Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients coinfected with HIV

Abstract 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)

Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients coinfected with HIV

Abstract 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)

Whole Blood Stimulation Assay as a Treatment Outcome Monitoring Tool for VL Patients in Ethiopia: A Pilot Evaluation.

Visceral leishmaniasis (VL) is a lethal disease if left untreated. Current treatments produce variable rates of treatment failure and toxicity without sterile cure, rendering treatment efficacy monitoring essential. To avoid repeated invasive tissue aspirates as well as empirical treatment, there is a need for new tools that allow a less-invasive and early assessment of treatment efficacy in the field. Cross-sectional studies have suggested levels of cytokines/chemokines after whole blood stimulation as good markers of cure, but longitudinal studies are lacking. In this study, we followed 13 active VL cases in an endemic area in Ethiopia by measuring the production of IFN-γ, TNF-α, IP-10, IL-2, IL-10, MCP-1, and MIG before, during, and at the end of treatment. After 24 hours of stimulation of whole blood with soluble Leishmania antigen, we observed an early, robust, and incremental increase of IFN-γ, TNF-α, and IP-10 levels in all patients during treatment. Moreover, based on the IFN-γ levels that showed an average 13-fold increase from the time of diagnosis until the end of treatment, we could almost perfectly discriminate active from cured status. Similar concentrations and patterns were found in stimulation assays with the two main Leishmania species. The levels of IFN-γ, IP-10, or TNF-α also seemed to be inversely associated with the parasite load at baseline. Despite a 1/10 drop in concentrations, similar patterns were observed in IFN-γ and IP-10 levels when dried plasma spots were stored at 4°C for an average of 225 days. All the above evidence suggests a detectable restoration of cell-mediated immunity in VL and its association with parasite clearance. With a potential application in rural settings by means of dried plasma spots, we recommend to further explore the early diagnostic value of such assays for treatment efficacy monitoring in large cohort studies including treatment failure cases.Funding was provided by the Belgian Directorate-General for Development Cooperation under the ITM-DGDC framework agreement FA-IIII. WA is personally supported by a Research Foundation Flanders postdoctoral fellowship. In addition, this work was funded by the Instituto de Salud Carlos III via the project PI18CIII/00029 and via the Red de Enfermedades Tropicales, Subprograma RETICS del Plan Estatal de I+D+I 2013-2016, which is cofunded by FEDER “Una manera de hacer Europa” funds, via projects RD16/0027/0017 and RD16CIII/0003/0002.S

Synthesis and post-functionalization of alternate-linked-meta-para-[2(n). 1(n)]thiacyclophanes

In recent decades, considerable research attention has been devoted to new synthetic procedures for thiacyclophanes. Thiacyclophanes are widely used as host molecules for the molecular recognition of organic compounds as well as metals. Herein, we report the selective and high-yielding synthesis of novel alternate-linked-meta-para-thiacyclophanes. These novel thiacyclophanes are selectively synthesized in high-yielding procedures. Furthermore, post-functionalization of the phenolic moieties was successfully performed. The 3D structure of the alternate-linked-meta-para-[22.12]thiacyclophane was further elucidated via X-ray crystallographic analysis

Serum Levels of Soluble CD40 Ligand and Neopterin in HIV Coinfected Asymptomatic and Symptomatic Visceral Leishmaniasis Patients

Human Immunodeficiency Virus (HIV) co-infection drastically increases the risk of developing overt visceral leishmaniasis (VL). The asymptomatic Leishmania infection window constitutes an opportunity to identify those HIV patients at highest risk by defining early markers associated with disease susceptibility or resistance. As intracellular parasite killing is essential, we investigated whether serum markers of macrophage activation were notably affected in HIV patients with an asymptomatic Leishmania infection or overt visceral leishmaniasis disease. Serum levels of soluble CD40 ligand and neopterin were assessed in 24 active VL-HIV patients, 35 HIV patients with asymptomatic Leishmania infection and 35 HIV endemic controls. All patients were recruited in L. donovani endemic regions of North-West Ethiopia. The serum levels of sCD40L and neopterin significantly decreased and increased in HIV patients with active VL compared to HIV patients with asymptomatic Leishmania infection, respectively. No statistically significant differences could be detected in neopterin and sCD40L levels between Leishmania asymptomatically infected HIV patients and endemic HIV control patients. However, an inverse trend, between Leishmania antibody positivity or VL development and neopterin levels could be seen. The CD4+ T-cell count was inversely correlated with serum neopterin levels, but not with sCD40L levels. Our results in HIV coinfected patients, correspond with the postulated protective role of sCD40L in VL and underline the importance of the CD40-CD40L pathway in resistance against the parasite. Neopterin levels suggest an increased macrophage activation upon infection and could have a value in clinical algorithms to, although non-specifically, improve prediction of VL development in HIV patients with asymptomatic Leishmania infection

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Klinische impact van immunosenescentie en de complexe interactie met Cytomegalievirus

08 - Chapter1: Introduction Clinical implications of the hallmarks of immunosenescence Part 1: prognostic value of 'inflammaging' markers for adverse outcomes 26 - Chapter 2: Identification of global functional impairment in the oldest old 45 - Chapter 3: Prediction of short-term global functional decline in the oldest old 66 - Chapter 4: IL-6 as a first-rated serum inflammatory marker to predict mortality and hospitalization in the oldest old Part 2: Clinical features of T-cell senescence 96 - Chapter 5: Identification and evolution of CD4:8 ratio phenotypes and the association with impaired physical/mental functioning. 123 - Chapter 6: Survival and CD4:8 ratios in the oldest old: a protective role of CMV infection? 143 - Chapter 7: T-cell response, CMV-specific immunosurveillance and inflammation in relation to CD4:8 ratio subsets Consequence of immunosenescence on influenza vaccination response 164 - Chapter 8: The INCIVAR study: Influence of CMV on influenza vaccination response in older persons. Discussion & Conclusion 180 - Chapter 9: General Discussion and future challenges Appendices 206 - Curriculum Vitae and publication list 213 - English Summary 215 - French Summary 218 - Dutch Summary 221 - Acknowledgementsnrpages: 224status: publishe