Circulating Biomarkers of Immune Activation, Oxidative Stress and Inflammation Characterize Severe Canine Visceral Leishmaniasis.

Manuela S Solcà,Patrícia Sampaio Tavares Veras,Patrícia Torres Bozza,Melissa Moura Costa Abbehusen,Claudia Ida Brodskyn,Ricardo Khouri,Valeria Matos Borges,Clarissa R Teixeira,Jesus G Valenzuela,Shaden Kamhawi,Deborah Bittencourt Mothé Fraga,Bruno B Andrade

doi:10.1038/srep32619

Abstract

Clinical manifestations in canine visceral leishmaniasis (CVL) have not been clearly associated with immunological status or disease progression. We simultaneously assessed biomarkers of inflammation, immune activation, oxidative stress, and anti-sand fly saliva IgG concentrations in dog sera with different clinical manifestations to characterize a biosignature associated with CVL severity. In a cross-sectional exploratory study, a random population of 70 dogs from an endemic area in Brazil was classified according to CVL clinical severity and parasitological evaluation. A panel of biomarkers and anti–sand fly saliva IgG were measured in canine sera. Assessment of protein expression of profile biomarkers identified a distinct biosignature that could cluster separately animal groups with different clinical scores. Increasing severity scores were associated with a gradual decrease of LTB4 and PGE2, and a gradual increase in CXCL1 and CCL2. Discriminant analyses revealed that combined assessment of LTB4, PGE2 and CXCL1 was able to distinguish dogs with different clinical scores. Dogs with the highest clinical score values also exhibited high parasite loads and higher concentrations of anti-saliva antibodies. Our findings suggest CVL clinical severity is tightly associated with a distinct inflammatory profile hallmarked by a differential expression of circulating eicosanoids and chemokines.

Highlights

Clinical signs of canine VL (CVL) are non-specific, there is a widespread range of clinical manifestations varying from visceral to cutaneous presentation of the disease[5,6], on the other hand some animals do not display any clinical signs during the course of infection[7]
We evaluated different parameters associated to canine visceral leishmaniasis (CVL) severity, considering distinct groups of naturally infected dogs from a highly endemic area, in Camaçari, Bahia, Brazil
We have demonstrated that Receiver-Operator Characteristic (ROC) curve analyses using combined biomarkers are able to distinguish dogs exhibiting different degrees of CVL severity

Summary

Introduction

Clinical signs of canine VL (CVL) are non-specific, there is a widespread range of clinical manifestations varying from visceral to cutaneous presentation of the disease[5,6], on the other hand some animals do not display any clinical signs during the course of infection[7]. Experiments in vitro with human macrophages demonstrated that SOD increased the parasite burden in these cells due to the inhibition of reactive oxygen species (ROS)[10]. Knowledge of their role in CVL will further our understanding of the complex pathogenicity of the disease. Integrated studies of multiple biomarkers are needed to better understand their role in the outcome of L. infantum infection In this cross sectional exploratory study, we identified a distinct biosignature in dogs with different clinical scores where an increase in the severity of disease was characterized by a continuous decrease in levels of LTB4 and PGE2 and an increase in levels of CXCL1 and CCL2. This study allows the evaluation of multiple biomarkers in dogs, which could be important for CVL surveillance in endemic areas

Methods

Results

Conclusion