The role of human pentraxins for the Leishmania-vector interaction

Survival and transmission of the protozoan Leishmania is dependent on attachment by the parasite to the sand fly midgut. Without this, Leishmania parasites are lost when the sand fly defecates the bloodmeal remnants. Previous work found human pentraxin C-reactive protein (CRP) was able to bind Leishmania lipophosphoglycan (LPG), and activate complement. Only one published study has investigated human pentraxin Serum Amyloid P (SAP) with Leishmania, finding no interaction. However, preliminary experiments by both the Rogers and Raynes labs have suggested otherwise. Here, we hypothesise SAP acts as a cross-linker between Leishmania and the vector midgut, allowing attachment. We expand on CRP binding with Leishmania, specifically with the promastigote secretory gel (PSG). The methods and results of in vivo fly infections and ex vivo midgut binding assays are assessed through a systematic review and meta-analysis. From comparing previous in vivo fly infection experiments, we propose there is a cap in the number of parasites a sand fly can sustain. Though SAP binds both Leishmania mexicana and Lutzomyia longipalpis midgut extract, it is not a cross-linker between the two, with anti-SAP antibodies and drug unable to block Leishmania-midgut attachment. An inverse correlation was seen between PSG repeating disaccharide side chain substitutions and the strength of CRP binding. We have not observed SAP binding to midgut extract from midge Culicoides sonorensis in preliminary experiments, however N-acetylgalactosamine (GalNAc) may be displayed on midge midguts as previously found for permissive sand flies. Together, this work shows pentraxins likely have a role in the Leishmania lifecycle within the sand fly midgut, with the extent of pentraxin interaction likely differing between species due to differing surface molecule composition. Future models of Leishmania-vector interaction should include the roles of bloodmeal components, providing a fuller picture of the Leishmania lifecycle for development of transmission-blocking strategies.