Evaluating Treatment Efficacy in Canine Visceral Leishmaniasis: The Role of Individual Factors and Co-Infections in Disease Control and Therapeutic Response. - PROJECT SUMMARY Visceral leishmaniasis (VL) is a zoonotic parasitic disease, and in the Americas is caused by the protozoan Leishmania infantum and transmitted by phlebotomine sand flies. The parasite infects several species of mammals, with the domestic dog serving as the main reservoir host. Canine VL (CVL) cases are associated with an increased risk of human cases, emphasizing the importance of effective diagnosis and control strategies. Brazil accounts for more than 90% of VL cases in the Americas and less than 10 years ago adopted miltefosine- based treatment for L. infantum-infected dogs, aiming to reduce transmission. However, despite treatment efforts, therapeutic failures persist, necessitating a deeper understanding of factors influencing treatment outcomes. Our preliminary data on L. infantum naturally infected dogs treated with miltefosine combined with allopurinol and domperidone identified that the majority of dogs respond to the treatment, with a significant improvement in clinical signs and a decrease in parasite load, both persisting for months after treatment. However, for some dogs the parasite load increased to levels higher than before treatment, indicating a possible therapeutic failure. These data suggest that there are two possible factors involved in this response i) the parasite's inherent resistance to the drug, and ii) the existence of an individual response in the dogs, certainly influenced by various factors, which may lead to successful treatment and control of the L. infantum infection. In experiments aimed at addressing the first hypothesis, L. infantum strains were isolated from dogs with therapeutic failure and no resistance to miltefosine was found. Given these findings, we aim to identify potential biomarkers of treatment response in dogs with VL, hypothesizing that variations in immune modulation and gene expression, alongside co-infections with other blood-borne pathogens, play pivotal roles. Through comprehensive analysis, we aim to achieve two specific aims (1) identifying differential markers of response to treatment with miltefosine combined with allopurinol and domperidone in dogs with VL; and (2) diagnosing co- infections that may influence the response to L. infantum infection and treatment. We will reveal important information for the prognosis and development of more effective therapeutic strategies for CVL, including the concomitant need for rapid diagnosis and treatment of co-infections. These findings have the potential to significantly improve the treatment and control of CVL, positively impacting human and animal health in endemic regions.
