Abortive T Follicular Helper Development Is Associated with a Defective Humoral Response in Leishmania infantum-Infected Macaques

Rodrigues, Vasco; Laforge, Mireille; Campillo-Gimenez, Laure; Soundaramourty, Calaiselvy; Ana, Correia-de-Oliveira; Dinis-Oliveira, Ricardo Jorge; Ouaissi, Ali; Cordeiro-da-Silva, Anabela; Silvestre, Ricardo; Estaquier, Jérǒme

doi:10.1371/journal.ppat.1004096

Cited by 40 publications

(53 citation statements)

References 67 publications

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“…Indeed, follicular T cell-mediated regulation of the B lymphocyte compartment may account for beneficial or pathogenic responses during distinct states of infection with L . infantum [68], a hypothesis that is supported by significant differences in structural and functional features of immunoglobulin G isolated from VL patients and asymptomatic individuals [8]. …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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“…It is likely that other cells contribute to IL-10-mediated immune regulation during progressive human VL. Follicular dendritic cells (DCs) (45), natural killer cells (NK) (46), or T follicular helper cells (45, 47) were shown to be immune regulators of VL. IgD hi regulatory B cells may be an early inducer of additional regulatory cell populations.…”

Section: Discussionmentioning

confidence: 99%

Regulatory IgDhi B Cells Suppress T Cell Function via IL-10 and PD-L1 during Progressive Visceral Leishmaniasis

Schaut

Lamb

Toepp

et al. 2016

The Journal of Immunology

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During visceral leishmaniasis (VL), T helper 1 (Th1)-based inflammation is induced to control intracellular parasites. Inflammation-based pathology has been shown to be dampened by interleukin 10 and eventual Programmed Death1 (PD1)-mediated T cell exhaustion. Cell type(s) responsible for the initiation of T cell-produced IL-10 during VL are unknown. CD19+, CD5−, CD1d−, IgDhi regulatory B cells from healthy controls produced IL-10 in absence of infection or stimulation in contrast to IgDlo/neg B cells. IgDhi B cells may have a de novo vs. induced regulatory program. IgDhi B cells increased three-fold in population size as VL progressed. B cells from VL dogs were necessary and sufficient to suppress T helper 1 (Th1) cell effector function. IgDhi B cells induced T cell and IgDlo B cell IL-10 production. Blockage of B cell-specific PD-L1 restored Th1 responses. IgDhi regulatory B cells represent a novel regulatory B cell which may precipitate T cell exhaustion during VL.

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“…DNA was extracted using the phenolchloroform-isoamyl alcohol method. Parasite burden was assessed, using a TaqMan-based qPCR assay for detection and quantitation of L. donovani kinetoplastid DNA [24].…”

Section: Experimental Leishmania Infectionmentioning

confidence: 99%

Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis

et al. 2020

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BackgroundThe disturbance of host metabolic pathways by Leishmania parasites has crucial consequences for the activation status of immune cells and the outcome of infection. Glutamine has been described as an immunomodulatory amino acid, yet its role during Leishmania infection is still unknown.Visceral leishmaniasis is a life threatening neglected tropical disease affecting around 500,000 and killing 50,000 individuals a year. Despite its obligatory dependence on host cell metabolism and the lack of effective, non-toxic, orally bioavailable anti-leishmanial drugs, Leishmania-perturbed host cell metabolomes and its relation to anti-leishmanial chemotherapy remains unexplored. Transcriptomic analysis performed on L. donovaniinfected macrophages identified patterns of gene expression associated with glutamine metabolism. In vitro and in vivo pharmacological inhibition of glutaminase (GLS), which catalyzes the first reaction in the primary pathway for the catabolism of glutamine, significantly increased the susceptibility to infection demonstrating the role of glutamine metabolism to L. donovani infection. More importantly, we demonstrated that glutamine supplementation during miltefosine treatment potentiates L. donovani clearance through the development of a more effective anti-Leishmania innate and adaptive immune response. Overall, our work demonstrated that glutamine-miltefosine synergy is a novel combined host-and pathogen-directed treatment for combating visceral leishmaniasis.

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Abortive T Follicular Helper Development Is Associated with a Defective Humoral Response in Leishmania infantum-Infected Macaques

Cited by 40 publications

References 67 publications

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

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

Regulatory IgDhi B Cells Suppress T Cell Function via IL-10 and PD-L1 during Progressive Visceral Leishmaniasis

Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis

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