Kenneth S. Warren

Mild prolonged schistosomiasis in mice: Alterations in host response with time and the development of portal fibrosis

Abstract Mice with mild prolonged infection with Schistosoma mansoni showed a considerable variation in the appearance of the hepatic granulomas appearing around mature eggs in the course of infection. An earlier large, necrotic, exudative-proliferative lesion turned later into small, rounded granulomas composed of a few histiocytes and fibroblasts. This was interpreted as morphological expression of hypersensitivity and immunity developing in the course of prolonged infection. Gradual resorption of older granulomas and a more effective and economical response to new eggs were the principal mechanisms by which the host protected itself more efficiently. The mild prolonged infection was accompanied by portal inflammation and later also by fibrosis, which was similar to the early “pipe-stem” fibrosis as seen in human beings. Whether this was a late sequela of earlier changes or a progressive lesion due to the infection was not determined.

Schistosoma mansoni: Antigenic secretions and the etiology of egg granulomas in mice

Abstract In order to determine the exact role of antigenic secretions in the formation of the granuloma around S. Mansoni eggs, the following three experiments were performed: 1. (1) The early stages of granuloma formation around eggs injected intravenously into the pulmonary microvasculature of mice were studied at 12-hr intervals and correlated with the onset of delayed footpad swelling. No reaction was seen around the eggs until 72 hr, at which time delayed footpad swelling was also first seen. 2. (2) Immature eggs (without secretory glands) obtained from worms maintained in tissue culture resulted in virtually no granuloma formation at 8 days in un-sensitized animals. Soluble egg antigens extracted from immature eggs and injected intraperitoneally did not sensitize mice to granuloma formation around eggs subsequently injected into the pulmonary veins. 3. (3) Eggs maintained in tissue culture over a period of 14 days gradually lost their ability to elicit granuloma formation when injected into the pulmonary vessels. Tissue culture medium obtained at similar time intervals and injected intraperitoneally into mice, concurrently lost its ability to sensitize the animals to granuloma formation around fresh eggs later injected intravenously. On the basis of the above results it is concluded that granuloma formation around S. mansoni eggs is due wholly to their output of antigenic secretions.

The influence of treatment on the development and course of murine hepato-splenic schistosomiasis mansoni

Abstract 1. 1) Previous studies have shown that mice treated at 5 weeks following infection with Schistosoma mansoni developed no disease, whereas their untreated counterparts rapidly developed hepato-splenic schistosomiasis. These findings were confirmed in the present study and, in addition, it was found that mice treated at 7.5 weeks when there were many eggs in the liver, and at 10 weeks when hepato-splenic schistosomiasis was fully developed, rapidly reverted to normal in regard to portal pressure and liver and spleen size. 2. 2) Having eliminated the source of eggs by killing the worms, it was possible to study the devolution of the egg lesions that were already present. The inflammatory cells rapidly disappeared, followed thereafter by a relatively sudden resorption of fibrous tissue. Between 25 and 52 weeks following treatment there was an almost complete disappearance of all egg lesions. 3. 3) Mice surviving treatment lived indefinitely, whereas all untreated animals died within 25 weeks following infection.

A comparison of Puerto Rican, Brazilian, Egyptian and Tanzanian strains of Schistosoma mansoni in mice: penetration of cercariae, maturation of schistosomes and production of liver disease.

Abstract 4 geographical strains of Schistosoma mansoni, Puerto Rican, Brazilian, Egyptian and Tanzanian, each maintained in its local snail host, were studied in mice. On exposure to a given number of cercariae the animals infected with the Puerto Rican strain developed the largest number of worms, followed by the Egyptian strain and then by the Tanzanian and Brazilian strains. The production of liver disease was studied in mice each harbouring only one pair of worms. The Brazilian and Puerto Rican strains appeared to be most virulent in this regard, the Egyptian strain causing the least severe liver reaction and the Tanzanian strain producing the fewest eggs.

Chronic murine hepatosplenic schistosomiasis mansoni: Relative irreversibility after treatment

Abstract Previous studies in the experimental animal on hepatosplenic schistosomiasis mansoni after antischistosomal treatment have revealed marked regression of both overt disease and liver lesions; treatment in all instances was instituted at the acute or early chronic stage of the disease. In the present study treatment was started in the late chronic stages of hepatosplenic schistosomiasis: regression of the disease was relatively slight over a 25-week period.

Comparative susceptibility to Schistosoma mansoni of the squirrel monkey, the slow loris and the tree shrew.

Abstract After exposure to cercariae of Schistosoma mansoni it was found that a New World monkey (Saimiri sciurea—the squirrel monkey) was susceptible to infection, a prosimian primate (Nycticebus coucang—the slow loris) was relatively resistant, and a “pre-primate” (Tupaia glis—the tree shrew) was virtually insusceptible to infection. On the basis of this and other studies with primates, it appears that the lower primates are less susceptible to infection with S. mansoni than the higher primates.

Production of Portal Hypertension and Esophageal Varices in the Mouse.

Summary A useful technic for producing portal hypertension and esophageal varices in the laboratory animal has been described. Ten weeks following infection of mice with S. mansoni, there was a significant increase in portal pressure in 51% of our animals, and the development of esophageal varices in 43%.

Schistosoma mansoni: Utilization of exogenous metabolites by eggs in vitro

Abstract Schistosoma mansoni eggs were isolated from the livers of mice infected for 8 wk and were purified by a series of settling and sieving procedures. Aliquots of eggs were suspended in saline with added Eagles minimal essential medium supplemented with NaHCO 3 , glutamine, penicillin, and streptomycin to which a variety of radioisotope labelled metabolites were added. The uptake and utilization of tritiated thymidine demonstrated a high rate of DNA synthesis, particularly in the more immature eggs studied. RNA synthesis as shown with tritiated uridine was also significant. Large amounts of 14 C-labelled isoleucine and arginine were incorporated into protein. Little glycolytic activity was demonstrated on prolonged incubation with 14 C-labelled glucose. A high rate of catabolism of amino acids to CO 2 was observed, as was a very high rate of acetate metabolism. Degradation of radiolabelled glutamate after incubation of eggs with 14 C acetate revealed labelling consistent with metabolism via the Krebs cycle. Thus, Schistosoma mansoni eggs utilize a wide variety of exogenous metabolites. They show active DNA and RNA metabolism, incorporation of amino acids into protein, and intermediary metabolism characterized by a low rate of glycolysis and an active Krebs cycle.

Studies on the treatment of molluscan schistosomiasis mansoni with antibiotics, non-antibiotic metabolic inhibitors, molluscicides and anti-schistosomal agents

Abstract 50% of 16 antibiotics, non-antibiotic metabolic inhibitors, molluscicides and antischistosomal agents suppressed molluscan schistosomiasis mansoni. In addition to chloramphenicol which had previously been shown to do so, 3 other antibiotic inhibitors of protein synthesis also suppressed the disease (puromycin, erythromycin and streptomycin) as did both non-antibiotic metabolic inhibitors (6 mercaptopurine and methotrexate) and all 3 antischistosomal agents (antimony potassium tartrate, stibophen and lucanthone hydrochloride). Methotrexate was the first drug found to eradicate the infection rather than merely suppress it, and lucanthone hydrochloride is the most potent drug thus far discovered. In addition to suppression of the disease at 0·4 ppm, it completely prevents snail growth and egg laying at a concentration of 0·3 ppm.

The interaction between Entamoeba histolytica and Schistosoma mansoni infections in mice.

Abstract A synergistic relationship between caecal amoebiasis and S. mansoni infections has been demonstrated in the mouse. The interaction affected both the infectivity of an E. histolytica inoculum and also the likelihood of amoebic tissue invasion. There was some correlation with worm load. Prepatent schistosome infections were apparently without effect but animals with unisexual infections were somewhat more susceptible than controls. Possible mechanisms include intramucosal tissue damage produced by schistosome ova and an altered immunological responsiveness.