Immune effector mechanisms against schistosomiasis: looking for a chink in the parasite's armour

Abstract

A recombinant antigen vaccine against Schistosoma mansoni remains elusive, in part because the parasite deploys complex defensive and offensive strategies to combat immune attack. Nevertheless, research on rodent and primate models has shown that schistosomes can be defeated when appropriate responses are elicited. Acquired protection appears to involve protracted inhibition of larval migration or key molecular processes at the adult surfaces, not rapid cytolytic killing mechanisms. A successful vaccine will likely require a cocktail of antigens rather than a single recombinant protein. In addition, ways need to be found of keeping the immune system on permanent alert, either to achieve adequate inhibition of protein function in adults, or because a trickle of incoming parasites does not amplify the secondary response.

Figure 1

Antibody responses to cercarial secretions in baboons receiving five exposures to irradiated cercariae at 4 week intervals before challenge with normal cercariae at 3 or 12 weeks after the last vaccination [38]. The saw-tooth response reveals that persistent antigenic pressure is needed to increase IgG titre. When that is removed, it rapidly falls, and with it the level of protection. This decline is one reason why we have not sought to emulate malaria researchers [77] by advocating the development of the irradiated cercaria vaccine for human use.

Figure I

Micrographs of key larval stages. (a) Skin schistosomulum ex vivo after transformation from the cercaria, illustrating the dense spination; (b) skin schistosomulum exiting the dermis by penetrating a blood vessel (V) using head gland secretions; (c) lung schistosomulum (cf. part a) showing extension of the body and loss of spination to faciliatate transit through capillary beds; (d) juvenile liver worm with black haematin pigment in the caecum (C) revealing the start of feeding on erythrocytes and increase in body mass. Scale bar = 20 µm (a,c,d), and 50µm (b).

Figure I

(a) Diagram showing the main features of the syncytial tegument. The plasma membrane is overlain by a secreted membranocalyx that acts as a physical barrier to antibody binding and complement fixation, and is formed from the contents of multilaminate inclusions in the tegument cytosol. (b) Diagram showing the main features of the gut epithelial monolayer that is active both as secretory layer, and in the absorption of nutrients. (c) Stereoscan electron micrograph of a starved worm reveals the lamellate nature of the gut epithelial surface extensions; scale bar = 2 µm. (d) The location of the oesophageal glands astride the posterior oesophagus revealed by whole mount in situ hybridisation of Antigen 10.3 mRNA that encodes the only protein currently known to be synthesised there [28]; scale bar = 50 µm.

Figure I

(a) Dendritic cell (DC) grazing on the surface of an attenuated schistosomulum (S) in a skin-draining lymph node primes the immune system for a Th1 response. (The tissue was not post-fixed in uranyl acetate to stabilise the membranocalyx.) Scale bar = 1 µm. (b) Intimate contact between the schistosomulum tegument (T) and pulmonary capillary endothelium (EN) may facilitate transfer of surface proteins to the interstitial spaces as vesicles (V) mediating transcytosis are evident at the luminal surface. Bar = 0.25 µm. (c) Challenge schistosomulum (S) in the lungs of a vaccinated mouse surrounded by an inflammatory focus largely composed of lymphocytes and monocytes. A pleural infiltrate (P) is also evident on the lung surface. The focus impedes migration and deflects some larvae into the alveoli, rather than killing them by cytolytic mechanisms. Scale bar = 50 µm.