The Inflammatory Effects of Dietary Lipids Regulate Growth of Parasites during Visceral Leishmaniasis

Abstract

Leishmaniasis is a spectrum of diseases caused by Leishmania species protozoa that is most common in warm climates, coinciding with impoverished regions. Visceral leishmaniasis is a potentially fatal disease in which parasites infect reticuloendothelial organs and cause progressive wasting and immunocompromise. ABSTRACT Visceral leishmaniasis is a potentially fatal disease caused by the protozoon Leishmania donovani or L. infantum (Li). Although previous studies revealed that high lipid intake reduces parasite burdens in Leishmania donovani-infected mice, the specific contributions of dietary lipids to Li-associated pathogenesis are not known. To address this, we evaluated parasite growth, liver pathology, and transcriptomic signatures in Li-infected BALB/c mice fed either a control, high-fat, high-cholesterol, or high-fat–high-cholesterol diet. Using quantitative PCR (qPCR), we observed significantly reduced liver parasite burdens in mice fed the high-fat–high-cholesterol diet compared to mice fed the control diet. In contrast to the liver, parasite expansion occurred earlier in the spleens of mice fed the experimental diets. Histological examination revealed an intense inflammatory cell infiltrate in livers predominantly composed of neutrophils caused by the high-fat–high-cholesterol diet specifically. After 8\u2009weeks of infection (12\u2009weeks of diet), Illumina microarrays revealed significantly increased expression of transcripts belonging to immune- and angiogenesis-related pathways in livers of both uninfected and Li-infected mice fed the high-fat–high-cholesterol diet. These data suggest that increased fat and cholesterol intake prior to Li infection leads to a hepatic inflammatory environment and thus reduces the parasite burden in the liver. Defining inflammatory signatures as well as pathology in the liver may reveal opportunities to modify the therapeutic approach to Li infection. IMPORTANCE Leishmaniasis is a spectrum of diseases caused by Leishmania species protozoa that is most common in warm climates, coinciding with impoverished regions. Visceral leishmaniasis is a potentially fatal disease in which parasites infect reticuloendothelial organs and cause progressive wasting and immunocompromise. The distribution and demographics of visceral leishmaniasis have changed over recent years, coinciding with modernizing societies and the increased availability of Western diets rich in lipid content. We report here that increased dietary fat and cholesterol intake affected disease pathogenesis by increasing inflammation and reducing localized parasite burdens in the liver. These diet-induced changes in disease pathogenesis might explain in part the changing epidemiology of visceral leishmaniasis. A relationship between diet and inflammatory responses may occur in leishmaniasis and other microbial or immune-mediated diseases, possibly revealing opportunities to modify the therapeutic approach to microbial infections.