Macrophage Heterogeneity, Antigen Presentation, and Membrane Fluidity: Implications in Visceral Leishmaniasis

Abstract

Morphological and functional heterogeneity of the splenic macrophage (Mf) population was studied in Leishmania donovani (LD) infected BALB/c mice. On a discontinuous percoll gradient two distinct Mf populations were separated. They differed significantly in size as evident from Scanning Electron Microscopy (SEM). Morphologically, the bigger Mf (LM) showed surface projections, whereas the smaller Mf (SM) was round. As regards the antigen-presenting abilities, the LM of infected animals showed defective antigen-presenting abilities at a later stage of the disease, i.e. 6 months post infection ( 6 I-LM) but not earlier, whereas the SM population remained functionally intact throughout the course of the infection. Further, the 6 I-LM showed a much enhanced A d status as compared to their controls. Interestingly, both the 6 I-LM and the control set showed a comparable level of binding of a known A d restricted peptide. Despite the presence of sufficient A d molecules and the ability to bind the appropriate peptide, 6 I-LM were unable to stimulate peptide specific T-cell hybridoma. Further, the 6 I-LM showed an increase in membrane fluidity and distorted morphology with membrane fissure and blebs as evident from SEM. It is possible that an increase in the membrane fluidity may lead to the defective antigen-presenting ability of 6 I-LM. Thus, the LD infection functionally keep the 6 I-LM out of antigen presentation and this may contribute to the defective cell mediated immune response in leishmaniasis.

Leishmania donovani Affects Antigen Presentation of Macrophage by Disrupting Lipid Rafts

“…Previously, we have demonstrated that a subset of splenic M of Leishmania-infected BALB/c mice display an increase in membrane fluidity coupled with defective Ag-presenting function; this inability to present Ag was not due to the lack of peptide-MHC complex formation on the surface of M (11). The present work demonstrates for the first time that during their intracellular life cycle, Leishmania parasites disrupt the membrane raft of M by increasing membrane fluidity.…”

“…Previously we demonstrated that a subset of splenic M of LD-infected BALB/c mice showed increased membrane fluidity and defective Ag-presenting ability (11). The question arises of whether the rigidity of the membrane lipid bilayer is a critical determinant of the Ag-presenting ability of M in vitro.…”

Biochemical and nutritional evaluation of patients with visceral leishmaniasis before and after treatment with leishmanicidal drugs

“…Internalization involves interaction between the parasite and the plasma membrane of the cell host 36,55,56 . Low cholesterol levels in humans decrease the number of circulating lymphocytes, thus increasing the chances of mortality 23,34 .…”

“…In addition to playing an important role in the maintenance of membrane fl uidity, cholesterol is essential for the proper function of antigen presenting cells and is also a prognostic indicator of increased morbidity and mortality associated with pathological conditions [34][35][36] . This lipid is responsible for the formation of membrane rafts, which are essential for Leishmania entry [37][38][39] .…”

Leishmania-Induced Inhibition of Macrophage Antigen Presentation Analyzed at the Single-Cell Level

“…Thus, CD28 signaling is not required for inducing MTOC reorientation under these conditions, probably reflecting the lower activation threshold and relative costimulation independence of effector T cells (3). Finally, it has recently been reported that Leishmania-infected macrophages display altered membrane fluidity, with changes in the distribution and activity of membranous projections (41). However, macrophage membrane mobility also did not appear to be necessary for activating T cells for a MTOC response, as prefixation of macrophages with paraformaldehyde had no effect on this event (Fig.…”