The Malnutrition-Related Increase in Early Visceralization of Leishmania donovani Is Associated with a Reduced Number of Lymph Node Phagocytes and Altered Conduit System Flow

Abstract

In a murine model of moderate childhood malnutrition we found that polynutrient deficiency led to a 4–5-fold increase in early visceralization of L. donovani (3 days post-infection) following cutaneous infection and a 16-fold decrease in lymph node barrier function (p<0.04 for all). To begin to understand the mechanistic basis for this malnutrition-related parasite dissemination we analyzed the cellularity, architecture, and function of the skin-draining lymph node. There was no difference in the localization of multiple cell populations in the lymph node of polynutrient deficient (PND) mice, but there was reduced cellularity with fewer CD11c+dendritic cells (DCs), fibroblastic reticular cells (FRCs), MOMA-2+ macrophages, and CD169+ subcapsular sinus macrophage (p<0.05 for all) compared to the well-nourished (WN) mice. The parasites were equally co-localized with DCs associated with the lymph node conduit network in the WN and PND mice, and were found in the high endothelial venule into which the conduits drain. When a fluorescent low molecular weight (10 kD) dextran was delivered in the skin, there was greater efflux of the marker from the lymph node conduit system to the spleens of PND mice (p<0.04), indicating that flow through the conduit system was altered. There was no evidence of disruption of the conduit or subcapsular sinus architecture, indicating that the movement of parasites into the subcortical conduit region was due to an active process and not from passive movement through a leaking barrier. These results indicate that the impaired capacity of the lymph node to act as a barrier to dissemination of L. donovani infection is associated with a reduced number of lymph node phagocytes, which most likely leads to reduced capture of parasites as they transit through the sinuses and conduit system.

Deficiency of Lymph Node-Resident Dendritic Cells (DCs) and Dysregulation of DC Chemoattractants in a Malnourished Mouse Model of Leishmania donovani Infection

“…Ϫ/Ϫ mice, we found no change in the localization of uninfected or L. donovaniinfected myeloid cells within the lymph node (18). This contrasts with the reduced migration of Langerhans cells to the lymph nodes and retention of those cells in the subcapsular sinus in CCR2 Ϫ/Ϫ mice infected with L. major (39).…”

“…In our previous studies, we found increased early visceralization following inoculation of L. donovani in the skin of malnourished mice. The increased numbers of visceral parasites in the malnourished group was not the result of impaired parasite killing but was due to parasites escaping the barrier function of the skin-draining lymph node (15,18). We also demonstrated a reduced number of macrophages, neutrophils, and DCs in the lymph nodes of malnourished mice (18).…”

“…The increased numbers of visceral parasites in the malnourished group was not the result of impaired parasite killing but was due to parasites escaping the barrier function of the skin-draining lymph node (15,18). We also demonstrated a reduced number of macrophages, neutrophils, and DCs in the lymph nodes of malnourished mice (18). This suggested that the increased dissemination of L. donovani might be due to the reduced number of phagocytes and/or the ineffective capture of parasites as they transited to and through the lymph nodes.…”

“…The nutritional status of the host is also a key determinant for the progression of L. donovani infection to active visceral leishmaniasis (6,11,12,(41)(42)(43). In our previous work, we demonstrated that polynutrient (protein, energy, zinc, and iron) deficiency impaired the barrier function of the draining lymph node, resulting in increased early dissemination of L. donovani to the spleen and liver (15,18). The loss of the lymph node barrier was associated with reduced numbers of phagocytes (e.g., macrophages and DCs) in the subcortical region and subcapsular sinus.…”

“…However, approximately 10% of infected people develop fever, severe hepatosplenomegaly, pancytopenia, and cachexia, which ultimately progresses to death if left untreated (6)(7)(8)(9). Clinical (10)(11)(12)(13) and experimental (14)(15)(16)(17)(18) studies have documented that malnutrition is a strong predisposing factor for the progression of L. donovani or L. infantum infection to active VL and increased mortality. A child with moderate or severe malnutrition (based on weight for age or height for age) has a 9-fold greater risk of developing VL than a child of normal nutritional status or mild malnutrition (11)(12)(13).…”