A Special Interest Group Report
By
Robert Griffin
David Ryan
Lisa Stagon
Bradford Turner
A Dangerous Misconception Regarding Worms?
Mention the word "worm", and what comes to mind? Fish-bait? A beneficial animal living in the dirt, endlessly tilling loam and playing friend to Joe the farmer? A slimy little creature popping out of the lawn to say, "hello", every time it rains? Although true for the most part, these images of the worm are extremely misleading. There is another side to the worm. A side that drastically impacts more than 200 million people worldwide: people who are infected by parasitic, extracellular worms called helminthes (1,4).
Schistosoma: The Unbeatable Worm?
The Schistosoma species, S. mansoni, S. japonicum, and S. haematobium are the helminthes implicated in the chronic, often fatal disease schistosomiasis; as many as 800,000 people a year die due to Schistosoma infection.
Schistosoma infections primarily afflict areas of the world where poor hygiene and unclean water predominate; as a result, the majority of these infections occur in underdeveloped, sub-tropical and tropical regions (1,4).
And it is through unclean water that a Schistosome, the helminth, is able to infect human beings. It does this by using a freshwater snail vector. The snail, genus Biomphalaria, excretes the larval form of the worm, called a cercariae. It is the cercariae that enters the human host by consumption of contaminated drinking water or through penetrating the skin (4).
Once inside the host, the cercariae develop into sexually mature worms. These adults migrate to and anchor themselves to the walls of the vascular system or to the walls of the urinary tract. The male and females pair off and mate, producing large numbers of eggs (up to 300 a day), which migrate throughout the body by way of the blood. And strangely enough, it is the eggs-- not the worm-- that cause the disease schistosomiasis and generate a very strong immune response (4).
As mentioned above, the worm itself, the schistosome, is not a focus of the human immune response to helminthic infections. This is because the Schistosoma species frequently switch their own surface antigens with those of the human host, making recognition of the worm by cytotoxic T-lymphocytes difficult. Research has shown that even if cytotoxic T-lymphocytes do manage to bind to the surface of a helminth, they have extremely limited success in generating the immune response required to kill it (3,4,5).
The presence of Schistosoma eggs generates a very strong TH2 immune response, primarily involving IgE. Epitopes on the helminth eggs are recognized by the IgE, which, along with mediation by monocytes and eosinphils, leads to an antibody-dependent-cell mediated-cytotoxicity response (ADCC). The result: massive host tissue damage surrounding the eggs in the form of granulomas and fibrosis. Formation of such granulomas in the liver, kidney, or brain can lead to the death of the afflicted person (3,4,5).
What Are The Current Approaches To Developing A Vaccine For
Schistosomiasis?
Presently, there is a real cause for hope in the development of a
schistosomiasis vaccine.
One laboratory in France has centered its potentially groundbreaking
research on creating a vaccine that will directly target and eliminate
the infecting worm.
Great promise has been shown in their findings.
Specifically, this laboratory has isolated a schistosome antigen called Sm10 (it is undetermined whether this is a surface or internal peptide) that induces a strong skin response in previously sensitized donors. This worm immunogen, Sm10, has been sequenced and cloned into a cDNA library. From this library, researchers have successfully produced the Sm10 polypeptide. Researchers suspect that the Sm10 polypeptide can be used in a vaccine that will provide protective immunity against worm infection. Researchers are hoping that protective immunity will be generated by having T-cells present in the blood that have been primed with the Sm10 polypeptide. The matter of Sm10 being internally or externally expressed is not believed to be important. When antigen presenting cells (APC'S) encounter an invading schistosome, the entire worm is "attacked"; both internal and external polypeptides will be ingested by the APC and presented to the Sm10-primed T-cells. The Sm10 specific T-cells can then participate in a cytotoxic response that will clear the schistosome infection (2).
In laboratory mice, it was also shown that immunizing with Sm10 increases the levels of IgE in the sera. It is not known what effect this will have on the ability of Sm10 to act as an effective schistosome vaccine; further testing is still required (2).
Anti-pathology vaccine strategies against Schistosomes have been chiefly
centered on the cytokine Interluekin-12 (IL-12) [3,4].
According to a recent study conducted by the National Institutes of
Health, IL-12 has been shown to significantly boost the TH1 response
when administered with antigens from the worm. A heightened, or
"boosted", TH1 response will do very little to remove the worm itself,
or its eggs; in this situation, the T-cells have not been previously
exposed to antigen, or primed. One very important thing does happen when
IL-12 levels and the Th-1 response are increased: the down-regulation of
the TH2 response (3).
The down regulation of the TH2 response is critical to an anti-pathology
(anti-disease) vaccine because, if you'll recall, it is during the TH2
response that massive tissue damage results in response to the worm.
This damage results from the production of IgE. And if IgE can be down
regulated the degranulation and tissue damage associated with a TH2
response can be prevented (3,4,5).
This approach has some drawbacks. Inhibition of the TH2 response is a double-edged sword. While tissue destruction and granuloma formation may be reduced or prevented by an anti-pathology vaccine, it is these damaging responses that serve to protect the body against the worm and its eggs. If granulomas do not form around the schistosome eggs, then the worm eggs may break open and release potentially harmful, immunogenic schistosome antigens into the blood and tissues (3,4,5). While this technique may not be a preventative cure, it certainly may, after further developments in research, provide relief from the painful physical effects of schistosome infections.
Designing an effective vaccine against the parasitic helminthes, in
this case Schistosoma requires one thing: the mysteries surrounding the
immunological response to this killer worm must be unraveled.
Investigation of this topic has shown that researchers may be close to
their goal of a workable schistosome vaccine. This vaccine may come in
several forms and serve to protect against infection on several
immunological levels. If a vaccine serves to block infection or simply
helps to relieve the suffering of those who do have the misfortune of
becoming infected, the scientific community-and the world-- can agree on
one thing.
A vaccine can't come too soon.
Until more is known about the helminth, it will continue to kill nearly one million people every year. More research dollars and more scientists are needed in the battle against the helminth (1,4). Only then will we have the helminth right where we want it: on the end of a proverbial fishhook, unable to afflict humanity.