Panning for molecular gold in whipworm genomes

Two new studies report genomic data on three species of whipworm, soil-transmitted parasitic worms responsible for trichuriasis. These genomes provide insights into host-pathogen interactions and potential for new drug targets for helminth therapy.

Trichuriasis is one of the three major soil-transmitted gastrointestinal helminth infections that cause chronic and debilitating diseases in an estimated 1 billion people worldwide. Trichuriasis, together with ascariasis and hookworm, accounts for a major burden of global disease, with ensuing economic consequences¹. On page 693 of this issue, Matthew Berriman and colleagues² report the genome sequences of two Trichuris species: Trichuris trichiura, a human pathogen, and Trichuris muris, its mouse counterpart. On page 701, Aaron Jex and colleagues³ report the genome sequence of the pig whipworm Trichuris suis. According to the most recent estimates, T. trichiura alone infects more than 700 million people, mostly children⁴. T. muris, used as a model of the human disease, has been exploited to better understand the role of the host immune system in control of the infection⁵. Importantly, the ova of this T. suis are currently being investigated as a new therapeutic agent against autoimmune diseases⁶.

Map to new targets

Foth et al.² and Jex et al.³, along with the recent report of the genome sequence of Trichinella spiralis⁷, provide substantial genomic information for clade I parasitic nematodes. Foth et al.² report the whole-genome sequencing and assembly of the mouse whipworm genome for T. muris, using multiple worms and a combination of complementary sequencing approaches. This high-quality T. muris reference map was then used to assemble the draft genome of a single T. trichiura male isolated from an infected patient in Ecuador. Jex et al.³ sequenced to ∼140× coverage the whole genomes from single adult male and female T. suis worms, estimating the genome sizes to be 83.6 Mb and 87.2 Mb, respectively. The haploid genome for the T. muris female, in contrast, at 106 Mb is 20% larger than its female counterpart in T. suis. Gene numbers across the three species vary widely from 9,650 in the 75-Mb T. trichiura draft genome to 11,000 in the T. muris genome and to more than 14,500 in the T. suis genome. Although intrachromosomal rearrangements were apparent in the comparison of T. muris, T. trichiura and T. spiralis², gene content on homologous chromosomes appears largely conserved. Both studies found high conservation of genes across the Trichuris species, with species-specific differences largely due to genes of unknown function. Surprisingly, no evidence was found for genes specific to the Y chromosome, which was shown to contain mostly repetitive sequence.

Foth et al.² report whole-transcriptome analysis for T. trichiura and T. muris, and they used this dual-species transcriptome analysis to identify genes showing sex- or life stage–specific expression. In addition, they characterized the transcriptional landscape of the bacillary band and stichosome, specialized cellular structures found in the anterior region of whipworms. To explore the host-parasite interaction in more detail, they also looked at changes in host gene expression during the helper T 1 (T_H1)-like immune response of whipworm-infected mice. Jex et al.³ report the whole-transcriptome analysis for T. suis, along with stage-, sex- and tissue-specific gene expression patterns.

Deworming—or anthelmintic treatment—is carried out primarily through mass administration of benzimidazole drugs, but there is a high rate of reinfection⁸. Foth et al.² identify close to 400 genes and putative drug targets for anthelmintic treatment on the basis of their essentiality, expression patterns and inferred druggability. For a number of these genes, drugs already exist to treat other diseases. Jex et al.³ identify specific short noncoding RNAs that have an important regulatory role in stage-specific differentiation and the sexual development of T. suis, providing another avenue for gene disruption. Although T. trichiura–specific antigens have not yet been identified for vaccine development as with other helminths⁸, the availability of these new genome sequences also provides an incentive to develop trichuriasis vaccines.

Host-pathogen interactions

By combining genome sequence with tissue-specific gene expression data, both Foth et al.² and Jex et al.³ give valuable insights into how these parasites potentially modulate the host response. Mammals become infected with Trichuris when they ingest embryonated eggs, which hatch in the small intestine and undergo larval development into adult worms (Fig. 1). The worms eventually penetrate the intestinal epithelium of the cecum, where they establish intimate contact with their hosts by transforming the epithelial cells into a tunnel-like structure where the stichosome and bacillary band are embedded. Thereafter, the parasite is able to exchange molecules and nutrients directly with the cytoplasm of the transformed cells. Foth et al.² and Jex et al.³ each identified serine proteases and serine protease inhibitors as being highly overexpressed in tissue-specific gene expression profiles for these specialized organs in both T. muris and T. suis. The protease inhibitors also appear to comprise protein domains (such as the WAP (whey acidic protein) domain) associated with immunomodulatory functions, indicating a likely role in controlling inflammation during invasion of the intestinal epithelium.

Figure 1: The life cycle of the whipworm T. trichiura infecting a human host.

Debbie Maizels/Nature Publishing Group

Embryonated eggs are ingested by the human host as a result of soil-contaminated hands or food. In the small intestine, the eggs hatch into larvae that mature into adults, which eventually establish themselves in the mucosa of the cecum and ascending colon. Female worms can shed thousands of eggs per day.

Low-dose infection of certain mouse strains with T. muris leads to chronic infection and reproduces the pathology seen in human ulcerative colitis. To investigate the host response during infection, Foth et al.² performed transcriptome analyses of mouse cecum and mesenteric lymph nodes from the same infected mice. Both tissues had similar gene expression profiles and, when compared to tissues from naive mice, displayed an upregulation of immune-specific genes consistent with a T_H1 response, typical of chronic worm infections^9,10. Worms like Trichuris remain remarkably persistent within their vertebrate host, suggesting that they employ immunomodulatory strategies to regulate host immunity in favor of parasite persistence, with minimal induction of immunopathology. The transcripts for two cytokines thought to control tissue damage in chronic infections (interleukin (IL)-10 and IL-22) were seen by Foth et al.² to be upregulated in the infected host. Jex et al.³, conversely, propose a model of Trichuris-driven immunomodulation in which the parasite secretes various molecules with relevant properties, including the ability to stimulate anti-inflammatory IL-10–producing T cells.

Parasite products as immunomodulators

Many reports indicate that helminth-derived molecules have potent regulatory or stimulatory effects on the immune system of their mammalian hosts¹¹ and that these effects could be harnessed as immunotherapeutics against diseases considered to primarily affect the developed world, such as type 1 diabetes and multiple sclerosis¹². Jex et al.³ predict that more than 600 of the T. suis genes encode excretory-secretory proteins. Significantly, whereas these secreted proteins make up 4% of the T. suis genes, they constitute 10% of the transcript abundance across all developmental stages. A key finding in both Foth et al.² and Jex et al.³ is that many of the genes shown to have higher expression in the anterior region of the worm could have a central role in immunosuppression and in inhibiting inflammation during damage to the epithelium of the gut. Already, T. suis ova are licensed as a medicine and are largely considered to be a safe therapy because they are rapidly expulsed by the human host¹³. They have been administered to treat Crohn's disease and ulcerative colitis, but their potential use in controlling inflammatory bowel diseases (IBD) recently suffered a setback when clinical studies failed to demonstrate a statistically significant effect¹⁴. In contrast, clinical tests in multiple sclerosis are proving encouraging¹⁵. The analyses by Foth et al.² and Jex et al.³ of these three Trichuris genomes highlight specific molecules that could be considered to be immunomodulators with therapeutic potential for immune-mediated diseases. These are likely to become more popular in future clinical tests than the alternative, which requires the ingestion of a live parasite.