477 - 177. http://hdl.handle.net/11427/34715en_ZA
dc.identifier.chicagocitationCorrêa Soares, Juliana B R, Diego Menezes, Marcos A Vannier-Santos, Antonio Ferreira-Pereira, Giulliana T Almeida, Thiago M Venancio, Sergio Verjovski-Almeida, et al "Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols." <i>PLoS Neglected Tropical Diseases</i> 3, 7. (2009): e477 - 177. http://hdl.handle.net/11427/34715en_ZA
dc.identifier.citationCorrêa Soares, J.B.R., Menezes, D., Vannier-Santos, M.A., Ferreira-Pereira, A., Almeida, G.T., Venancio, T.M., Verjovski-Almeida, S. & Zishiri, V.K. et al. 2009. Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols. <i>PLoS Neglected Tropical Diseases.</i> 3(7):e477 - 177. http://hdl.handle.net/11427/34715en_ZA
dc.identifier.issn1935-2727
dc.identifier.issn1935-2735
dc.identifier.ris TY - Journal Article AU - Corrêa Soares, Juliana B R AU - Menezes, Diego AU - Vannier-Santos, Marcos A AU - Ferreira-Pereira, Antonio AU - Almeida, Giulliana T AU - Venancio, Thiago M AU - Verjovski-Almeida, Sergio AU - Zishiri, Vincent K AU - Kuter, David AU - Hunter, Roger AU - Egan, Timothy J AU - Oliveira, Marcus F AB - BackgroundThe parasitic trematode Schistosoma mansoni is one of the major causative agents of human schistosomiasis, which afflicts 200 million people worldwide. Praziquantel remains the main drug used for schistosomiasis treatment, and reliance on the single therapy has been prompting the search for new therapeutic compounds against this disease. Our group has demonstrated that heme crystallization into hemozoin (Hz) within the S. mansoni gut is a major heme detoxification route with lipid droplets involved in this process and acting as a potential chemotherapeutical target. In the present work, we investigated the effects of three antimalarial compounds, quinine (QN), quinidine (QND) and quinacrine (QCR) in a murine schistosomiasis model by using a combination of biochemical, cell biology and molecular biology approaches.Methodology/Principal FindingsTreatment of S. mansoni-infected female Swiss mice with daily intraperitoneal injections of QN, and QND (75 mg/kg/day) from the 11th to 17th day after infection caused significant decreases in worm burden (39%–61%) and egg production (42%–98%). Hz formation was significantly inhibited (40%–65%) in female worms recovered from QN- and QND-treated mice and correlated with reduction in the female worm burden. We also observed that QN treatment promoted remarkable ultrastructural changes in male and female worms, particularly in the gut epithelium and reduced the granulomatous reaction to parasite eggs trapped in the liver. Microarray gene expression analysis indicated that QN treatment increased the expression of transcripts related to musculature, protein synthesis and repair mechanisms.ConclusionsThe overall significant reduction in several disease burden parameters by the antimalarial quinoline methanols indicates that interference with Hz formation in S. mansoni represents an important mechanism of schistosomicidal action of these compounds and points out the heme crystallization process as a valid chemotherapeutic target to treat schistosomiasis.Author SummaryHeme is an essential molecule to most living organisms, but once in a free state it exerts toxic effects. Blood-feeding organisms evolved efficient ways to detoxify free heme derived from hemoglobin digestion. A key mechanism present in some hematophagous organisms consists of the crystallization of heme into a pigment named hemozoin. Schistosoma mansoni is one of the etiologic agents of human schistosomiasis, a parasitic disease that affects over 200 million people in tropical and subtropical areas. Hemozoin formation represents the main heme detoxification pathway in S. mansoni. Here, we report that the antimalarial quinoline methanols quinine and quinidine exert schistosomicidal effects notably due to their capacity to interfere with hemozoin formation. When quinine or quinidine were administered intraperitoneally during seven days to S. mansoni-infected mice (75 mg/kg/day), both worm and eggs burden were significantly reduced. Interestingly, hemozoin content in female worms was drastically affected after treatment with either compound. We also found that quinine caused important changes in the cellular organization of worm gastrodermis and increased expression of genes related to musculature, protein synthesis and repair mechanisms. Together, our results indicate that interference with hemozoin formation is a valid chemotherapeutic target for development of new schistosomicidal agents. DA - 2009 DB - OpenUCT DP - University of Cape Town IS - 7 J1 - PLoS Neglected Tropical Diseases LK - https://open.uct.ac.za PY - 2009 SM - 1935-2727 SM - 1935-2735 T1 - Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols TI - Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols UR - http://hdl.handle.net/11427/34715 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/34715
dc.identifier.vancouvercitationCorrêa Soares JBR, Menezes D, Vannier-Santos MA, Ferreira-Pereira A, Almeida GT, Venancio TM, et al. Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols. PLoS Neglected Tropical Diseases. 2009;3(7):e477 - 177. http://hdl.handle.net/11427/34715.en_ZA
dc.language.isoeng
dc.publisher.departmentDepartment of Chemistry
dc.publisher.facultyFaculty of Science
dc.sourcePLoS Neglected Tropical Diseases
dc.source.journalissue7
dc.source.journalvolume3
dc.source.paginatione477 - 177
dc.source.urihttps://dx.doi.org/10.1371/journal.pntd.0000477
dc.subject.otherAnimals
dc.subject.otherAnthelmintics
dc.subject.otherFemale
dc.subject.otherGastrointestinal Tract
dc.subject.otherGene Expression Profiling
dc.subject.otherHemeproteins
dc.subject.otherIntestinal Mucosa
dc.subject.otherLiver
dc.subject.otherMale
dc.subject.otherMice
dc.subject.otherParasite Egg Count
dc.subject.otherQuinacrine
dc.subject.otherQuinidine
dc.subject.otherQuinine
dc.subject.otherSchistosoma mansoni
dc.titleInterference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols
dc.typeJournal Article
uct.type.publicationResearch
uct.type.resourceJournal Article
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