Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients co-infected with HIV
Background: Visceral leishmaniasis (VL) treatment in HIV patients very often fails and is followed by high relapse and case-fatality rates. Hence, treatment efficacy assessment is imperative but based on invasive organ aspiration for parasite detection. In the search of a less-invasive alternative a...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-05-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396420301237 |
| _version_ | 1818295458360983552 |
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| author | Wim Adriaensen Bart Cuypers Carlota F. Cordero Bewketu Mengasha Séverine Blesson Lieselotte Cnops Paul M. Kaye Fabiana Alves Ermias Diro Johan van Griensven |
| author_facet | Wim Adriaensen Bart Cuypers Carlota F. Cordero Bewketu Mengasha Séverine Blesson Lieselotte Cnops Paul M. Kaye Fabiana Alves Ermias Diro Johan van Griensven |
| author_sort | Wim Adriaensen |
| collection | DOAJ |
| description | Background: Visceral leishmaniasis (VL) treatment in HIV patients very often fails and is followed by high relapse and case-fatality rates. Hence, treatment efficacy assessment is imperative but based on invasive organ aspiration for parasite detection. In the search of a less-invasive alternative and because the host immune response is pivotal for treatment outcome in immunocompromised VL patients, we studied changes in the whole blood transcriptional profile of VL-HIV patients during treatment. Methods: Embedded in a clinical trial in Northwest Ethiopia, RNA-Seq was performed on whole blood samples of 28 VL-HIV patients before and after completion of a 29-day treatment regimen of AmBisome or AmBisome/miltefosine. Pathway analyses were combined with a machine learning approach to establish a clinically-useful 4-gene set. Findings: Distinct signatures of differentially expressed genes between D0 and D29 were identified for patients who failed treatment and were successfully treated. Pathway analyses in the latter highlighted a downregulation of genes associated with host cellular activity and immunity, and upregulation of antimicrobial peptide activity in phagolysosomes. No signs of disease remission nor pathway enrichment were observed in treatment failure patients. Next, we identified a 4-gene pre-post signature (PRSS33, IL10, SLFN14, HRH4) that could accurately discriminate treatment outcome at end of treatment (D29), displaying an average area-under-the-ROC-curve of 0.95 (CI: 0.75–1.00). Interpretation: A simple blood-based signature thus holds significant promise to facilitate treatment efficacy monitoring and provide an alternative test-of-cure to guide patient management in VL-HIV patients. Funding: Project funding was provided by the AfricoLeish project, supported by the European Union Seventh Framework Programme (EU FP7). |
| first_indexed | 2024-12-13T03:47:58Z |
| format | Article |
| id | doaj.art-1a49a3cee76f4f79880d77a03854c685 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-13T03:47:58Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-1a49a3cee76f4f79880d77a03854c6852022-12-22T00:00:47ZengElsevierEBioMedicine2352-39642020-05-0155Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients co-infected with HIVWim Adriaensen0Bart Cuypers1Carlota F. Cordero2Bewketu Mengasha3Séverine Blesson4Lieselotte Cnops5Paul M. Kaye6Fabiana Alves7Ermias Diro8Johan van Griensven9Unit of Neglected Tropical Diseases, Department of Clinical Sciences, Institute of Tropical Medicine, Nationalestraat 122, 2000 Antwerp, Belgium; Corresponding author.Unit of Molecular Parasitology, Department of Biomedical Sciences, Institute of Tropical Medicine, Nationalestraat 122, 2000 Antwerp, Belgium; Adrem Data Lab, Department of Mathematics and Computer Science, University of Antwerp, Middelheim 1, 2020 Antwerp, BelgiumUnit of Neglected Tropical Diseases, Department of Clinical Sciences, Institute of Tropical Medicine, Nationalestraat 122, 2000 Antwerp, BelgiumLeishmaniasis Research and Treatment Centre, University of Gondar, Gondar, EthiopiaDrugs for Neglected Diseases initiative, 15 Chemin Louis-Dunant, 1202 Geneva, SwitzerlandUnit of Neglected Tropical Diseases, Department of Clinical Sciences, Institute of Tropical Medicine, Nationalestraat 122, 2000 Antwerp, BelgiumYork Biomedical Research Institute, University of York, United KingdomDrugs for Neglected Diseases initiative, 15 Chemin Louis-Dunant, 1202 Geneva, SwitzerlandLeishmaniasis Research and Treatment Centre, University of Gondar, Gondar, EthiopiaUnit of Neglected Tropical Diseases, Department of Clinical Sciences, Institute of Tropical Medicine, Nationalestraat 122, 2000 Antwerp, BelgiumBackground: Visceral leishmaniasis (VL) treatment in HIV patients very often fails and is followed by high relapse and case-fatality rates. Hence, treatment efficacy assessment is imperative but based on invasive organ aspiration for parasite detection. In the search of a less-invasive alternative and because the host immune response is pivotal for treatment outcome in immunocompromised VL patients, we studied changes in the whole blood transcriptional profile of VL-HIV patients during treatment. Methods: Embedded in a clinical trial in Northwest Ethiopia, RNA-Seq was performed on whole blood samples of 28 VL-HIV patients before and after completion of a 29-day treatment regimen of AmBisome or AmBisome/miltefosine. Pathway analyses were combined with a machine learning approach to establish a clinically-useful 4-gene set. Findings: Distinct signatures of differentially expressed genes between D0 and D29 were identified for patients who failed treatment and were successfully treated. Pathway analyses in the latter highlighted a downregulation of genes associated with host cellular activity and immunity, and upregulation of antimicrobial peptide activity in phagolysosomes. No signs of disease remission nor pathway enrichment were observed in treatment failure patients. Next, we identified a 4-gene pre-post signature (PRSS33, IL10, SLFN14, HRH4) that could accurately discriminate treatment outcome at end of treatment (D29), displaying an average area-under-the-ROC-curve of 0.95 (CI: 0.75–1.00). Interpretation: A simple blood-based signature thus holds significant promise to facilitate treatment efficacy monitoring and provide an alternative test-of-cure to guide patient management in VL-HIV patients. Funding: Project funding was provided by the AfricoLeish project, supported by the European Union Seventh Framework Programme (EU FP7).http://www.sciencedirect.com/science/article/pii/S2352396420301237Visceral leishmaniasisHIVRNA signatureTreatment efficacyBlood signature |
| spellingShingle | Wim Adriaensen Bart Cuypers Carlota F. Cordero Bewketu Mengasha Séverine Blesson Lieselotte Cnops Paul M. Kaye Fabiana Alves Ermias Diro Johan van Griensven Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients co-infected with HIV EBioMedicine Visceral leishmaniasis HIV RNA signature Treatment efficacy Blood signature |
| title | Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients co-infected with HIV |
| title_full | Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients co-infected with HIV |
| title_fullStr | Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients co-infected with HIV |
| title_full_unstemmed | Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients co-infected with HIV |
| title_short | Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients co-infected with HIV |
| title_sort | host transcriptomic signature as alternative test of cure in visceral leishmaniasis patients co infected with hiv |
| topic | Visceral leishmaniasis HIV RNA signature Treatment efficacy Blood signature |
| url | http://www.sciencedirect.com/science/article/pii/S2352396420301237 |
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