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Title: Studies on coinfections with Schistosoma mansoni and Leischmania
Author: Hassan, Mohammed Fathalla
Awarding Body: London School of Hygiene & Tropical Medicine
Current Institution: London School of Hygiene and Tropical Medicine (University of London)
Date of Award: 2004
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Schistosomiasis and visceral leishmaniasis, each responsible for serious morbidity and mortality, also have overlapping endemicities e. g. in the Sudan. Both cause granulomatous responses in the liver. Leishmania donovani amastigotes are killed by Th1 dependent macrophage activation whereas schistosome eggs induce Th2 dependent granulomas which protect the liver tissue from toxic products and from Th1 dependent inflammatory responses. In view of the reciprocal counter-regulation of Th1 and Th2 responses it was hypothesized that co-infection would lead to altered immune responses and exacerbation of disease. This was modelled in the mouse using Schistosoma mansoni and L. donovani. When C57BL/6 mice were infected with 25 cercariae of S. mansoni and superinfected, 8 weeks later with L. donovani the co-infected mice (CO-INFECT) suffered increased morbidity and mortality and elevation of serum liver enzymes, ALT/AST (aspartate/alanine aminotransaminase) compared with mice given the single infections (LEISH or SCHISTO). Schistosome worm and egg burdens and egg granulomatous responses were comparable in CO-INFECT and SCHISTO mice. In contrast, CO-INFECT and LEISH mice showed comparable L. donovani infection (Leishman Donovan units [LDUs]) in both liver and spleen at +2 weeks but the CO-INFECT mice showed progressively increased LDU up to +8weeks post Leishmania infection compared to declining LDUs in the LEISH group. The S. mansoni infection induced significant IL-4 and IL-10 but not IFN-γ splenocyte and liver lymphocyte recall responses to schistosome antigens and mitogen whereas the LEISH infection induced specific IFN-γ production but not IL-4 to Leishmania antigen (Formalin fixed Leishmania amastigote antigen, FLAA). This IFN-γ response was markedly lower at +2 and +8 weeks post infection in the CO-INFECT mice but FLAA- specific IL- 10 responses were higher. Since B-cells have been reported to be a major source of IL-10 in S. mansoni infected mice, co-infection experiments were carried out in μMT mice which lack B cells. Indeed there was lower IL-10 production in the CO-INFECT μMT mice and also a lower fold increase in LDU in the liver of CO-INFECT vs. LEISH mice compared with the wild-type (WT, C57BL/6) mice. However, the μMT mice were also much less susceptible to infection with L. donovani alone than the WT mice so it is difficult to interpret the significance of these results. Administration of anti-IL-10 receptor antibody (anti-IL-10R) between weeks 6-8 after super-infection reduced the high L. donovani LDU in the CO-INFECT mice but the significance of this was uncertain since anti-IL-10R treated LEISH mice also had lower LDUs. Morphologically mature L. donovani granulomas are associated with leishmanicidal activity. Histology and immuno-histology showed an increasing proportion of morphologically mature granulomas in the hepatic parenchyma of LEISH mice as the infection resolved (i.e. between weeks +2 and +8) but in the CO-INFECT mice this proportion did not change. Higher mean amastigote numbers in L. donovani granulomas in the parenchyma of CO-INFECT mice suggested reduced leishmanicidal activity. Throughout the time course 60% of the foci of L. donovani infection were seen in various locations within the egg granulomatous response, most commonly in a ring around the outside of the granulomas but occasionally within giant cells in egg shells at the centre of the granulomas. Typical hepatic L. donovani granulomas did not form around such foci and the amastigotes appeared partly contained. The data suggests that in LEISH mice mature granulomas effectively kill the contained amastigotes limiting new infections so that by +8 weeks the granulomas are all mature or fully resolved. In contrast although morphologically normal mature L. donovani granulomas form in the parenchyma of CO-INFECT mice these show reduced leishmanicidal activity resulting in spread and establishment of new infections. It is concluded that raised Th2 responses to S. mansoni results in lowered Leishmania specific IFN-γ responses and raised levels of IL-10, both of which would reduce Th1 mediated macrophage activation required for killing of L. donovani amastigotes. The effects of IL-10 plus the failure of Leishmania granulomas to develop around foci within the egg granulomas suggests very poor leishmanicidal activity in such foci. The final section of these studies was concerned with the effects of an established L. donovani infection on a S. mansoni infection superimposed 2 weeks later. At 8 weeks post super-infection, there was no effect on the schistosome worm or egg burdens or the immunological and pathological response to the eggs i.e. a strong Th2 response still developed. However, lower L. donovani LDUs were seen in the CO-INFECT mice than in the LEISH alone and it is suggested that the early phase of the schistosome infection which is characterised by Th1 responses may have promoted the protective anti-leishmanial response
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral