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Whipworm Genomes Offer Peek at Parasitic Interactions, Potential Anti-inflammatory Applications

NEW YORK (GenomeWeb News) – A pair of genome sequencing studies published online yesterday in Nature Genetics is providing insights into the biology of parasitic whipworms, interactions with their hosts, and potential applications for treating inflammatory disease.

For the first study, a team from the UK, Japan, and Ecuador sequenced the genomes of Trichuris trichiura and T. muris — whipworm species known for infecting humans and mice, respectively. The resulting assemblies spanned nearly 95 percent of the total genome size for each of those species. By folding in RNA sequence data from different whipworm tissues and developmental stages and from whipworm-infected mice, the researchers tracked down genes associated with whipworm development and infectiousness.

With gene expression information from the mouse large intestine, meanwhile, they saw a set of T-helper immune genes with enhanced expression after chronic whipworm infection, but a dip in the expression of genes from inflammation-related pathways — information that may help in designing whipworm-based therapies for conditions characterized by unnecessary inflammation.

"Our work starts to unravel the whipworm's intimate relationship with humans and paves the way for new approaches to prevent or clear whipworm infections," Wellcome Trust Sanger Institute's researcher Matthew Berriman, a co-senior author on the study, said in a statement.

Berriman and his colleagues used Illumina instruments to tackle genomic DNA from an adult male T. trichiura isolated in the clinic, producing a high-quality draft genome assembly spanning 75 million bases. For the mouse-infecting T. muris species, they put together an 85 million base assembly with sequences produced on a combination of platforms. To that, they added multiple whipworm transcriptomes and genome re-sequencing data from additional representatives of each species.

The team's analyses of the genomes unearthed some 9,650 predicted protein-coding T. trichiura genes and an estimated 11,004 protein-coding genes in the T. muris genome. More than 6,600 whipworm genes belonged to gene families found in both species, while almost 6,200 more were specific to one whipworm or the other.

With whipworm expression patterns, the researchers defined sets of worm genes involved in sperm function, development, digestion, host immune-dodging, and more.

Meanwhile, RNA sequencing on cecum tissue from T. muris-infected mice suggested that chronic whipworm infection dials up the expression of 868 genes and decreases the expression of almost 600 more.

Many of the upregulated mouse genes belonged to an immune pathway governed by regulated T-helper cells, the study's authors noted, including genes coding for pro-inflammatory cytokines and tumor necrosis factor.

In contrast, the expression of genes from an inflammatory immune pathway associated with resistance to whipworm infection was lower than usual in infected mice, consistent with the notion that whipworm infection could help dial back the inflammatory responses that contribute to inflammatory bowel disease or multiple sclerosis.

A pig whipworm species called T. suis is already being used by some as an IBD treatment, the researchers noted, adding that "[c]omparative immunology of these infections should help in developing more targeted therapies in the future."

"The present study shows how both the parasite and the host respond to each other at a level of detail never seen before, [which] will help us identify how to exploit the ways in which the worm modifies our bodies," co-senior author Richard Grencis, a life sciences researcher at the University of Manchester, said in a statement. "This finely tuned interaction that has developed over the course of evolution can lead us to design better drug treatments and more effective clinical trials using worms and their products."

In another Nature Genetics study, researchers from the University of Melbourne, BGI-Shenzhen, and elsewhere focused on T. suis — the pig-infecting whipworm being proposed as an inflammatory disease treatment.

"We know that humans infected with the harmless 'pig whipworm' can have significantly reduced symptoms linked to autoimmune diseases," the University of Melbourne's Aaron Jex, first author on that study, said in a statement.

"[N]ow we have the genetic sequence of the worm," Jex added, noting that this "opens the door to future human drug designs and treatment."

He and his colleagues came up with 76-million-base and 81-million-base T. suis genome assemblies for female and male worms, respectively, each covered to an average depth of at least 140-fold. They also sequenced messenger RNAs and small RNAs from several T. suis tissue types and developmental stages.

Again, this combination of sequence data provided a peek at whipworm genes that could contribute to infection and interactions with host animals — either pigs suffering from deleterious infections or humans being treated for inflammation-related disease, for instance.

Amongst the predicted protein-coding genes in pig whipworm — almost 14,500 in the female worm genome and a few hundred more in the male genome — the team identified genes coding for secreted proteins, enzymes, and other protein participants in the whipworm infection process.

That analysis also provided details about RNA interference networks present in the pig whipworm. For example, members of the team uncovered hundreds of microRNAs and more than a million potential small RNAs, including small interfering RNAs and tiny non-coding RNAs.

"By sequencing the T. suis genome and transcriptomes (mRNAs and small RNAs), we provide deep insights into the molecular biology of this parasite and its modulation of host immune responses," Jex and his co-authors wrote. "These data provide a solid basis for exploring human trichuriasis, developing new anti-parasitic drugs, and elucidating how helminthes suppress autoimmune disorders."