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

Abstract

Malnutrition is thought to contribute to more than one-third of all childhood deaths via increased susceptibility to infection. Malnutrition is a significant risk factor for the development of visceral leishmaniasis, which results from skin inoculation of the intracellular protozoan Leishmania donovani. We previously established a murine model of childhood malnutrition and found that malnutrition decreased the lymph node barrier function and increased the early dissemination of L. donovani. In the present study, we found reduced numbers of resident dendritic cells (conventional and monocyte derived) but not migratory dermal dendritic cells in the skin-draining lymph nodes of L. donovani-infected malnourished mice. Expression of chemokines and their receptors involved in trafficking of dendritic cells and their progenitors to the lymph nodes was dysregulated. C-C chemokine receptor type 2 (CCR2) and its ligands (CCL2 and CCL7) were reduced in the lymph nodes of infected malnourished mice, as were CCR2-bearing monocytes/macrophages and monocyte-derived dendritic cells. However, CCR7 and its ligands (CCL19 and CCL21) were increased in the lymph node and CCR7 was increased in lymph node macrophages and dendritic cells. CCR2-deficient mice recapitulated the profound reduction in the number of resident (but not migratory dermal) dendritic cells in the lymph node but showed no alteration in the expression of CCL19 and CCL21. Collectively, these results suggest that the malnutrition-related reduction in the lymph node barrier to dissemination of L. donovani is related to insufficient numbers of lymph node-resident but not migratory dermal dendritic cells. This is likely driven by the altered activity of the CCR2 and CCR7 chemoattractant pathways.

Transcriptional Profiling of Immune-Related Genes in Leishmania infantum-Infected Mice: Identification of Potential Biomarkers of Infection and Progression of Disease

“…In our assays, the upregulation of Cxcr3, Cxcl9 , and Cxcl10 suggest that the mouse immune system attempts to control infection by chemoattraction of lymphocytes and DC to the spleen. On the other hand, our data also showed downregulation on mRNA levels of Mcp-1 or Ccl2 , that mediates the recruitment of CC chemokine receptor 2 (CCR2) expressing cells (Ibrahim et al, 2014 ), which in mice includes the inflammatory monocytes subset (Gordon and Taylor, 2005 ; Gordon, 2007 ).…”

Dendritic Cells andLeishmaniaInfection: Adding Layers of Complexity to a Complex Disease

“…The migration of monocyte-derived DCs to the lymph nodes is driven by CCR2 and its ligands [ 52 ]. In VL, there is a lack of protective immune response, partially, due to an altered DC migration to the spleen and dLNs [ 53 – 56 ]. This is also observed in CL.…”

Deception and Manipulation: The Arms of Leishmania, a Successful Parasite

“…The absence of Th1 cell-attracting chemokines in these lesions may reflect the downregulation of the expression of genes linked with Th1 trafficking, such as the ones coding for CXCR3 chemokines ( 165 ). Last but not least, it was described that Leishmania may also profit from malnutrition to impair chemokine secretion and to establish infection ( 158 , 166 ). Interestingly, differential expression of chemokines induced by distinct parasite strains leads to various infection and disease outcomes.…”