The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronic Trypanosoma cruzi infection.
<h4>Background</h4>Chagas disease, chronic infection with Trypanosoma cruzi, mainly manifests as cardiac disease. However, the liver is important for both controlling parasite burdens and metabolizing drugs. Notably, high doses of anti-parasitic drug benznidazole (BNZ) causes liver damag...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-11-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0011519&type=printable |
| _version_ | 1797392914309971968 |
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| author | Duc Minh Nguyen Cristina Poveda Jeroen Pollet Fabian Gusovsky Maria Elena Bottazzi Peter J Hotez Kathryn Marie Jones |
| author_facet | Duc Minh Nguyen Cristina Poveda Jeroen Pollet Fabian Gusovsky Maria Elena Bottazzi Peter J Hotez Kathryn Marie Jones |
| author_sort | Duc Minh Nguyen |
| collection | DOAJ |
| description | <h4>Background</h4>Chagas disease, chronic infection with Trypanosoma cruzi, mainly manifests as cardiac disease. However, the liver is important for both controlling parasite burdens and metabolizing drugs. Notably, high doses of anti-parasitic drug benznidazole (BNZ) causes liver damage. We previously showed that combining low dose BNZ with a prototype therapeutic vaccine is a dose sparing strategy that effectively reduced T. cruzi induced cardiac damage. However, the impact of this treatment on liver health is unknown. Therefore, we evaluated several markers of liver health after treatment with low dose BNZ plus the vaccine therapy in comparison to a curative dose of BNZ.<h4>Methodology</h4>Female BALB/c mice were infected with a bioluminescent T. cruzi H1 clone for approximately 70 days, then randomly divided into groups of 15 mice each. Mice were treated with a 25mg/kg BNZ, 25μg Tc24-C4 protein/ 5μg E6020-SE (Vaccine), 25mg/kg BNZ followed by vaccine, or 100mg/kg BNZ (curative dose). At study endpoints we evaluated hepatomegaly, parasite burden by quantitative PCR, cellular infiltration by histology, and expression of B-cell translocation gene 2(BTG2) and Peroxisome proliferator-activated receptor alpha (PPARα) by RT-PCR. Levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were quantified from serum.<h4>Results</h4>Curative BNZ treatment significantly reduced hepatomegaly, liver parasite burdens, and the quantity of cellular infiltrate, but significantly elevated serum levels of ALT, AST, and LDH. Low BNZ plus vaccine did not significantly affect hepatomegaly, parasite burdens or the quantity of cellular infiltrate, but only elevated ALT and AST. Low dose BNZ significantly decreased expression of both BTG2 and PPARα, and curative BNZ reduced expression of BTG2 while low BNZ plus vaccine had no impact.<h4>Conclusions</h4>These data confirm toxicity associated with curative doses of BNZ and suggest that while dose sparing low BNZ plus vaccine treatment does not reduce parasite burdens, it better preserves liver health. |
| first_indexed | 2024-03-08T23:54:25Z |
| format | Article |
| id | doaj.art-1a67838d992942c3894c9ef56f930384 |
| institution | Directory Open Access Journal |
| issn | 1935-2727 1935-2735 |
| language | English |
| last_indexed | 2024-03-08T23:54:25Z |
| publishDate | 2023-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj.art-1a67838d992942c3894c9ef56f9303842023-12-13T05:33:00ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352023-11-011711e001151910.1371/journal.pntd.0011519The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronic Trypanosoma cruzi infection.Duc Minh NguyenCristina PovedaJeroen PolletFabian GusovskyMaria Elena BottazziPeter J HotezKathryn Marie Jones<h4>Background</h4>Chagas disease, chronic infection with Trypanosoma cruzi, mainly manifests as cardiac disease. However, the liver is important for both controlling parasite burdens and metabolizing drugs. Notably, high doses of anti-parasitic drug benznidazole (BNZ) causes liver damage. We previously showed that combining low dose BNZ with a prototype therapeutic vaccine is a dose sparing strategy that effectively reduced T. cruzi induced cardiac damage. However, the impact of this treatment on liver health is unknown. Therefore, we evaluated several markers of liver health after treatment with low dose BNZ plus the vaccine therapy in comparison to a curative dose of BNZ.<h4>Methodology</h4>Female BALB/c mice were infected with a bioluminescent T. cruzi H1 clone for approximately 70 days, then randomly divided into groups of 15 mice each. Mice were treated with a 25mg/kg BNZ, 25μg Tc24-C4 protein/ 5μg E6020-SE (Vaccine), 25mg/kg BNZ followed by vaccine, or 100mg/kg BNZ (curative dose). At study endpoints we evaluated hepatomegaly, parasite burden by quantitative PCR, cellular infiltration by histology, and expression of B-cell translocation gene 2(BTG2) and Peroxisome proliferator-activated receptor alpha (PPARα) by RT-PCR. Levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were quantified from serum.<h4>Results</h4>Curative BNZ treatment significantly reduced hepatomegaly, liver parasite burdens, and the quantity of cellular infiltrate, but significantly elevated serum levels of ALT, AST, and LDH. Low BNZ plus vaccine did not significantly affect hepatomegaly, parasite burdens or the quantity of cellular infiltrate, but only elevated ALT and AST. Low dose BNZ significantly decreased expression of both BTG2 and PPARα, and curative BNZ reduced expression of BTG2 while low BNZ plus vaccine had no impact.<h4>Conclusions</h4>These data confirm toxicity associated with curative doses of BNZ and suggest that while dose sparing low BNZ plus vaccine treatment does not reduce parasite burdens, it better preserves liver health.https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0011519&type=printable |
| spellingShingle | Duc Minh Nguyen Cristina Poveda Jeroen Pollet Fabian Gusovsky Maria Elena Bottazzi Peter J Hotez Kathryn Marie Jones The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronic Trypanosoma cruzi infection. PLoS Neglected Tropical Diseases |
| title | The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronic Trypanosoma cruzi infection. |
| title_full | The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronic Trypanosoma cruzi infection. |
| title_fullStr | The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronic Trypanosoma cruzi infection. |
| title_full_unstemmed | The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronic Trypanosoma cruzi infection. |
| title_short | The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronic Trypanosoma cruzi infection. |
| title_sort | impact of vaccine linked chemotherapy on liver health in a mouse model of chronic trypanosoma cruzi infection |
| url | https://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0011519&type=printable |
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