1. Developmental Biology
  2. Microbiology and Infectious Disease
Download icon

Tropical Disease: Dissecting the schistosome cloak

  1. Carolyn E Adler  Is a corresponding author
  1. Cornell University, United States
Insight
  • Cited 2
  • Views 872
  • Annotations
Cite this article as: eLife 2018;7:e36813 doi: 10.7554/eLife.36813

Abstract

Two proteins required for the growth of a skin-like structure called the tegument in parasitic flatworms could be new targets for drugs to kill these parasites.

Main text

Schistosomiasis is a devastating disease that affects around 200 million people worldwide. It is caused by parasitic flatworms known as flukes or schistosomes, which can infect people through exposure to contaminated drinking water and poor sanitation. Current treatments only work after infection has occurred, which makes it difficult to eradicate this disease completely (World Health Organization, 2018).

Schistosomes belong to the animal clade called neodermata, which consists of approximately 100,000 species of parasitic flatworms (Littlewood, 2006). The key evolutionary innovation defining this clade is a skin-like structure called the tegument that allows the parasites to withstand particularly harsh environments, such as the human digestive system and the bloodstream. It also helps the worms to absorb nutrients and attach to their hosts, important adaptions that potentially enabled the worms to become parasites.

Since all parasitic flatworms have a tegument, it is a prime target for drug development. Indeed, the only drug that is currently available for the treatment of schistosomiasis, praziquantel, is thought to work by dissolving the tegument, although the mechanisms involved remain unknown (Chai, 2013). We also do not fully understand how adult schistosomes generate and maintain their teguments.

Some studies indicate that schistosomes can survive inside human hosts for decades without getting detected by the immune system (Basch, 1991). Until recently, visualizing the tegument has required the use of electron microscopy, a technique that is difficult to combine with other strategies for highlighting cells. Now, in eLife, James Collins and colleagues at the University of Texas Southwestern Medical Center (UTSW), James Cook University and the Wellcome Trust Sanger Institute – including George Wendt of UTSW as first author – report a straightforward method to label the tegument with fluorescent dyes (Wendt et al., 2018).

Soaking mature schistosomes in water causes the tegument to swell, which damages its membrane and so allows the fluorescent dyes to seep into it. Unlike electron microscopy, fluorescent dyes are compatible with other cell biology techniques, such as lineage-tracing, in situ hybridization and antibody labeling. By using these methods, Wendt et al. were able to determine the identity and birthdate of the cells in the tegument. The results showed that far from being a static structure, the tegument constantly incorporates new cells, which are produced by adult stem cells (Figure 1; Collins et al., 2013). The rapid turnover of cells in the tegument resembles the production of epithelial cells in free-living flatworms called planarians, from which parasitic flatworms have evolved (Laumer et al., 2015; Egger et al., 2015).

Schematic of the tegument in adult flatworms.

Parasitic flatworms (schistosomes) live in the human bloodstream and are covered by a skin-like structure called the tegument, which is constantly replenished by newly produced stem cells (see inset) and so protects the worms from being detected by the host immune system. The tegument (blue) is made of cells that have fused together to form a continuous structure and express a protein called TSP-2 (purple). The cells in the tegument derive from stem cells (orange). These stem cells divide to produce intermediate cells (yellow), which mature to produce the cells (blue) that fuse to form the tegument. These tegument-fated intermediate cells express ‘zinc-finger’ proteins (zfp) and are necessary to build the skin-like structure. Creating drugs that could block these genes may present a new opportunity to treat schistosomiasis.

Wendt et al. then used an antibody that recognizes TSP-2: this protein, which is found on the surface of the tegument, is a molecular target in efforts to develop a schistosome vaccine (Pearson et al., 2012). This antibody allowed the researchers to purify the tegument cells, to determine the genes that are expressed by these cells, and to identify the proteins that are required to build the tegument. Wendt et al. identified two ‘zinc-finger’ proteins, which are only found in flatworms. These two proteins are necessary for forming the cells that produce the tegument. When one of these proteins is blocked, the schistosomes can no longer adhere to substrates, which may affect their ability to interact with the host.

Intriguingly, free-living planarians also rely on stem cells that express a similar zinc-finger protein to generate their epidermis (van Wolfswinkel et al., 2014; Tu et al., 2015). So, even though they have very different surfaces, parasitic flatworms and free-living flatworms employ strikingly similar molecular processes to make their ‘skin’. These conserved mechanisms may therefore be a prime target for drugs that treat schistosomiasis by preventing the formation of the tegument.

The dynamic nature of the tegument demonstrated in the study of Wendt et al. raises key questions about schistosomes and their host-parasite relationships. In particular, it is unclear how the integrity of the tegument can be maintained while its cells are constantly turning over. Over the course of its life, a schistosome displays antigens on its exterior that, presumably, reveal to its host that it is a foreign invader. So how does the worm regulate which proteins remain on its surface when new cells constantly join the tegument?

It has previously been hypothesized that rapid shedding of the tegument could be a mechanism to evade the immune system of the host, to potentially prevent antigens from being exposed (Abath and Werkhauser, 1996). More research is needed to determine how the constant replacement of the tegument cells contributes to the schistosome’s ability to evade host immune systems. Furthermore, expanding the repertoire of potential treatments remains a high priority, given the extreme number and diversity of parasitic flatworms, and the debilitating effects of the diseases they cause in livestock and in humans.

References

  1. Book
    1. Basch PF
    (1991)
    Schistosomes: Development, Reproduction, and Host Relations
    Oxford University Press.
  2. Book
    1. Littlewood DT
    (2006)
    The evolution of parasitism in flatworms
    In: Maule A. G, Marks N. J, editors. Parasitic Flatworms: Molecular Biology, Biochemistry, Immunology and Physiology. Wallingford: CABI. pp. 1–36.

Article and author information

Author details

  1. Carolyn E Adler

    Carolyn E Adler is in the College of Veterinary Medicine, Cornell University, Ithaca, United States

    For correspondence
    cea88@cornell.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3883-0654

Publication history

  1. Version of Record published: April 27, 2018 (version 1)

Copyright

© 2018, Adler

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 872
    Page views
  • 52
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Developmental Biology
    2. Physics of Living Systems
    Meisam Zaferani et al.
    Research Article

    Mammalian sperm rolling around their longitudinal axes is a long-observed component of motility, but its function in the fertilization process, and more specifically in sperm migration within the female reproductive tract, remains elusive. While investigating bovine sperm motion under simple shear flow and in a quiescent microfluidic reservoir and developing theoretical and computational models, we found that rolling regulates sperm navigation in response to the rheological properties of the sperm environment. In other words, rolling enables a sperm to swim progressively even if the flagellum beats asymmetrically. Therefore, a rolling sperm swims stably along the nearby walls (wall-dependent navigation) and efficiently upstream under an external fluid flow (rheotaxis). By contrast, an increase in ambient viscosity and viscoelasticity suppresses rolling, consequently, non-rolling sperm are less susceptible to nearby walls and external fluid flow and swim in two-dimensional diffusive circular paths (surface exploration). This surface exploration mode of swimming is caused by the intrinsic asymmetry in flagellar beating such that the curvature of a sperm’s circular path is proportional to the level of asymmetry. We found that the suppression of rolling is reversible and occurs in sperm with lower asymmetry in their beating pattern at higher ambient viscosity and viscoelasticity. Consequently, the rolling component of motility may function as a regulatory tool allowing sperm to navigate according to the rheological properties of the functional region within the female reproductive tract.

    1. Cell Biology
    2. Developmental Biology
    Sun-Hee Hwang et al.
    Research Article

    The role of compartmentalized signaling in primary cilia during tissue morphogenesis is not well understood. The cilia-localized G-protein-coupled receptor—Gpr161 represses hedgehog pathway via cAMP signaling. We engineered a knock-in at Gpr161 locus in mice to generate a variant (Gpr161mut1), which was ciliary localization defective but cAMP signaling competent. Tissue phenotypes from hedgehog signaling depend on downstream bifunctional Gli transcriptional factors functioning as activators/repressors. Compared to knockout (ko), Gpr161mut1/ko had delayed embryonic lethality, moderately increased hedgehog targets and partially down-regulated Gli3-repressor. Unlike ko, the Gpr161mut1/ko neural tube did not show Gli2-activator-dependent expansion of ventral-most progenitors. Instead, the intermediate neural tube showed progenitor expansion that depends on loss of Gli3-repressor. Increased extraciliary receptor (Gpr161mut1/mut1) prevented ventralization. Morphogenesis in limb buds and midface requires Gli-repressor; these tissues in Gpr161mut1/mut1 manifested hedgehog hyperactivation phenotypes—polydactyly and midfacial widening. Thus, ciliary and extraciliary Gpr161 pools likely establish tissue-specific Gli-repressor thresholds in determining morpho-phenotypic outcomes.