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Anti-parasite therapy drives changes in human visceral leishmaniasis-associated inflammatory balance.

ABSTRACT: Visceral leishmaniasis (VL) remains a major public health problem worldwide. Cytokine balance is thought to play a critical role in the development of this disease. Here, we perform a prospective exploratory study addressing whether simultaneous assessment of circulating levels of different lipid mediators and cytokines could highlight specific pathways involved with VL pathogenesis. VL patients displayed substantial increases in serum levels of Prostaglandin F₂? (PGF₂?), Leukotriene B₄ (LTB₄), Resolvin D1 (RvD1), IL-1?, IL-6, IL-8, IL-10, IL-12p70 and TNF-? compared with uninfected endemic control group, while exhibiting decreased levels of TGF-?1. Hierarchical cluster analysis of the prospective changes in the expression level of theses parameters upon anti-Leishmania treatment initiation revealed that the inflammatory profile observed in active disease gradually changed over time and was generally reversed at day 30 of therapy. Furthermore, not only the individual concentrations of most of the inflammatory biomarkers changed upon treatment, but the correlations between those and several biochemical parameters used to characterize VL disease activity were also modified over time. These results demonstrate that an inflammatory imbalance hallmarks active VL disease and open perspective for manipulation of these pathways in future studies examining a potential host-directed therapy against VL.

SUBMITTER: Araujo-Santos T

PROVIDER: S-EPMC5489532 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Anti-parasite therapy drives changes in human visceral leishmaniasis-associated inflammatory balance.

Araújo-Santos Théo T Andrade Bruno B BB Gil-Santana Leonardo L Luz Nívea F NF Dos Santos Priscila L PL de Oliveira Fabrícia A FA Almeida Meirielly Lima ML de Santana Campos Roseane Nunes RN Bozza Patrícia T PT Almeida Roque P RP Borges Valeria M VM

Scientific reports 20170628 1

Visceral leishmaniasis (VL) remains a major public health problem worldwide. Cytokine balance is thought to play a critical role in the development of this disease. Here, we perform a prospective exploratory study addressing whether simultaneous assessment of circulating levels of different lipid mediators and cytokines could highlight specific pathways involved with VL pathogenesis. VL patients displayed substantial increases in serum levels of Prostaglandin F<sub>2</sub>α (PGF<sub>2</sub>α), L ...[more]

PMID: 28659627

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Project description:Visceral leishmaniasis (VL) is a potentially fatal disease caused mainly by Leishmania infantum in South America and Leishmania donovani in Asia and Africa. Disease outcomes have been associated with patient genotype, nutrition, age, sex, comorbidities, and coinfections. In this study, we examine the effects of parasite genetic variation on VL disease severity in Brazil. We collected and sequenced the genomes of 109 L. infantum isolates from patients in northeastern Brazil and retrieved matching patient clinical data from medical records, including mortality, sex, HIV coinfection, and laboratory data (creatinine, hemoglobin, and leukocyte and platelet counts). We identified genetic differences between parasite isolates, including single nucleotide polymorphisms (SNPs), small insertions/deletions (indels), and variations in genic, intergenic, and chromosome copy numbers (copy number variants [CNVs]). To describe associations between the parasite genotypes and clinical outcomes, we applied quantitative genetics methods of heritability and genome-wide association studies (GWAS), treating clinical outcomes as traits that may be influenced by parasite genotype. Multiple aspects of the genetic analysis indicate that parasite genotype affects clinical outcomes. We estimate that parasite genotype explains 83% chance of mortality (narrow-sense heritability [h2] = 0.83 ± 0.17) and has a significant relationship with patient sex (h2 = 0.60 ± 0.27). Impacts of parasite genotype on other clinical traits are lower (h2 ≤ 0.34). GWAS analysis identified multiple parasite genetic loci that were significantly associated with clinical outcomes; 17 CNVs were significantly associated with mortality, two with creatinine, and one with bacterial coinfection, jaundice, and HIV coinfection, and two SNPs/indels and six CNVs were associated with age, jaundice, HIV and bacterial coinfections, creatinine, and/or bleeding sites. Parasite genotype is an important factor in VL disease severity in Brazil. Our analysis indicates that specific genetic differences between parasites act as virulence factors, enhancing risks of severe disease and mortality. More detailed understanding of these virulence factors could be exploited for novel therapies. IMPORTANCE Multiple factors contribute to the risk of mortality from visceral leishmaniasis (VL), including, patient genotype, comorbidities, and nutrition. Many of these factors are influenced by socioeconomic biases. Our work suggests that the virulence of the infecting parasite is an important risk factor for mortality. We pinpoint some specific genomic markers that are associated with mortality, which can lead to a greater understanding of the molecular mechanisms that cause severe VL disease, to the identification of genetic markers for virulent parasites, and to the development of drug and vaccine therapies.

Project description:UnlabelledVisceral leishmaniasis (VL) has a high fatality rate if not treated; nevertheless, the majority of human infections with the causative agent, Leishmania infantum chagasi, are asymptomatic. Although VL patients often present with increased levels of serum immunoglobulins, the contribution of antibodies to resistance or progression to disease remains unknown. Effector and regulatory functions of antibodies rely on their interactions with type I and II Fc receptors, and these interactions are tuned by the patterns of antibody Fc N-glycosylation. In view of these facts, we applied a robust method of IgG Fc N-glycopeptide profiling of serum samples from 187 patients with VL, 177 asymptomatic individuals, 116 endemic controls (individuals residing in areas where VL is endemic) and 43 nonendemic controls (individuals living in an area where VL is not endemic). We show that, in comparison to the overall IgG Fc N-glycan profiles of asymptomatic or uninfected healthy individuals, those of patients with VL are profoundly altered. These changes correlate with levels of serum cytokines and the inflammation marker C-reactive protein. We also fitted univariate and multivariate ordinal logistic regression models to demonstrate the ability of IgG Fc N-glycosylation features and immunity regulators present in serum to predict disease severity in VL patients. Importantly, we show that Fc N-glycosylation profiles change after treatment of VL. This study introduces important concepts contributing to the understanding of antibody responses in infections with Leishmania parasites and provides new insights into the pathology of human VL.ImportanceImmunoglobulins (Ig) have been shown to present pro- and anti-inflammatory functions according to the profile of carbohydrates attached to their Fc region. Glycosylation features of serum IgG have been examined in relation to several autoimmune and infectious diseases and provide a mechanistic basis for the protective or pathogenic role of antibodies. Leishmania infantum chagasi is the causative agent of visceral leishmaniasis (VL) in South America, and we show that VL patients produce IgG with patterns of Fc glycans similar to those found in other inflammatory conditions. Specific Fc N-glycosylation features and levels of serum cytokines and C-reactive protein are significantly associated with the development of severe clinical symptoms and, notably, Fc glycosylation changes after treatment. The modifications detected in the N-glycosylation features of IgG Fc from VL patients raise new perspectives on the effector or regulatory role of antibodies in immune responses elicited by infection with Leishmania parasites.

Project description:Herein, we evaluated the treatment strategy employing a therapeutic heterologous vaccine composed of antigens of Leishmania braziliensis associated with MPL adjuvant (LBMPL vaccine) for visceral leishmaniasis (VL) in symptomatic dogs naturally infected by Leishmania infantum. Sixteen dogs received immunotherapy with MPL adjuvant (n = 6) or with a vaccine composed of antigens of L. braziliensis associated with MPL (LBMPL vaccine therapy, n = 10). Dogs were submitted to an immunotherapeutic scheme consisting of 3 series composed of 10 subcutaneous doses with 10-day interval between each series. The animals were evaluated before (T0) and 90 days after treatment (T90) for their biochemical/hematological, immunological, clinical, and parasitological variables. Our major results showed that the vaccine therapy with LBMPL was able to restore and normalize main biochemical (urea, AST, ALP, and bilirubin) and hematological (erythrocytes, hemoglobin, hematocrit, and platelets) parameters. In addition, in an ex vivo analysis using flow cytometry, dogs treated with LBMPL vaccine showed increased CD3+ T lymphocytes and their subpopulations (TCD4+ and TCD8+), reduction of CD21+ B lymphocytes, increased NK cells (CD5-CD16+) and CD14+ monocytes. Under in vitro conditions, the animals developed a strong antigen-specific lymphoproliferation mainly by TCD4+ and TCD8+ cells; increasing in both TCD4+IFN-γ+ and TCD8+IFN-γ+ as well as reduction of TCD4+IL-4+ and TCD8+IL-4+ lymphocytes with an increased production of TNF-α and reduced levels of IL-10. Concerning the clinical signs of canine visceral leishmaniasis, the animals showed an important reduction in the number and intensity of the disease signs; increase body weight as well as reduction of splenomegaly. In addition, the LBMPL immunotherapy also promoted a reduction in parasite burden assessed by real-time PCR. In the bone marrow, we observed seven times less parasites in LBMPL animals compared with MPL group. The skin tissue showed a reduction in parasite burden in LBMPL dogs 127.5 times higher than MPL. As expected, with skin parasite reduction promoted by immunotherapy, we observed a blocking transmission to sand flies in LBMPL dogs with only three positive dogs after xenodiagnosis. The results obtained in this study highlighted the strong potential for the use of this heterologous vaccine therapy as an important strategy for VL treatment.

Project description:Chronic disease caused by infections, cancer or autoimmunity can result in profound immune suppression. Immunoregulatory networks are established to prevent tissue damage caused by inflammation. Although these immune checkpoints preserve tissue function, they allow pathogens and tumors to persist, and even expand. Immune checkpoint blockade has recently been successfully employed to treat cancer. This strategy modulates immunoregulatory mechanisms to allow host immune cells to kill or control tumors. However, the utility of this approach for controlling established infections has not been extensively investigated. Here, we examined the potential of modulating glucocorticoid-induced TNF receptor-related protein (GITR) on T cells to improve anti-parasitic immunity in blood and spleen tissue from visceral leishmaniasis (VL) patients infected with Leishmania donovani. We found little effect on parasite growth or parasite-specific IFN? production. However, this treatment reversed the improved anti-parasitic immunity achieved by IL-10 signaling blockade. Further investigations using an experimental VL model caused by infection of C57BL/6 mice with L. donovani revealed that this negative effect was prominent in the liver, dependent on parasite burden and associated with an accumulation of Th1 cells expressing high levels of KLRG-1. Nevertheless, combined anti-IL-10 and anti-GITR mAb treatment could improve anti-parasitic immunity when used with sub-optimal doses of anti-parasitic drug. However, additional studies with VL patient samples indicated that targeting GITR had no overall benefit over IL-10 signaling blockade alone at improving anti-parasitic immune responses, even with drug treatment cover. These findings identify several important factors that influence the effectiveness of immune modulation, including parasite burden, target tissue and the use of anti-parasitic drug. Critically, these results also highlight potential negative effects of combining different immune modulation strategies.

Dataset Information

Anti-parasite therapy drives changes in human visceral leishmaniasis-associated inflammatory balance.

Publications

Anti-parasite therapy drives changes in human visceral leishmaniasis-associated inflammatory balance.

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