Abstract
Lymphatic filariasis and onchocerciasis are neglected parasitic diseases which pose a threat to public health in tropical and sub-tropical regions. Strategies for control and elimination of these diseases by mass drug administration (MDA) campaigns are designed to reduce symptoms of onchocerciasis and transmission of both parasites to eventually eliminate the burden on public health. Drugs used for MDA are predominantly microfilaricidal, and prolonged rounds of treatment are required for eradication. Understanding parasite biology is crucial to unravelling the complex processes involved in host-parasite interactions, disease transmission, parasite immune evasion, and the emergence of drug resistance. In nematode biology, large gaps still exist in our understanding of iron metabolism, iron-dependent processes and their regulation. The acquisition of iron from the host is a crucial determinant of the success of a parasitic infection. Here we identify a filarial ortholog of Divalent Metal Transporter 1 (DMT1), a member of a highly conserved family of NRAMP proteins that play an essential role in the transport of ferrous iron in many species. We cloned and expressed the B. malayi NRAMP ortholog in the iron-deficient fet3fet4 strain of Saccharomyces cerevisiae, performed qPCR to estimate stage-specific expression, and localized expression of this gene by immunohistochemistry. Results from functional iron uptake assays showed that expression of this gene in the iron transport-deficient yeast strain significantly rescued growth in low-iron medium. DMT1 was highly expressed in adult female and male B. malayi and Onchocerca volvulus. Immunolocalization revealed that DMT1 is expressed in the intestinal brush border, lateral chords, and reproductive tissues of males and females, areas also inhabited by Wolbachia. We hypothesize based on our results that DMT1 in B. malayi functions as an iron transporter. The presence of this transporter in the intestine supports the hypothesis that iron acquisition by adult females requires oral ingestion and suggests that the intestine plays a functional role in at least some aspects of nutrient uptake.
Highlights
The human filarial diseases lymphatic filariasis (LF) and onchocerciasis affect around 150 million people in tropical and subtropical regions
We hypothesized that a homolog of Divalent Metal Transporter 1 (DMT1) in B. malayi plays a role in iron transport and that it is expressed in the parasite intestine
Molecular cloning of the B. malayi NRAMP-like transporter (Genbank sequence: XM_001899422.1) generated a 1491 bp cDNA encoding an open reading frame of 496 amino acids (XP_001899457_1) with a predicted molecular mass of 55,774 Da. This region was amplifed from total RNA and expressed for functional studies in yeast. As this sequence was based on an earlier version of the B. malayi genome (Assembly ASM299v2), a BLASTN was later performed with this sequence against the current B. malayi genome version (B.malayi-4.0) in Wormbase Parasite, which revealed an overlap with gene Bm13827
Summary
The human filarial diseases lymphatic filariasis (LF) and onchocerciasis affect around 150 million people in tropical and subtropical regions. LF is a debilitating disease caused by infection with the filarial nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori and is endemic in 60 countries, affecting approximately 120 million people with 1.23 billion people at risk of infection (WHO, 2014b). Control and elimination programmes primarily through mass drug administration (MDA), with vector control where appropriate, aim to reduce transmission of these neglected tropical diseases and to alleviate suffering and disability (APOC, 2005; Ottesen, 2000). MDA has markedly reduced transmission of human filarial parasites, the drugs used in control programmes are predominantly microfilaricidal and do not kill the adult worms, which can remain in the host for many years. Simultaneous administration of albendazole + ivermectin + diethylcarbamazine appears to be macrofilaricidal against W. bancrofti (Thomsen et al, 2016; Fischer et al, 2017), this
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