A parasite that infects 200 million people around the world, and leads
to the disease schistosomiasis, relies on its host’s immune response to
survive. This discovery, by American researchers, will fascinate biologists
and offers clues to treatments that might overcome the parasite. It could
also lead to therapies for other common diseases, including TB and syphilis.
Schistosomiasis, or bilharzia, is caused by flatworms of the genus Schistosoma.
The worms, which are transmitted by infected snails, are common in parts
of Africa and Latin America. Water development projects, such as the building
of dams and irrigation schemes, appear to favour the parasites. They lay
their eggs in human intestines, causing inflammation and the build-up of
nodules known as granulomas.
Granulomas do as much damage as the parasite itself. They develop because
the T cells of the human immune system attempt to defend the body against
the parasite, causing inflammation. Until now, immunologists had thought
that a complex mix of immune reactions was responsible, involving different
T cell types and cytokines, the messenger proteins of the immune system.
Now, however, James McKerrow, Payman Amiri and their colleagues at the
University of California at San Francisco have shown that one cytokine alone
is responsible for granuloma formation. More surprisingly, they have discovered
that female schistosomes will only lay their eggs when the cytokine is present.
The team studied specially bred mice known as SCID mice which have no
immune system: they lack T and B cells so cannot produce cells and antibodies
against infection. When infected with Schistosoma mansoni, these mice did
not form granulomas and the number of eggs the worms produced was sharply
McKerrow and his colleagues then returned part of the immune system
of the infected SCID mice by injecting T-helper cells known as Th2 cells.
These cells produce a specific set of cytokines. By blocking each cytokine
in turn with a specific antibody, and observing what effect this had on
granuloma formation, the team narrowed the search to one cytokine, TNF alpha.
Next, the team injected schistosome-infected SCID mice with purified
TNF alpha alone. Granulomas formed around the eggs: the more TNF, the more
granulomas. Also, the greater the dose of TNF, the more eggs the females
laid. When the researchers cultured adult pairs of worms in the presence
of varying amounts of TNF, egg-laying increased in line with the dose (Nature,
16 April, p 604).
The findings demonstrate the close relationship between parasite and
host. ‘The parasite is dependent on its host’s immune response, which is
supposed to be protective,’ says McKerrow.
The research also has ‘profound implications’ for therapy, he says.
Blocking TNF with a specific antibody should stop the damaging granulomas
and the laying of eggs. Another group of researchers on the same track is
already testing an anti-TNF antibody in humans.
McKerrow is more cautious, because granulomas turn out to have a purpose.
While they certainly cause long-term disease, they may prevent a more acute
disease. Schistosome eggs secrete a substance, as yet unidentified, that
is highly toxic to the liver. The granulomas prevent the toxin from escaping,
suggesting the immune system has evolved this form of partial protection.
McKerrow is working with a team at the University of Wales to identify the
toxin and make a specific antibody to block it. The two treatments could
then be tested together, he hopes.
Granulomas are an important cause of the damage caused in TB and syphilis,
among other infections. Anti-TNF therapy might also help these diseases.