Leishmania major and hematopoiesis: effect of the parasite or sand fly saliva peptide maxadilan

Abstract

Experimental models of leishmaniasis tend to overlook the vector role in transmission of the parasite. Saliva clearly exacerbates Leishmania infection. The vasodilatory peptide maxadilan has been isolated from the saliva of the sand fly Lutzomyia longipalpis. This molecule exhibits immunomodulatory properties by acting as an analogue of the neuropeptide pituitary adenylate cyclase activating-peptide (PACAP). PACAP receptors have been found in rat bone marrow-derived stromal cells and PACAP has been shown to induce interleukin-6 (IL-6) (an important cytokine in hematopoiesis) production by these cells. Maxadilan has been shown to increase IL-6 production. Moreover, increased hematopoiesis has been associated with increased susceptibility to L. major infection. Thus, we were interested in studying hematopoiesis in the murine model of leishmaniasis. Clonogenic progenitor assays were used to assess hematopoiesis. We hypothesized that hematopoiesis would be increased in BALB/c mice and decreased in CBA mice due to their differences in cytokine profiles produced during the course of the immune response. We found that bone marrow hematopoiesis three days after L. major infection, was increased in BALB/c mice and decreased in CB A mice. We used feeder layer-based assays to assess the importance of IL-4 and TNF-α on the hematopoietic response to the parasite in both strains of mice. We found that IL-4 was responsible for the increased hematopoiesis seen in BALB/c mice and TNF-α for the decreased hematopoiesis seen in CBA mice. Due to its effects on IL-6 production and PACAP receptors, we hypothesized that maxadilan will increase hematopoiesis in both susceptible and resistant mice. We found that maxadilan increased bone marrow hematopoiesis in both strains of mice. This increase in hematopoiesis was further supported by increased circulating reticulocytes in maxadilan-treated mice. Incubation of hematopoietic progenitors with maxadilan resulted in stimulation of hematopoiesis. Using long-term bone marrow cultures and feeder layer-based assays, we found that maxadilan stimulated hematopoiesis in both strains of mice through PACAP receptor binding and IL-6 production, and that maxadilan acted on bone-marrow stromal cells, more particularly macrophages and fibroblasts. Thus, maxadilan might exacerbate L. major infection by stimulating hematopoiesis.