Increased understanding of the development of schistosomes in yellow cattle and water buffalo, and elucidation of the related molecular mechanisms involved in S. japonicum infection caused by these two important natural hosts will provide useful information for the design and delivery of a vaccine against schistosomiasis. In this study, we confirmed that yellow cattle were more suited to the development and survival of schistosomes than water buffalo. Studies have shown that in some animal hosts, such as rats, pigs, and water buffalo, in the period after S. japonicum infection, the worm burden drops sharply, mainly owing to parasite clearance by the immune system and non-immune system factors, called the self-cure phenomenon [12, 17, 18]. This phenomenon is not found in mice, yellow cattle and some other schistosome-susceptible hosts. Several epidemiological surveys have reported that the natural infection of yellow cattle with schistosomiasis is obviously more severe than that of water buffalo [5, 19–21]. But water buffalo reared in endemic areas have more chances and longer time to contact with the contaminated water, that is, there are more chances for water buffalo to get infection and re-infection than yellow cattle and other animals, so although water buffalo are less suitable for the development of S. japonicum, they still retained a higher infection rate for this parasite. For many diseases, genetically determined host susceptibility can play a role in the clinical outcome. The pathogenesis of schistosomiasis and the apparent involvement of the immune response in both susceptibility and resistance have proved complex and difficult to understand, and therefore more research on these topics is required. The characterization of schistosome responses to host factors and the host factors that elicit/prevent developmental responses in schistosomes is important and also warrants further investigation [22, 23].
The tissue immune response and pathological damage caused by S. japonicum infection were observed in this study. The results revealed that the disease was much more serious in yellow cattle than in water buffalo; it seems that yellow cattle produce a stronger immune response than water buffalo, but the molecular mechanism for this phenomenon is still unknown.
It has been reported that schistosomes require signals from the host's immune system in order to develop fully into egg-producing adults [24, 25]. In the present study, we observed that the percentage of CD4+ T cells or the ratio of CD4/CD8 in yellow cattle was significantly higher than those in water buffalo from pre-infection to 7w post infection (Figure 4 and 5). This may be one explanation why schistosomes grow better in yellow cattle than in water buffalo. It has been supposed that a highly evolved relationship exists between schistosomes and their hosts that may include parasite exploitation of host endocrine and immune signals [26, 27]. Recent studies have confirmed, further, that S. mansoni failed to receive appropriate signals from the host immune system after infection of immunodeficient mice (RAG-1-/-), which resulted in the appearance of attenuated forms. Hepatic CD4+ T lymphocyte populations were identified as an integral component of the immune signal recognized by the parasite. Reconstitution with CD4+ cells rescued schistosome development during prepatency, which resulted in larger parasites, higher levels of pairing, and dramatically increased levels of egg production. Depletion of CD4+ cells but not CD8+ cells from wild-type mice in vivo by the administration of specific antibodies reduced egg production by the parasites. Therefore, the authors suggested that CD4+ T lymphocytes were responsible for promoting early schistosome development . CD4+ T lymphocytes have also been found to be necessary for the development of a parasitic protozoan: Houpt et al. reported that the depletion of CD4+ cells diminished both parasite burden and inflammation significantly in the mouse model of amebic colitis . Lamb et al. further found that schistosomes co-opt innate immune signals to facilitate worm development, and that CD4+ T cells influence the parasites indirectly by modulating monocyte/macrophage function . In this study, our results support the hypothesis proposed by Davies et al. and other investigators, and suggest that CD4+ T lymphocytes might be an integral component of the immune response and might related with worm development in yellow cattle, a natural host of the schistosome, but more investigations should be carried out to confirm it and whether susceptibility is correlated with the differences in the innate immune system between yellow cattle and water buffalo also needs further investigation.
Our observations also showed that the proportion of CD4+ T cells in yellow cattle decreased, the CD8+ T cells proportion in water buffalo increased, and the CD4/CD8 ratios were decreased in both species after challenge with schistosomes. The observations in yellow cattle were consistent with a previous report on mice, another schistosome-sensitive host . Subsets of CD4+ T cells are characterized by their cytokine-production profiles. Th1 cells produce primarily IFN-γ, and generally provide protection against intracellular pathogens, whereas Th2 cells produce mainly IL-4, IL-5 and IL-13, and are important for immunity against helminth parasites. During the schistosome infection process, the immune response includes at least three stages. In the first 3-5 weeks, mainly immature parasites migrate inside the host, which shows a dominant Th1-type response. In the following 5-6 weeks, the worms mature and begin spawning in pairs, and the immune response changes significantly: the Th1-type response decreases, but the Th2-type response becomes significantly enhanced. This response is stimulated mainly by the egg antigen. In chronic infection, after a long period of time with the continuous generation of parasite eggs, the Th2-type response is altered by the eggs and the egg granulomas become smaller than before . A study in mice found that the Th2-type cell-mediated granulomatous response appears to protect liver cells, but severe fibrosis occurs during the development of human schistosomiasis . From the acute phase to the chronic phase, the immune response against the infection changes from the Th1-type to the Th2-type, and induces a significant increase of CD4+ CD25+ regulatory T cells, which have a broad immune suppression function . In this study, we observed that, in yellow cattle, the IFN-γ level was higher pre-infection and at 4 weeks post infection, then decreased significantly and was at a very low level 7 weeks post infection. In addition, the level of IL-4 was very low pre-infection and 2w post infection; IL-4 was also expressed at a lower level at 4w but had increased at 7w post challenge with schistosomes. Th1 polarized immunity during the early phase of infection shifted to Th2 polarized immunity at 5-6 weeks. This was shown clearly in schistosome-infected yellow cattle, and was similar to the shift observed in other schistosome-susceptible hosts such as humans and mice . Previous reports have suggested that CD8+ T cells may erode the Th2 cell population steadily during chronic infection, which results in a reduced inflammatory reaction in murine schistosomiasis . In water buffalo, the percentage of CD8+ T cells was always significantly higher than that in yellow cattle; the level of IFN-γ was low in pre-infected animals, increased during early infection (2w), then decreased at 4w and 7w post infection. The IL-4 level was high in pre-infected water buffalo, then decreased post infection, and was at a very low level 7w post infection. No obvious shift of Th1-type to Th2-type polarized immunity was observed in water buffalo after infection with schistosomes. In addition, there were few egg granulomas and little pathological damage was seen in schistosome-infected water buffalo.