Expression profiling of Sudanese visceral leishmaniasis patients pre‐ and post‐treatment with sodium stibogluconate

Salih, M. A. M.; Fakiola, Michaela; Lyons, Paul; Younis, Brima M.; Musa, Ahmed; Elhassan, Ahmed M.; Anderson, Denise; Syn, Genevieve; Ibrahim, Muntaser E.; Blackwell, Jenefer M.; Mohamed, Hiba S.

doi:10.1111/pim.12431

Cited by 17 publications

(15 citation statements)

References 36 publications

(40 reference statements)

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“…VL is a systemic disease and understanding disease progression and the response to chemotherapy is dependent upon a more complete understanding of how target tissues respond over time. Although in recent years the evaluation of immune and other changes associated with human disease progression and drug response has adopted a more systematic approach employing -omics technologies, the invasive nature of tissue sampling has largely restricted this approach to whole blood 20,21, 44,45 . Here, we used the BALB/c model of VL to directly explore the breadth of transcriptomic changes associated with AmBisome ® treatment.…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific transcriptomic changes associated with AmBisome® treatment of BALB/c mice with experimental visceral leishmaniasis

Forrester¹,

Siefert²,

Ashwin³

et al. 2019

Wellcome Open Res

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Background: Liposomal amphotericin B (AmBisome®) as a treatment modality for visceral leishmaniasis (VL) has had significant impact on patient care in some but not all regions where VL is endemic. As the mode of action of AmBisome® in vivo is poorly understood, we compared the tissue-specific transcriptome in drug-treated vs untreated mice with experimental VL. Methods: BALB/c mice infected with L. donovani were treated with 8mg/kg AmBisome®, resulting in parasite elimination from liver and spleen over a 7-day period. At day 1 and day 7 post treatment (Rx+1 and Rx+7), transcriptomic profiling was performed on spleen and liver tissue from treated and untreated mice and uninfected mice. BALB/c mice infected with M. bovis BCG (an organism resistant to amphotericin B) were analysed to distinguish between direct effects of AmBisome® and those secondary to parasite death. Results: AmBisome® treatment lead to rapid parasitological clearance. At Rx+1, spleen and liver displayed only 46 and 88 differentially expressed (DE) genes (P<0.05; 2-fold change) respectively. In liver, significant enrichment was seen for pathways associated with TNF, fatty acids and sterol biosynthesis. At Rx+7, the number of DE genes was increased (spleen, 113; liver 400). In spleen, these included many immune related genes known to be involved in anti-leishmanial immunity. In liver, changes in transcriptome were largely accounted for by loss of granulomas. PCA analysis indicated that treatment only partially restored homeostasis. Analysis of BCG-infected mice treated with AmBisome® revealed a pattern of immune modulation mainly targeting macrophage function. Conclusions: Our data indicate that the tissue response to AmBisome® treatment varies between target organs and that full restoration of homeostasis is not achieved at parasitological cure. The pathways required to restore homeostasis deserve fuller attention, to understand mechanisms associated with treatment failure and relapse and to promote more rapid restoration of immune competence.

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Section: Discussionmentioning

confidence: 99%

Tissue-specific transcriptomic changes associated with AmBisome® treatment of BALB/c mice with experimental visceral leishmaniasis

Forrester¹,

Siefert²,

Ashwin³

et al. 2019

Wellcome Open Res

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“…The reduction in phagocytosis and FCγRIII expression after treatment could be a protective monocyte/macrophage mechanism. Salih state that Fcγ‐mediated phagocytosis could play a role in tipping the balance from a Th1 to a Th2 response. Moreover, we demonstrated that Glucantime ® treatment changes the monocyte functional profile to a more effective proinflammatory.…”

Section: Discussionmentioning

confidence: 99%

Fcγ‐RI, Fcγ‐RII and IL‐10 as predictive biomarkers for post‐therapeutic cicatrization time in monocytes from cutaneous leishmaniasis patients

Rodrigues-Alves

Melo-Júnior

Coelho-dos-Reis³

et al. 2018

Parasite Immunology

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Cutaneous leishmaniasis (CL) treatment is based on therapy with Glucantime , yet, there are few laboratory methods to monitor its success. In this study, ex vivo and in vitro evaluations of peripheral blood monocytes were performed in a longitudinal study to characterize the impact of Glucantime on overall phenotypic/functional features of these cells from CL patients to identify predictive biomarkers for post-therapeutic monitoring by flow cytometry. The ex vivo evaluation from CL patients demonstrated a modulatory profile before treatment, with a decrease in TLR-2, FcγRII, HLA-DR, CD86, IFN-γR, TNF, IL-12, NO, and an increase in FcγRIII and IL-10R. Conversely, treatment changes some of these biomarker expressions by decreasing FcγRIII and IL-10R and increasing IFN-γR, IL-12 and NO. Moreover, an in vitro analysis of these patients showed a reduced phagocytic capacity of Leishmania braziliensis and higher levels of IL-10 and TGF-β modulating functional profile. Regardless of the compromised L. braziliensis phagocytic capacity, treatment re-established the production of IL-12, IL-10, TGF-β and NO at the basal level. Notably, monocytes from patients with early cicatrization showed enhanced FcγRI and FcγRII expressions and reduced IL-10, which was further corroborated by a baseline fold change analysis. Finally, the logistic regression model emphasized the performance of FcγRI, FcγRII and IL-10 as robust predictive biomarkers for post-therapeutic cicatrization during cutaneous leishmaniasis.

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“…In human disease, this has largely focused on cutaneous leishmaniasis 35 – 37 . A single study has reported on transcriptional changes in the draining lymph node of Sudanese patients with VL before and after treatment with sodium stibogluconate, identifying a potential role for nuclear factor of activated T cells (NFAT)-regulated immune responses in treatment response 38 . One study has examined whole blood transcriptional responses in healthy controls versus asymptomatic and symptomatic VL patients in Brazil 39 .…”

Section: Introductionmentioning

confidence: 99%

Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis

Ashwin¹,

Seifert²,

Forrester³

et al. 2019

Wellcome Open Res

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Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen interaction, disease pathogenesis, and parasite transmission. In addition, they have an essential role in the identification and pre-clinical evaluation of new drugs and vaccines. However, our understanding of these models remains fragmentary. Although the immune response to Leishmania donovani infection in mice has been extensively characterized, transcriptomic analysis capturing the tissue-specific evolution of disease has yet to be reported. Methods: We provide an analysis of the transcriptome of spleen, liver and peripheral blood of BALB/c mice infected with L. donovani. Where possible, we compare our data in murine experimental visceral leishmaniasis with transcriptomic data in the public domain obtained from the study of L. donovani-infected hamsters and patients with human visceral leishmaniasis. Digitised whole slide images showing the histopathology in spleen and liver are made available via a dedicated website, www.leishpathnet.org. Results: Our analysis confirms marked tissue-specific alterations in the transcriptome of infected mice over time and identifies previously unrecognized parallels and differences between murine, hamster and human responses to infection. We show commonality of interferon-regulated genes whilst confirming a greater activation of type 2 immune pathways in infected hamsters compared to mice. Cytokine genes and genes encoding immune checkpoints were markedly tissue specific and dynamic in their expression, and pathways focused on non-immune cells reflected tissue specific immunopathology. Our data also addresses the value of measuring peripheral blood transcriptomics as a potential window into underlying systemic disease. Conclusions: Our transcriptomic data, coupled with histopathologic analysis of the tissue response, provide an additional resource to underpin future mechanistic studies and to guide clinical research.

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Expression profiling of Sudanese visceral leishmaniasis patients pre‐ and post‐treatment with sodium stibogluconate

Cited by 17 publications

References 36 publications

Tissue-specific transcriptomic changes associated with AmBisome® treatment of BALB/c mice with experimental visceral leishmaniasis

Tissue-specific transcriptomic changes associated with AmBisome® treatment of BALB/c mice with experimental visceral leishmaniasis

Fcγ‐RI, Fcγ‐RII and IL‐10 as predictive biomarkers for post‐therapeutic cicatrization time in monocytes from cutaneous leishmaniasis patients

Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis

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