Malnutrition exacerbates pathogenesis of Lutzomyia longipalpis sand fly-transmitted Leishmania donovani

Visceral leishmaniasis (VL) is transmitted by Leishmania-infected sand fly bites and malnutrition is a known risk factor in human VL. Models using sand fly transmission or malnutrition promote parasite dissemination. By investigating features of L. donovani-Lutzomyia longipalpis transmission to malnourished mice, we show that a comparable IL1-β-driven acute inflammation is maintained in malnourished (MN-SF) and well-nourished (WN-SF) sand fly-infected mice. However, parasite dissemination was more pronounced in MN-SF that had a significantly higher acute (P ≤ 0.001) and chronic (P ≤ 0.0001) splenic parasite burden compared to WN-SF. Compared to WN-SF, MN-SF exhibited chronic clinical symptoms (P ≤ 0.0001), neutrophilia (P ≤ 0.001), lymphocytopenia (P ≤ 0.0001), increased heme oxygenase-1 (P ≤ 0.001) and IL17-A (P ≤ 0.0001) levels, dysregulation of liver enzymes, lymph node barrier dysfunction, and augmented dysbiosis, all associated with enhanced VL severity. Combining vector-transmission and malnutrition provides an improved model to study VL pathogenesis and host defense.