Single-cell sequencing vs. Schistosoma mansoni

CAMBRIDGE, UK—As sequencing technology has grown by leaps and bounds in the past few decades, it has been used to explore genomes in search of answers, resulting in valuable data in projects such as the Human Protein Atlas and the Cancer Genome Atlas. One of the most recent atlases, however, does not involve human genomes at all, but rather that of a parasitic worm: Schistosoma mansoni. A team of researchers from the Wellcome Sanger Institute and collaborating institutions have generated the first cell atlas for S. mansoni, and detailed their work in a Nature Communications paper titled “Single-cell atlas of the first intra-mammalian developmental stage of the human parasite Schistosoma mansoni.”

“Though significant advances in our understanding of Schistosoma mansoni have been made in recent years, we have yet to identify targets leading to a viable vaccine,” said Dr. Carmen Diaz Soria, a first author of the study from the Wellcome Sanger Institute. “Single-cell RNA sequencing provides a whole new level of biological detail, including previously unidentified cell types, that will allow us to better understand each cell population in the parasite.”

S. mansoni larvae emerge from snails into rivers and lakes, and then enter humans through the skin when they come in contact with infested water. Once it has infected the host, the parasite's intra-mammalian stage consists of a series of transitions as the larva matures to adulthood. Once a worm reaches that stage, it resides within human blood vessels and reproduces, generating eggs that either pass into water to continue the cycle of infection or remain in the body and cause schistosomiasis. This long-term illness can lead to organ failure and death, with hundreds of millions people affected each year; according to the World Health Organization, approximately “290.8 million people required preventative treatment for schistosomiasis in 2018.”

At present, there is only one treatment option available, and it is inappropriate for use in young children. In addition, the authors of the Nature Communications paper note that “While the only drug currently available to treat schistosomiasis (praziquantel) works efficiently to kill adult parasites, it is less effective against immature parasites, including schistosomula.”

This work focused on early-stage parasites, which were divided into individual cells. Those cells were characterized using single-cell RNA sequencing, and the resulting data were analyzed to identify cell types based on the genes that individual cells expressed and where in the body they were located.

This led the team to identify 13 distinct cell types, which included types in the nervous system and parenchymal system (which is comprised of a “filler” tissue that connects all the tissues of the parasite) that were previously unknown. Fluorescent probes were developed for genes expressed by each cell type, and scientists at the Morgridge Institute for Research applied the probes to confirm the locations of the newly discovered cells in whole parasites.

“Previously, S. mansoni cell types have been revealed primarily through a combination of morphological and ISH studies of specific tissues, with stem and tegument cell populations being among the best characterised,” the authors explained. “In the present study, we have identified and validated new markers, including a novel stem cell marker calmodulin (Smp_032950) that, to our knowledge, has not previously been associated with stem cells. Calmodulins are Ca²⁺ binding proteins involved in the miracidium-to-sporocyst transition, sporocyst growth and egg hatching. In addition, we found this calmodulin-encoding gene to be expressed in the reproductive organs of adult males and females.”

Dr. Jayhun Lee, a first author of the study from the Morgridge Institute for Research, noted: “We found genes in the muscular system of Schistosoma mansoni that might be specific to schistosomes. Because they are found in these parasites but not in humans, they are one possible treatment target identified by the study. The muscle allows the parasite to travel through our bodies, so if we were able to hinder that ability, we may be able to halt its life cycle before reproduction takes place.”

Another potential treatment target may lie with parenchymal cells. Previously, separating these cells for analysis has been a stumbling block, but this study revealed that some genes that play a role in how S. mansoni digests food are associated with parenchymal tissue, and as such, it could be possible to target parenchymal cells to interfere with the parasite's feeding process.

“Schistosomiasis is one of the most serious neglected parasitic diseases and gaining a deeper understanding of the parasite’s biology will help to expose vulnerabilities that could one day be targeted by new treatments. We hope that this cell atlas for the first intra-mammalian stage of Schistosoma mansoni will provide researchers with valuable clues to help accelerate the development of new treatments and eliminate this parasite from the lives of hundreds of millions of affected people each year,” remarked Dr. Matt Berriman, senior author of the paper from the Wellcome Sanger Institute.