Heme crystallization in a Chagas disease vector acts as a redox-protective mechanism to allow insect reproduction and parasite infection

Abstract

Heme crystallization as hemozoin represents the dominant mechanism of heme disposal in blood feeding triatomine insect vectors of the Chagas disease. The absence of drugs or vaccine for the Chagas disease causative agent, the parasite Trypanosoma cruzi, makes the control of vector population the best available strategy to limit disease spread. Although heme and redox homeostasis regulation is critical for both triatomine insects and T. cruzi, the physiological relevance of hemozoin for these organisms remains unknown. Here, we demonstrate that selective blockage of heme crystallization in vivo by the antimalarial drug quinidine, caused systemic heme overload and redox imbalance in distinct insect tissues, assessed by spectrophotometry and fluorescence microscopy. Quinidine treatment activated compensatory defensive heme-scavenging mechanisms to cope with excessive heme, as revealed by biochemical hemolymph analyses, and fat body gene expression. Importantly, egg production, oviposition, and total T. cruzi parasite counts in R. prolixus were significantly reduced by quinidine treatment. These effects were reverted by oral supplementation with the major insect antioxidant urate. Altogether, these data underscore the importance of heme crystallization as the main redox regulator for triatomine vectors, indicating the dual role of hemozoin as a protective mechanism to allow insect fertility, and T. cruzi life-cycle. Thus, targeting heme crystallization in insect vectors represents an innovative way for Chagas disease control, by reducing simultaneously triatomine reproduction and T. cruzi transmission.

Characterization of the Temporal Pattern of Blood Protein Digestion in Rhodnius prolixus: First Description of Early and Late Gut Cathepsins

“…Notably, the AMG had previously been described as a compartment in which there was only absorption of water, erythrocyte hemolysis, hemoglobin crystallization, and hemozoin formation ( Garcia et al, 2007 ; Ferreira et al, 2018 ). It has been hypothesized that the high levels of family A1 transcripts in the AMG might be caused by their synthesis as pro-enzymes, which would then be activated in the PMG ( Ribeiro et al, 2014 ).…”

Non-immune Traits Triggered by Blood Intake Impact Vectorial Competence

“…Hydrophobic proteins located in their surface and sugar residues present in perimicrovillar membrane glycoproteins appear to be necessary for this interaction ( Zingales et al, 1982 ; Golgher et al, 1993 ; Pereira-Chioccola et al, 2000 ; Alves et al, 2007 ; Nogueira et al, 2007 ). In R. prolixus , it has been shown that another function of the perimicrovillar membranes is the promotion of the aggregation of heme molecules, forming nucleation sites that convert heme into hemozoin crystals and hence preventing heme toxicity toward both the host and the parasite, that consequently creates a favorable environment for pathogen growth ( Oliveira et al, 2000 ; Stiebler et al, 2014 ; Ferreira et al, 2018 ).…”

Heme Acquisition by trypanosomatids: Evaluation of the heme-dependent behavior and its biochemical implications

“…An oxidant environment must stimulate epimastigote proliferation and an antioxidant environment promotes metacyclogenesis (Nogueira et al, 2015). Ferreira et al (2018) suggested that heme undergoes a crystallization process in the gut of the insect that is both a protective process to T. cruzi and the triatomine.…”