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Sanger-led Team Sequences Patient's Brain Tapeworm

MRI showing tapeworm in patient brain.

NEW YORK (GenomeWeb) – Using DNA from a tapeworm creeping across a patient's brain, a team from the Wellcome Trust Sanger Institute and elsewhere have sequenced and assembled a draft genome for the Spirometra erinaceieuropaei flatworm.

As they reported online today in Genome Biology, the researchers identified the cerebral tapeworm culprit through targeted barcode gene sequencing on a sample biopsied from the brain of a 50-year-old man suffering from headaches and neurological problems. From there, they did genome sequencing on the sample, producing a 1.26 billion S. erinaceieuropaei draft genome assembly that contained nearly 40,000 predicted protein-coding genes.

Subsequent analyses of the genome provided a peek at not only the tapeworm's biology and interactions with the human host, but also possible treatment targets for the tapeworm, which only rarely infects human tissues. For instance, the investigators predicted that the worm would be unlikely to respond to microtubule-targeting benzimidazole drugs such as albendazole, since its genome contained mutations in a beta-tubulin gene that are known to boost resistance to the drug in other tapeworms.

"The target for albendazole is quite well known because it's been around a long time and has been well used in livestock and in veterinary medicine," the study's first author Hayley Bennett, a post-doctoral researcher in co-senior author Matthew Berriman's parasite genomics lab at the Sanger Institute, told GenomeWeb.

"There are certain residues [in the beta-tubulin gene] that change in resistant … nematodes," she said, noting that the same resistance-associated residues are present in the new tapeworm genome despite the rarity of S. erinaceieuropaei infections and apparent lack of drug-induced selection for such changes.

Sparganosis infections involving S. erinaceieuropaei and related worms are very rare in humans, she and her co-authors explained.

The tapeworm's complex life cycle typically takes it through a free-swimming stage, followed by parasitism and development in small crustaceans called copepods, which are consumed by animals such as snakes, tadpoles, or frogs. Within those vertebrate animals, the parasite transform into a secondary "sparganum" larval form that can infect humans.

Such infections can occur when individuals eat raw tadpoles or undercooked frog or snake meat containing sparganum, researchers noted. Alternatively, some cases seem to stem from swimming in or drinking contaminated water or from applying infected raw frog poultices to sites where larvae can enter the body such as the eyes or open wounds.

For the current study, researchers focused on a sample obtained from a man who lived in the UK but traveled frequently to China.

After years of enduring headaches, seizures, memory problems, flashbacks, and more, the man was ultimately diagnosed with sparganosis, when clinicians treating him at St. Thomas' Hospital and the Hospital found a larval worm that had migrated in his brain leaving a 5 centimeter (almost two inch) long lesion in its path.

To determine whether they were dealing with an infection involving S. erinaceieuropaei or a related species called S. proliferum, which causes a more dangerous form of the disease involving replicating worms, Bennett explained, the researchers sequenced the worm's cytochrome oxidase c1 (cox1) gene.

After verifying that the culprit was a S. erinaceieuropaei worm from its cox1 sequence, they decided to go a step further, using the Illumina HiSeq 2000 to do paired-end sequencing on the small sample of DNA that was available from a biopsy slide scraping.

The team's de novo genome assembly of those reads spanned roughly 1.26 billion bases, housing 39,856 apparent protein-coding genes. More than 450 of those represented core genes that tend to be shared across eukaryotic species, while 258 were very highly conserved eukaryote genes.

As suspected, a head-to-head genome comparison indicated that the S. erinaceieuropaei worm was quite distantly related to other tapeworms and flatworms sequenced in the past.

Relative to the genomes of other tapeworms, which are one-tenth the size of the S. erinaceieuropaei sequence, the new genome contained expansions to gene families coding for molecular motors, transcriptional regulators, members of detoxification pathways, protease enzymes, and other cellular players, Bennett said.

Such features may help S. erinaceieuropaei make its way into multiple host tissue types, she noted, though that possibility still needs to be tested experimentally.

The newly sequenced worm also carried a beta-tubulin gene mutation that has been implicated in benzimidazole resistance in other types of tapeworms, suggesting the parasite may not respond to that treatment. Still, a search for genes corresponding to targets of existing or proposed tapeworm drugs did uncover other possible vulnerabilities in S. erinaceieuropaei.

Because infections with that species are so rare, Bennet explained that the best bet for treating them will likely involve finding overlapping targets with tapeworms contributing to more common infections. She and her colleagues are continuing to sequence and characterize additional parasitic worms with an eye to identifying such shared tapeworm features.