Experimental models of Schistosoma mansoni infection

Experimental models of Schistosoma mansoni infections in mammals have contributed greatly to our understanding of the pathology and pathogenesis of infection. We consider here hepatic and extrahepatic disease in models of acute and chronic infection. Experimental schistosome infections have also contributed more broadly to our understanding of granulomatous inflammation and our understanding of Th1 versus Th2 related inflammation and particularly to Th2-mediated fibrosis of the liver.     

Natural infection of wild rodents by Schistosoma mansoni

In Planalto, a small locality in the interior of the Bahia state, Brazil, 47% of sylvatic rodents were found to be naturally infected with Schistosoma mansoni, whereas the prevalence of the infection in the inhabitants of the area was 3.26%. The rodents (Nectomys) live near the houses, in contact with water, passing viable schistosome eggs in the stools. Worm burden is variable amongst such rodents. Periovular granulomas are small, especially in liver and intestines, and hepatic fibrosis is mild or absent, with no morphological evidence of portal hypertension being noted. Miracidia isolated from the eggs recovered from Nectomys readly infected laboratory-raised Bahia strain of Biomphalaria glabrata. Cercariae then obtained infected Swiss mice in a similar way as the human strains of S. mansoni kept in laboratory. Also, Swiss mice left in contact with water collections in Planalto were easily infected, which proved the transmissibility potential of the area. In conclusion: sylvatic rodents found in the area of Planalto tolerate well S. mansoni infection, eliminate viable eggs in the stools, are usually infected with a strain probably of human origin and therefore may play a role in maintaining parasite cycle in the area.     

Natural versus drug-induced resistance in Schistosoma mansoni infection

Rodrigo Corrêa-Oliveira, Iramaya Rodrigues Caldas and Giovanni Gazzinelli here focus on the immune response of individuals with natural resistance to schistosomiasis, which differs significantly from that of post-treatment resistant and infected individuals. They suggest that the activation of T helper type 1 (Th1) and Th2 cells is needed for the induction of natural resistance against Schistosoma mansoni infection.     

Secondary amyloidosis due to Schistosoma mansoni infection.

Four children with Schistosoma mansoni infection and the nephrotic syndrome with varying degrees of renal dysfunction were found on histological examination to have amyloidosis. In one boy who had no evidence of renal failure complete clinical regression of his nephrotic syndrome and almost complete disappearance of renal amyloid deposits followed adequate treatment of his schistosomal infection. Conditions known to cause secondary amyloidosis were excluded in all four patients. Amyloidosis in association with mansoni infection is probably more common than is currently recognised. Early treatment of the infection, before renal function becomes impaired, may result in regression of the amyloidosis.     

Neuroinflammatory implication of Schistosoma mansoni infection in the mouse

Schistosomiasis is a parasitic disease due to Schistosoma mansoni. Schistosome infection is known to induce granulomas not only in the spleen, bladder, liver and intestine but also in the brain and spinal cord resulting in severe neuropathological and psychiatric disorders though the interaction between Schistosoma mansoni infection and the nervous system has received on the whole little attention. In the present review it has been discussed recent findings from experimental Schistosoma mansoni infection in mouse nervous system. We show that brain granulomas are associated with a significant alteration in the constitutive levels of nerve growth factor (NGF), a trophic factor playing an essential role in nerve growth and differentiation and in preventing neuronal damages. Animals infected with schistosomes suffered also of increased pain sensitivity which was inhibited by TNF-alpha antibody injections and not by anti-NGF. These findings suggest that the neuropathological dysfunctions in neuroschistosomiasis may be linked to changes in the basal levels and/or activity of neurotrophic factors caused by local formation of granulomas.     

Oxamniquine for treating Schistosoma mansoni infection in Sudan.

The efficacy and acceptability of oral oxamniquine were assessed in Sudanese patients infected with Schistosoma mansoni. Cure rates, determined by the absence of viable eggs in the stools six months after treatment, were 94.9% in patients treated with a total of 60 mg/kg, 78.8% in patients treated with 40 mg/kg, and 68.9% in patients treated with 30 mg/kg. All treatment regimens considerably reduced the egg count in those patients not cured. The drug was well tolerated and the side effects were minimal and transient, the most common being dizziness. Most of the patients noticed a reddish discoloration of their urine, which was probably caused by a metabolite of the drug. In patients who received 60 mg/kg oxamniquine there were transient rises in eosinophil counts and in serum alanine aminotransferase concentrations. Though 60 mg/kg was by far the most effective dose in terms of cure rate, egg counts were significantly reduced on all three doses. The lower doses could therefore be useful in a low-cost control programme in reducing transmission of S mansoni infection.     

The changing pattern of pathology due to Schistosoma mansoni infection

A survey of the autopsy data on hepatosplenic schistosomiasis during periods, before and after the advent of new chemotherapeutic drugs, revealed that: a) the pathological presentation was the same for the two periods; b) the number of cases in the last five years is progressively decreasing; c) hepatosplenic disease due to schistosomiasis is becoming rare in young people. These data represent a change in the pattern of pathology in schistosomiasis, probably related to new chemotherapy.     

Characterization of the immunosuppressive state during Schistosoma mansoni infection.

Analysis of a murine model of schistosomiasis revealed that both the thymus (T)- and bursa (B)-derived compartments of the immune system are modified during acute infection. The functional capacity of T and B lymphocytes to respond to mitogenic stimuli and the humoral response to thymus-dependent (SRBC) and thymus-independent (DNP-Ficoll) antigens are severely depressed. In addition, it was found that suppressor cells capable of inhibiting the response of normal lymphocytes to SRBC arise during acute infection. Although the splenic frequency of T (theta) and B (Ig+) cells remained constant during chronic infection, quantitative changes were detected in each population. In the T cell pool there was a decrease in the percentage of Ly-1+ cells and a concomitant increase in Ly-1+, 2+, 3+, cells, whereas the B cell pool showed a progressive loss of complement receptor-bearing lymphocytes, which apparently was the result of inactivation of surface complement receptor by a serum factor specifically found in infected mice. Characterization of the serum factor strongly suggests it is an immune complex. Thus, it appears that both suppressor cells and immune complexes contribute to changes noted in the immune system during acute schistosomiasis. Additional studies carried out in mice after unisexual infection revealed that egg production is not a necessary prerequisite for several of the immunologic phenomena associated with acute schistosomiasis.     

Origin and diversification of the human parasite Schistosoma mansoni

Schistosoma mansoni is the most widespread of the human-infecting schistosomes, present in 54 countries, predominantly in Africa, but also in Madagascar, the Arabian Peninsula, and the Neotropics. Adult-stage parasites that infect humans are also occasionally recovered from baboons, rodents, and other mammals. Larval stages of the parasite are dependent upon certain species of freshwater snails in the genus Biomphalaria, which largely determine the parasite's geographical range. How S. mansoni genetic diversity is distributed geographically and among isolates using different hosts has never been examined with DNA sequence data. Here we describe the global phylogeography of S. mansoni using more than 2500 bp of mitochondrial DNA (mtDNA) from 143 parasites collected in 53 geographically widespread localities. Considerable within-species mtDNA diversity was found, with 85 unique haplotypes grouping into five distinct lineages. Geographical separation, and not host use, appears to be the most important factor in the diversification of the parasite. East African specimens showed a remarkable amount of variation, comprising three clades and basal members of a fourth, strongly suggesting an East African origin for the parasite 0.30-0.43 million years ago, a time frame that follows the arrival of its snail host. Less but still substantial variation was found in the rest of Africa. A recent colonization of the New World is supported by finding only seven closely related New World haplotypes which have West African affinities. All Brazilian isolates have nearly identical mtDNA haplotypes, suggesting a founder effect from the establishment and spread of the parasite in this large country.     

Leucine aminopeptidase of the human blood flukes, Schistosoma mansoni and Schistosoma japonicum

An array of schistosome endoproteases involved in the digestion of host hemoglobin to absorbable peptides has been described, but the exoprotease responsible for catabolising these peptides to amino acids has yet to be identified. By searching the public databases we found that Schistosoma mansoni and Schistosoma japonicum express a gene encoding a member of the M17 family of leucine aminopeptidases (LAPs). A functional recombinant S. mansoni LAP produced in insect cells shared biochemical properties, including pH optimum for activity, substrate specificity and reliance on metal cations for activity, with the major aminopeptidase activity in soluble extracts of adult worms. The pH range in which the enzyme functions and the lack of a signal peptide indicate that the enzyme functions intracellularly. Immunolocalisation studies showed that the S. mansoni LAP is synthesised in the gastrodermal cells surrounding the gut lumen. Accordingly, we propose that peptides generated in the lumen of the schistosome gut are absorbed into the gastrodermal cells and are cleaved by LAP to free amino acids before being distributed to the internal tissues of the parasite. Since LAP was also localised to the surface tegument it may play an additional role in surface membrane re-modelling.     

High expression of co-stimulatory and adhesion molecules are observed on eosinophils during human Schistosoma mansoni infection

Herein we have focused attention on major phenotypic features of peripheral blood eosinophils from chronic Schistosoma mansoni-infected patients. For this purpose, detailed immunophenotypic profiles of a range of cell surface markers were performed, including activation markers (CD23/CD69/CD25/HLA-DR), co-stimulatory molecules (CD28/CD80/CD86), chemokine receptors (CXCR1/CXCR2/CCR3/CCR5) besides L-selectin-CD62L and adhesion molecules (CD18/CD54). Our major findings pointed out increased frequency of CD23+-cells, besides decreased percentages of CD69+-eosinophils, suggesting a chronic activation status with low frequency of early activated eosinophils in chronic S. mansoni-infected patients (INT) in comparison to non-infected individuals (NI). Moreover, a dichotomic expression of beta-chemokine receptors was observed during human schistosomiasis mansoni with higher CCR5 and lower levels of CCR3 observed between groups. Enhanced expression of co-stimulatory receptors (CD28/CD86) and adhesion molecules (CD54/CD18), besides striking lower frequency of L-selectin+ were reported for eosinophils from INT group as compared to NI. Interestingly, the frequency of CD62L+-eosinophils and a range of cell activation related molecules pointed out an opposite pattern of association in NI and INT, where only INT patients that display lower frequency of CD62L+-eosinophils (first CD62L tertile) kept the unusual relationship between the expression of L-selectin and the CD23 activation marker. These findings suggest that distinct dynamic of activation markers expressed by eosinophils may occur during chronic S. mansoni infection.     

The role of chemokines in Schistosoma mansoni infection: insights from human disease and murine models

Chemokines are a superfamily of low-molecular-weight cytokines that were initially described for their chemoattractant activity. It is now clear chemokines have several other activities that modulate immune processes. More than 50 chemokines ligands and at least 19 receptors have been described to date. Depending on the number of N-terminal cysteine residues, chemokines are grouped in the subfamilies CXC, CC, C or CX3C. A growing body of evidence suggests a role for chemokines in the pathogenesis of several inflammatory diseases. Our studies involving mice and humans infected with Schistosoma mansoni suggest an important role of the chemokine CCL3 and its receptors (CCR1 and CCR5) in the pathogenesis of severe schistosomiasis. We suggest that the differential activation of CCR1 or CCR5 during the course of schistosomiasis may dictate the outcome of the disease.