Schistosoma mansoni is a parasitic helminth of significant public health concern. Clinical disease is due to the granulomatous response to eggs that become trapped in the liver. In most people and all laboratory wild type mice, S. mansoni leads to the development of a strong Th2 response concurrent with the onset of parasite egg production. Although the granuloma induced by the Th2 response results in liver damage, it is critical for host protection. This is demonstrated in IL- 4-/- mice during S. mansoni infection. These animals are unable to mount a Th2 response and suffer from debilitating cachexia and enhanced mortality subsequent to the onset of egg production. One of the aims of this proposal is to address the role of inflammatory mediators in the development of severe cachexia and mortality in IL-4-/- mice. During severe disease in schistosome- infected IL-4-/- mice, splenocytes produce increased inflammatory mediators including NO and TNF-alpha, in vitro. TNF-alpha contributes to severe disease as treatment with anti-TNF-alpha antibody prolongs time to death in infected IL-4-/- mice. One hypothesis is that egg excretion results in increased endotoxin translocation across the gut wall and in mice lacking the ability to mount a Th2 response, severe inflammation ensues. This hypothesis will be tested by generating an IL-4-/- mouse strain that is hypo-responsive to LPS, the IL-4/TNF-receptor-1 double knockout strain and by generating an IL-4-/- strain that lacks exposure to LPS, a gnotobiotic IL-4-/- strain. The course of disease and in vitro responses will be followed in these strains; it is anticipated that if endotoxin induces the severe disease in infected IL-4-/- mice, cachexia and mortality will be minimized in theses strains.
The second aim of this proposal focuses on determining the importance and cause of a defect in splenocyte proliferation that has been observed in infected IL-4-/- mice. Mediators such as TGF-beta and NO are elevated in IL-4-/- mice during infection and are improved in infected IL-4-/- animals. The role of TGF-beta in inhibiting the signal transduction cascade which leads to T-cell proliferation will be evaluated. The level at which proliferation is inhibited by both NO and TGF-beta will be determined through analysis of activation of signaling proteins important in proliferative response and the levels of expression of cdks and cdk inhibitors.
