25 year-old man with advanced schistosomiasis
Among parasitic diseases, schistosomiasis is generally believed to rank second behind malaria in global importance. This disease infects more than 200 million people in 74 countries. Of these, 20 million people suffer severe consequences from schistosomiasis, with 800,000 dying, and 120 million others symptomatic. Furthermore, it is estimated that 500-600 million are at risk of infection. Schistosomiasis is caused primarily by three species: Schistosoma mansoni (Africa and South America), Schistosoma haematobium (Africa and the Middle East), and Schistosoma japonicum (Asia). Below is a map displaying the demographic range of each species of schistosome.
The current means of controlling this disease is through chemotherapy, vector elimination, sanitation, and health education. However, these measures are temporary and expensive and have not significantly reduced the burden of the disease. Chemotherapy with praziquantel has been highly effective with minimal side effects in curing the disease, but it does not prevent reinfection. In addition, this medicine is expensive, and as such, is not accessible to all. Therefore widespread use of chemotherapy requires continued, repeated treatments and indefinite surveillance. Also, there is always the possibility of the emergence of drug resistant strains. The use of molluscicides is very expensive and there is a fear that they may be detrimental to the environment. Furthermore, the increased use of irrigation worldwide has aided in the spread of schistosomiasis by expanding the habitat of the fresh water snail vector.
Unfortunately, schistosomiasis is a disease that primarily results from the lack of education and public health facilities, appalling unsanitary conditions, and poverty found in many underdeveloped nations. So long as such conditions persist, schistosomiasis will continue to plague humanity. Human exposure to freshwater in underdeveloped tropical and sub-tropical areas suffering from these problems is the major determinant to infection. The schistosome larvae (cercariae) can penetrate human skin or enter the human as he/she drinks infected water or uses it for personal hygiene. For example, the cercariae can easily infect workers who wade through the wet-rice fields in Central China without wearing anything to cover their legs and feet. Or it can infect a child in Ghana who uses a local lake to bathe because there is no running water or functional sewage system. The images below detail the life-cycles of the three species of schistosomes (click on a specific image to see a larger version).
It is a genus of freshwater snail (called the genus Biomphalaria) that sheds the schistosome cercariae into the freshwater source. A single snail can shed thousands of cercariae. The cercariae immediately seek out hosts, and upon entering the human, the larvae transform into schistosomules. These schistosomules enter the bloodstream and migrate to the lungs, then to the liver, and finally reside in its primary site of infection. The final site will vary according to the different species. Schistosoma mansoni and Schistosoma japonicum infect the portal and mesenteric veins, while Schistosoma haematobium infects the urogenital venous system.
The schistosomules, once residing in their final location, sexually mature and form pairs; these pairs live in copula for their whole life, and immediately begin to lay eggs at the rate of 300 eggs per day. An infected individual with 25 pairs of mature, sexually reproducing pairs could expect to have 7500 new eggs per day over the course of three to five years. It takes roughly five weeks for the schistosomule to go from skin penetration to a mature, sexually reproducing state.
As the eggs circulate through the individual and cause the pathology (remember the egg burden causes the pathology and not the worm), many find their way to the excretory system. As the eggs reach freshwater, they hatch and release mircidia which must infect the snail vector in a matter of hours to survive. Once in the body of the snail, the mircidia undergoes extensive asexual reproduction, and the resulting cercariae are released into the water at the rate of 300-3000 per day.
The pathology of the schistosomiasis is to create a granulamatous reaction towards the eggs that fail to be excreted by the host. The resulting fibrosis can cause hepatomegaly in the liver, or they can cause urinary obstruction in the bladder and kidney damage. The severity of morbidity is related to the intensity of the infection. Since the parasite does not reproduce inside the human host, clinical signs will not appear until the worm burden increases through more infections and until a sufficient number of granulomas have been formed.
The host reaction towards the eggs is characterized by a delayed-type hypersensitivity reaction. However, the response is associated with a Th2 response rather than the Th1 response that is normally characteristic of a DTH reaction.
The adult schistosome resides in a capillary net and avoids host immune attacks by various mechanisms. The worm membrane undergoes continuous and rapid turnover, progressively losing its own antigens and acquiring host antigens onto its surface. It is through this method that the schistosome avoids the humoral defense system of the host. Furthermore, the schistosome does not appear to be susceptible to CTL killing in vitro. Although the CTL's can adhere to the schistosome, they cannot kill it.
Part of the optimism towards the creation of a schistosomiasis vaccine stems from the findings that continual exposure to schistosomiasis elicits partial immunity and that complete, sterilizing immunity is not required since the parasite does not replicate within the human host. One drawback in developing the vaccine has been in finding an adequate animal model. The human schistosome infection cannot seem to be reproduced accurately in animals , and the mechanisms of protection have been found to differ among the various experimental models.
Resistance towards schistosomiasis in humans is associated with a Th2 response with enhanced IgE production against parasite antigens. It is believed that the IgE antibodies participate in an antibody-dependent, cell-mediated cytotoxicity (ADCC) response that is the main mechanism of killing the parasite which is mediated by monocytes, eosinophils, or platelets. Those with high resistance to infection by S. mansoni were found to have IgE levels that are six to eight fold higher than those with a low resistance to the infection. The IgG4 antibody class is believed to counteract this IgE-mediated immunity, since the odds of reinfection increase with decreasing IgE levels and with increasing IgG4 levels. IgG4 may inhibit the ADCC response by competing with IgE antibodies and blocking them from binding to the epitopes on the schistosome. A high concentration of IgG4 combined with low IgE brought about a 100 fold increase in chance of reinfection. There have also been findings that IgG2 levels also seem to correlate positively with susceptibility to reinfection.
Pathology from schistosomiasis , however, is also associated with a Th2 response. IL-12, a cytokine that shifts T cells away from the Th2 subset, has been shown to reduce granuloma formation and subsequent fibrosis. There is hope that administration of egg antigens plus IL-12 could be used as an "anti-pathology" vaccine for preventing granulomatous disease. And since the disease caused by schistosomiasis is largely caused by the host response to eggs, rather than the infecting worms themselves, an anti-pathology vaccine might prove to be more effective.
This administration of IL-12 as an adjuvant has been shown to potentiate Th1-mediated immune responses and induce resistance to reinfection. In a recent study carried out by Mountford, Anderson, and Wilson at the University of York, IL-12, a powerful inducer of Th1 lymphocyte development, was administered in conjunction with a lung-stage Ag from the larvae of Schistosoma mansoni. Shortly after vaccination with this cocktail, cells from the lymph nodes draining the site of injecton show abundant IFN-gamma and minimal IL-4 on restimulation with larval Ags. IL-12 promoted development of a response entirely dominated by Th1 lymphocytes.
However, some believe that if down-regulation of the granuloma response is carried too far, leaking egg antigens may elicit toxic effects that could damage the surrounding hepatocytes in the absence of any sequestering reaction. Furthermore, since IL-12 stimulates a Th1 response, it subsequently down-regulates IgE production. Therefore, a vaccine towards schistosomiasis may have to achieve a balance where a Th2 response is elicited towards the parasite with elevated IgE production while the Th2 response towards the eggs is inhibited.
The current vaccine candidates include: Glutathione-S-transferase (Sm28GST), a 28 kDa enzyme found in the schistosomula and adult stages; paramyosin (Sm97), a 97 kDa muscle protein found in the schistosomula and adult stages; irradiation-associated vaccine antigen (IrV-5), a 62 kDa muscle protein found in all stages; triose-phosphate isomerase (TPI), a 28 kDa enzyme found in all stages; Sm23, a 23 kDa membrane antigen found on all stages; and fatty acid binding protein ((FABP)-14 or Sm14), a 14 kDa membrane antigen found in the schistosomula stage. Other approaches include creating anti-idiotype vaccines against carbohydrate antigens, interfering with egg production, and blocking sex pairing.
In addition to these protein candidate antigens for vaccines, another interesting approach to schistosomiasis vaccine development inivolves the irradiation of the cercariae of Schistosoma mansoni. By optimally irradiating the cercariae with 20 krad of gamma radiation (the optimal radiation dose), the larvae become attenuated and when injected into mice can induce up to 70% protection against a challenge with normal parasites. Gamma irradiation of cercariae appears to have no effect on the subsequent surface antigenicity of schistosomula , their ultra structure, or their ability to stimulate the proliferation of human mononuclear cells. The major difference between irradiated and normal larvae is in its pattern of migration through the human host. These optimally irradiated cercariae show retarded movement. It is this altered movement pattern that has been proposed as the key factor for the induction of protection. The irradiated cercariae show constrictions of the body at random points. Gamma irradiation causes these constrictions which exerts a delayed effect on the neuromuscular coordination of the parasite, without causing its death.
When considering possible vaccine strategies, it is important to consider the fact that at least three distinct stages of the parasite can be found in a human: schistosomula, mature worms, and eggs. This results in a changing of antigenic determinants on the parasite as it switches stages. Perhaps a multivalent vaccine can be produced that can induce a response to many of the different antigens, producing a stronger immune response.
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click on image for a larger version
Mode of Infection
S. haematobium
S. japonicum
S. mansoni
This man has advanced schistosomiasis. Note the distension of the collateral veins due to portal hypertension.
Vaccine Strategies
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Questions or Comments?
Name-Nathan_Cahoon@brown.edu
Name-Jeffrey_Hsu@brown.edu
Name-Chester_Lee@brown.edu
Name-Steve_Liao@brown.edu
Name-Nate_Merriman@brown.edu
References