Blood Transcriptional Profiling Reveals Immunological Signatures of Distinct States of Infection of Humans with Leishmania infantum

Abstract

Visceral leishmaniasis (VL) can be lethal if untreated; however, the majority of human infections with the etiological agents are asymptomatic. Using Illumina Bead Chip microarray technology, we investigated the patterns of gene expression in blood of active VL patients, asymptomatic infected individuals, patients under remission of VL and controls. Computational analyses based on differential gene expression, gene set enrichment, weighted gene co-expression networks and cell deconvolution generated data demonstrating discriminative transcriptional signatures. VL patients exhibited transcriptional profiles associated with pathways and gene modules reflecting activation of T lymphocytes via MHC class I and type I interferon signaling, as well as an overall down regulation of pathways and gene modules related to myeloid cells, mainly due to differences in the relative proportions of monocytes and neutrophils. Patients under remission of VL presented heterogeneous transcriptional profiles associated with activation of T lymphocytes via MHC class I, type I interferon signaling and cell cycle and, importantly, transcriptional activity correlated with activation of Notch signaling pathway and gene modules that reflected increased proportions of B cells after treatment of disease. Asymptomatic and uninfected individuals presented similar gene expression profiles, nevertheless, asymptomatic individuals exhibited particularities which suggest an efficient regulation of lymphocyte activation and a strong association with a type I interferon response. Of note, we validated a set of target genes by RT-qPCR and demonstrate the robustness of expression data acquired by microarray analysis. In conclusion, this study profiles the immune response during distinct states of infection of humans with Leishmania infantum with a novel strategy that indicates the molecular pathways that contribute to the progression of the disease, while also providing insights into transcriptional activity that can drive protective mechanisms.

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

“…96% of these genes have been reported as interferon inducible, and clearly indicate the dominant nature of interferon signalling during murine VL. The clinical value of this signature is however questionable, given the lack of similarity between whole blood transcriptomic responses observed in our study and that of humans with VL in Brazil 39 . In a similar study in acute melioidosis, 26.9% of genes were similarly regulated in murine and human infection 21 .…”

“…By GSEA analysis blood was, not surprisingly, more similar to spleen than liver ( Figure 8). We next took advantage of a recently published whole blood transcriptomic analysis 39 to compare responses across murine EVL and human VL. Using day 36-infected mice as a comparator, our results suggest a high divergence in whole blood response between EVL and human VL ( Figure 11).…”

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

“…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.…”

“…Although not directly analysing the tissue response, others have examined the response to treatment at the transcriptional level. 44 . Despite limitations in study design, these data suggest that blood transcriptional profiles of patients in regression are distinct from both active cases and healthy controls.…”

Marcadores inflamatórios em pacientes com neoplasia gástrica: níveis sanguíneos e expressão gênica

“…A migração celular, que se dá pela circulação sanguínea entre os órgãos linfóides centrais e periféricos, influencia na eficácia da resposta imune nas infecções e na inflamação (Chaussabel et al, 2015). A análise de células periféricas circulantes proporciona uma plataforma para estudar o sistema imunológico humano por meio de métodos moleculares de escala genômica, utilizados para investigar perfis transcricionais e imunológicos (Gardinassi et al, 2016).…”