How a Schistosoma Parasite Prevented a War
During the Chinese Revolution of 1949, the Chinese Communist Party moved tens of thousands of troops to invade the island of Taiwan, then known as Formosa, in the ensuing war against the Nationalists. Due to the lack of ports on the island, the soldiers were required to swim to reach the shores of the Taiwanese island. However, unknown to them, during their swimming lessons in the Chinese canals, they were fighting another war that changed the course of history.
The soldiers fell ill with skin rashes, fever and abdominal pain, as a result of swimming in canals swarmed with snails harboring a microscopic blood parasite, Schistosoma japonicum. When the army recovered more than 6 months later, U.S. allies had already entered the territories, thwarting the invasion of the Chinese communists. Other such examples where the parasite species Schistosoma played important roles in warfare and society abound in history. In 1798, when Napolean's troops landed in Egypt, they described it as “the land of menstruating men.” In reality, people were infected with Schistosoma, and the production of parasite eggs in humans resulted in bladder inflammation that led to aturia or blood in the urine.
But schistosomiasis, the disease caused by Schistosoma, is not simply a disease of the past. In 2019, it still plagued about 240 million people worldwide. The disease is classified as a Neglected Tropic Disease (NTD), as it affects several developing countries and regions with high poverty rates. Among parasitic diseases, schistosomiasis comes a close second to malaria in terms of its public health impact and economic burdens in tropical and subtropical regions, including Africa, the Middle East, China, Indonesia, Brazil and Venezuela. The disease is also called "bilharzia," after the German physician, Theodor Bilharz, who first identified Schistosoma haematobium during an autopsy in Cairo in 1851. S. japonicum, S. haematobium, S. mansoni and S. mekongi are some species of blood flukes (flatworms) capable of causing schistosomiasis. Below is a discussion of the life cycle of Schistosoma, disease symptoms and currently available treatments for schistosomiasis.
The Life Cycle of Schistosoma
Schistosoma needs both snails and mammals to complete its complex life cycle, which spans both asexual and sexual reproduction. Upon contact with water, Schistosoma eggs hatch to form miracidia, free-swimming ciliated larvae. Miracidia do not have mouths and cannot feed themselves. Their sole purpose is to locate and colonize snails that serve as suitable intermediate hosts for further stages of their asexual reproduction cycle.
Miracidia use glandular secretions to attach to and decompose cells on the outside of their specific snail hosts. After penetrating snail tissues, miracidia develop into sac-like structures called mother sporocysts, which produce daughter sporocysts by asexual reproduction. These daughter cysts give rise to cercariae, free-swimming larvae that have tapering heads with large penetration glands at the anterior end and slender tails with a bifurcation fork at the posterior end. At this stage, cercariae leave the snail in search of suitable mammalian hosts, including humans.
Upon sensing specific chemicals from the human skin, like fatty acids and L-arginine, cercariae migrate toward and penetrate the skin by degrading host proteins, including elastin, keratin and collagen, that serve as barriers to invasion. During penetration, cercariae shed their forked tails to form schistosomulae, which subsequently migrate via blood circulation to different parts of the body. First, they travel to the lungs, then to the heart, and finally, they lodge themselves in the liver. Once there, the parasites feed on blood while they inhabit their hosts’ blood vessels.
Schistosomulae can acquire nutrients in 2 ways, either by ingestion of blood into the gut or direct uptake across their body surface. As the parasites feed, they also mature into separate-sex adults. It is estimated that an adult male S. mansoni can ingest ~39,000 erythrocytes per hour, while the female can ingest ~10-fold higher, as it requires additional energy for egg production. Digestion of blood converts heme to hemozoin, an insoluble brown pigment that schistosomes regurgitate as a waste product. Hemozoin is what gives schistosomes their characteristic dark appearance.
Both males and females have ~1-1.5 cm long cylindrical bodies, but females are slightly thinner (~0.015 cm wide female vs 0.1 cm wide male). This slight difference in width becomes critical during mating, when the male fluke grasps the female in a groove in its ventral surface, called the gynaecophoral canal. Contact via gynaecophoral canal likely plays a critical role in the transfer of hormones and nutrients between the male and female flukes. Male-female mating pairs that are formed in the liver are permanent and can survive that way for several years, a condition called in copula. In the absence of a male partner, the female is unable to mature sexually. Specifically, uncoupling the female from the male hinders the differentiation of gonads or sex organs and the formation of the egg-making organ called the vitelline gland.
The male-female pair continue their adventures from the liver to their final destination where they lay their eggs. The final resting place varies depending on the species. S. mansoni lodges near the large intestine, S. haemotobium goes to the bladder, S. japonicum ends up near the small intestine and S. nasale travels to the nose (in cows). At this final destination, the female lays ~300 eggs per day, most of which escape the host via feces or urine. However, some eggs can find their way back to the liver (via the bloodstream) where they can cause tissue damage.
Symptoms of Schistosomiasis
Most of the clinical symptoms following Schistosoma infection, including fever, cough and abdominal pain, result from the body’s reaction to the eggs. Progression of schistosomiasis can be acute (also called Katayama fever) or chronic. Rarely, the infection may also lead to lesions in the central nervous system, and eggs may end up in the brain or spinal cord.
Treatments and Prevention for Schistosomiasis
Praziquantel is currently the only drug available for treating schistosomiasis. Although its exact mechanism of action is still unknown, praziquantel is effective at paralyzing the adult worm. However, it cannot kill immature schistosomes or prevent reinfection, and evidence of praziquantel resistance is increasing.
In addition to drug treatment, the introduction of snail control in hot spots (mollusciciding) has been evaluated as a method for schistosomiasis elimination. However, molluscicides, particularly niclosamide, have toxic effects on other species in the aquatic ecosystem. Hence, some scientists are making efforts to explore other molluscicides with minimal off-target effects.
Currently, there are no vaccines available for human use against schistosomiasis, although research is underway with several antigen-based vaccines in Phase I and Phase II trials. One such candidate antigen is Sm14, a fatty acid-binding protein that helps the parasite acquire lipids from the mammalian host. The Phase II trial results of this vaccine study are not yet published.
Another candidate antigen is Sm-p80, the large subunit of a calcium-activated protease that helps the parasite evade the host immune response. It is a promising candidate because of its prophylactic, immunogenic and therapeutic effects, with a significant reduction in the abundance of adult worms and egg production. The Sm-p80-based vaccine is currently in Phase I trial, after demonstrating a robust protective effect in mice and non-human primates.
Limited funding and the body’s complex immune response to the worms has hindered progress in vaccine and drug development. As with other NTDs, schistosomiasis is a disease intrinsically linked to poverty, and equitable efforts are needed at various levels, both local and global, to effectively combat the disease. Non-profits like the Schisosomiasis Control Initiative (SCI) work with governments in sub-Saharan African countries to develop sustainable solutions in the fight against the parasitic disease. The World Health Organization set the year 2025 as a target year to globally eliminate schistosomiasis as a public health problem in countries where it is endemic.
Several countries have implemented control programs that show the elimination of disease is possible with proper surveillance methods. For instance, in 1950, the Japanese government launched a nationwide public health campaign against schistosomiasis that included lining canals with cement, better access to health and education, snail control and evidence-based policy by the government. This resulted in the elimination of the disease in 1977, although active surveillance continued into the 1990s to ensure the efforts remained successful. Hopefully, the evaluation of several new drugs in clinical trials and progress in novel vaccine technologies will help the goal of globally eliminating schistosomiasis by 2025 to become a reality.
Dr. Peter Hotez, founding Dean of the National School of Tropical Medicine at the Baylor College of Medicine, joins Meet the Microbiologist to discuss NTDs and the publication of the third edition of his book, Forgotten People, Forgotten Diseases.