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It is a major parasitic disease (also known as Bilharzia) infecting humans and domestic livestock, and caused by several species of flatworms in the genus Schistosoma. The World Health Organisation estimates that up to 200 million people are infected in parts of South America, Africa and Asia.
The long-lived adult worms inhabit the hepatic portal vasculature (S. mansoni, S. japonicum) or vesical veins of the bladder (S. haematobium), and the eggs laid by the females in the tissues are the cause of pathology, the severity of which is related to worm burden and intensity of the host response. The most recent estimates suggest mortality rates directly attributable to schistosomiasis in sub-Saharan Africa at 280,000 per year, with millions of people showing clinical symptoms. Schistosomiasis thus remains an important public health problem.
The Life Cycle
Aquatic snails of various genera act as intermediate hosts for schistosomes, and the presence of suitable snail species determines the distribution of the disease. Transmission from humans to snails is effected by ciliated miracidium larvae that hatch from the parasite eggs voided in the faeces or urine. After a period of asexual multiplication in the snails, a second aquatic larval stage, the cercaria, emerges and infects humans by direct penetration of the skin.
Lytic secretions from gland cells facilitate this process and as the cercaria penetrates it transforms into the next stage, the schistosomulum, which spends several days in the skin before exiting via blood vessels, or more rarely lymphatics. Migration to the portal system is entirely intravascular, with a developmental stage in the lungs adapting the larva for onward migration through capillary beds.
The larvae are distributed around the organs of the body in proportion to cardiac output, with those passing down splanchnic arteries reaching the gut directly, whilst the remainder must recirculate. Once in the portal vessels the larvae shorten, begin to feed on blood, and grow to maturity.
Males and females then pair and migrate upstream to the intestinal walls (S. mansoni, S. japonicum) or through the vesical plexus to the walls of the bladder (S. haematobium). Egg-laying by S. mansoni adults commences 5 weeks after initial infection and, although the majority of eggs are voided from the host, a significant number lodge in the intestine walls and liver.
The host reacts by forming a large granuloma around each egg, comprising cells of the immune system. This host response is the primary agent of pathology, which in severe cases culminates in hepatomegaly and/or splenomegaly, periportal fibrosis and portal hypertension, the whole syndrome being life-threatening.
Praziquantel is commonly used to treat schistosomiasis, and for travellers who have caught the disease whilst visiting an endemic region it represents a means of cure. So, is a vaccine even necessary? Drug treatment will kill the majority of adult worms within the bloodstream, but a single dose may not kill them all. There is a possibility that some worms will remain and, most importantly, any developing larvae are not affected by the drug and so can go on to re-establish the infection.
We normally think that if we have had a disease, that we will be immune to that same disease in the future. However, this is not the case with schistosomiasis, as these worms are masters at evading their hosts immune system surviving, in some cases, for up to 40 years in the bloodstream. As a result, those who live in endemic areas are at constant risk of re-infection, which can be very rapid. There is nothing to stop an individual getting re-infected on the same day that they receive treatment, particularly if their only source of fresh water is contaminated. In these circumstances, treatment does little more than postpone the onset of the chronic symptoms of the disease. Whilst it would be possible to constantly re-treat whole communities, in practice, this is impractical. The ideal solution would be to develop a vaccine which would prevent the infection becoming established, and this has been the goal of schistosome research groups for several decades. Given that no approved vaccine has yet emerged, why do we believe that this an achievable aim?
Evidence for Immunity to Schistosomiasis
Whilst most people will become infected with schistosomiasis on contact with the infective stages of the parasite, this is not the case for everyone or, indeed, for other animal models of the diseases. In particular, there are a number of well-characterised "non-permissive" hosts, such as the laboratory rat and the rhesus monkey, which always eliminate the parasites before they can become established. There is also evidence that some people can mount an effective immune response against the worms. These so-called "endemic normals" show no signs of having an active infection. However, they are exposed to infection to the same extent as other members of their community and also have antibodies that recognise worm proteins. This shows that they have been infected, but have eliminated the worms before they can cause significant pathology.
So How Can a Vaccine be Found?
We believe that finding a vaccine for schistosomiasis will only come from a two-pronged approach. Firstly, we need to study and dissect the mechanisms of immunity in protected people or animals. This also breaks down into two components: how the immunity is induced in these hosts and how the immune system actually eliminates the worms before they can before established. Secondly, we need to find the targets of the immune response. These will be proteins which the parasite needs, for some reason, to expose to the immune system. If we can find out which proteins represent an "Achilles' heel" for the worm, and how successful hosts can attack the worm, we will have the basis of a successful vaccine.
Miracidium (S. haematobium; courtesy of Alison Agnew, Leeds University)
Biomphalaria glabrata snail (WHO\TDR)
S. mansoni Cercariae
Scanning electron micrograph of a skin-stage schistosomulum
Schistosomulum penetrating the wall of a blood vessel
Scanning electron micrograph of a lung-stage worm
Section through liver tissue containing an immature worm
Adult worm pair (WHO\TDR)