Haem transporter HRG-1 is essential in the barber’s pole worm and an intervention target candidate

Abstract

Parasitic roundworms (nematodes) have lost genes involved in the de novo biosynthesis of haem, but have evolved the capacity to acquire and utilise exogenous haem from host animals. However, very little is known about the processes or mechanisms underlying haem acquisition and utilisation in parasites. Here, we reveal that HRG-1 is a conserved and unique haem transporter in a broad range of parasitic nematodes of socioeconomic importance, which enables haem uptake via intestinal cells, facilitates cellular haem utilisation through the endo-lysosomal system, and exhibits a conspicuous distribution at the basal laminae covering the alimentary tract, muscles and gonads. The broader tissue expression pattern of HRG-1 in Haemonchus contortus (barber’s pole worm) compared with its orthologues in the free-living nematode Caenorhabditis elegans indicates critical involvement of this unique haem transporter in haem homeostasis in tissues and organs of the parasitic nematode. RNAi-mediated gene knockdown of hrg-1 resulted in sick and lethal phenotypes of infective larvae of H. contortus, which could only be rescued by supplementation of exogenous haem in the early developmental stage. Notably, the RNAi-treated infective larvae could not establish infection or survive in the mammalian host, suggesting an indispensable role of this haem transporter in the survival of this parasite. This study provides new insights into the haem biology of a parasitic nematode, demonstrates that haem acquisition by HRG-1 is essential for H. contortus survival and infection, and suggests that HRG-1 could be an intervention target candidate in a range of parasitic nematodes.

Identification and characterisation of the haemozoin of Haemonchus contortus

“…The parasitic L4s and adult worms need to ingest a large amount of haemoglobin in their intestine to maintain their normal development and reproduction [ 40 ], so it is no surprise that we showed the intestine as a major organ forming haemozoin-like pigments. Recently, the mechanism of haem acquisition of H. contortus has also shown that the intestine is an important organ where haem-responsive gene-1 protein (HRG-1) can facilitate haem uptake and utilisation [ 41 ]. We observed that the haemozoins in lipid droplets were located in intestinal cytoplasm, which is in line with hookworm Nippostrongylus brasiliensis [ 6 ], but different from helminth Schistosoma mansoni and insect Rhodnius prolixus [ 42 ].…”

Fatty acid- and retinol-binding protein 6 does not control worm fatty acid content in Caenorhabditis elegans but might play a role in Haemonchus contortus parasitism

“…The free-living nematode C. elegans (wild-type N2 strain and mutant-type RB1515 strain) was obtained from the Caenorhabditis Genetics Center (CGC) and maintained following the manufacturer’s instructions. Parasitic nematode H. contortus (ZJ isolate) was experimentally maintained in Hu sheep and the eggs, first- (L1s), second- (L2s), third- (L3s), and fourth-stage larvae (L4s), and the adult worms were collected as described previously [ 33 , 34 ]. The human embryonic kidney 293 T (HEK 293 T) cell line (Beyotime, Shanghai) was maintained following the manufacturer’s instructions.…”

Notes from the Underground: Heme Homeostasis in C. elegans

“…HRG-5 has a histidine residue at a slightly different position within the same transmembrane domain, which might be involved in heme transport [23]. The hrg-1 orthologs in the filarial nematode Brugia malayi and barber's pole worm Haemonchus contortus, BmHRG-1 and HcHRG-1, are also regulated by heme levels [40,41]. BmHRG-1 and HcHRG-1 localize to both the cell surface and endocytic compartments, suggesting that they may have the function of both C. elegans HRG-1 and HRG-4 [40,41].…”

“…Orthologs of hrg-1 have been identified and characterized in mammals, fish, ticks, parasitic nematodes, and trypanosomatids [23,40,41,[49][50][51][52][53][54][55]. In mammals, the vast majority of iron used for the synthesis of heme and hemoglobin in differentiating erythroblasts is supplied by tissue macrophages, which are responsible for recycling iron from senescent red blood cells (RBCs) [56,57].…”