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Researchers Sequence Hookworm Genome, Transcriptome for Treatment Targets


NEW YORK (GenomeWeb) – A team of US researchers has sequenced the genome of the hookworm Ancylostoma ceylanicum and examined its transcriptome to uncover potential drug and vaccine targets.

Researchers led by the University of Massachusetts Medical School's Raffi Aroian sequenced the disease-causing parasite's 313-megabase genome and generated transcriptomic data from throughout its lifecycle, as they reported in Nature Genetics today. Using this data, Aroian and his colleagues identified various genes that are upregulated or downregulated at various points in the hookworm life cycle and uncovered possible targets for drug or vaccine development to treat or prevent hookworm disease.

"The sequencing of A. ceylanicum adds to a growing number of genomes for parasitic nematodes that, collectively, infect over 1 billion humans," Aroian and his colleagues wrote in their paper. "Practically, these genomes will be crucial for inventing new drugs and vaccines against nematodes that rapidly evolve drug resistance and that have been parasitizing vertebrates since the Cretaceous."

Each year, hookworms themselves infect more than 400 million people worldwide, leading to anemia and malnutrition, especially in impoverished rural regions.

As A. ceylanicum can be maintained in golden hamsters in the lab, the researchers selected it as a model for Necator americanus and A. duodenale, the two hookworm species that cause most human infections.

Aroian and his colleagues sequenced and assembled the 313-megabase genome, which they predicted to contain nearly 27,000 protein-coding genes with products larger than 100 residues and some 10,000 genes with smaller products. Much of the A. ceylanicum genome — about 40 percent — was repetitive, they noted.

The researchers also performed RNA-seq on samples they collected from throughout the hookworm's lifecycle from free-living larvae to parasitic adult to trace when certain genes were switched on or off.

For instance, they reported that 942 genes were significantly upregulated in vivo during the third larval stage some 24 hours after infection, including a number of proteases, protease inhibitors, and nucleases. Proteases and protease inhibitors, they said, are also upregulated at this time point in other hookworms like N. americanus. The researchers suggested the proteases might enable the parasite to digest and inactivate host immune proteins, while the protease inhibitors could also help suppress the host immune system.

While a number of the gene families upregulated during parasitic infection were already known from other parasitic nematodes, the researchers also uncovered a number of novel families.

They dubbed one such family ASP-related (ASPR) because they appeared to be distantly related to the ASP family that encodes secreted cysteine-rich proteins. The researchers hypothesized that proteins from this novel family could be an important aspect of hookworm infection in vivo.

Another novel family they called strongylids L4 proteins (SL4P) was upregulated at the start of parasitic feedingas the larvae molted into L4 larvae and differentiated sexually.They noted 24 SL4P genes encoding proteins of about 200 residues in length, 21 of which were predicted to be non-classically secreted, meaning they lacked a leader sequence. Parasitic nematodes, the researchers noted, often use such non-classical secretion to export proteins into their hosts.

To uncover possible drug targets, Aroian and his colleagues searched the A. ceylanicum genome for genes conserved across various parasites — but lacking in their mammalian hosts — that they might need to survive. Based on this, the researchers identified 72 possible targets, including the gene that encodes trehalose-6-phosphatase.

The investigators also looked for vaccine targets and focused on proteases and protease inhibitors that are exposed to the host immune systems, finding 12 cathepsin B-like protease genes and a novel protease inhibitor. The novel protease inhibitor, the researchers noted, had consistent strong expression and has a Haemonchus contortus homolog that's upregulated during infection.

"Treatments effective against A. ceylanicum might … also prove useful against other strongylids, such as Haemonchus contortus, that infect farm animals and depress agricultural productivity," the researchers said. "Characterizing the genome and transcriptome of A. ceylanicum is a key step toward such comparative analysis."