Schistosomiasis-from immunopathology to vaccines

Abstract

Schistosomiasis (bilharzia) is a neglected tropical disease caused by trematode worms of the genus Schistosoma. The transmission cycle involves human (or other mammalian) water contact with surface water contaminated by faeces or urine, as well as specific freshwater snails acting as intermediate hosts. The main disease-causing species are S. haematobium, S. mansoni and S. japonicum. According to the World Health Organisation, over 250 million people are infected worldwide, leading to considerable morbidity and the estimated loss of 1.9 million disability-adjusted life years (DALYs), a likely underestimated figure. Schistosomiasis is characterised by focal epidemiology and an over-dispersed population distribution, with higher infection rates in children. Complex immune mechanisms lead to the slow acquisition of immune resistance, but innate factors also play a part. Acute schistosomiasis, a feverish syndrome, is most evident in travellers following a primary infection. Chronic schistosomiasis affects mainly individuals with long-standing infections residing in poor rural areas. Immunopathological reactions against schistosome eggs trapped in host tissues lead to inflammatory and obstructive disease in the urinary system (S. haematobium) or intestinal disease, hepatosplenic inflammation and liver fibrosis (S. mansoni and S. japonicum). An effective drug-praziquantel-is available for treatment but, despite intensive efforts, no schistosomiasis vaccines have yet been accepted for public use. In this review, we briefly introduce the schistosome parasites and the immunopathogenic manifestations resulting from schistosomiasis. We then explore aspects of the immunology and host-parasite interplay in schistosome infections paying special attention to the current status of schistosomiasis vaccine development highlighting the advancement of a new controlled human challenge infection model for testing schistosomiasis vaccines.

Keywords: Controlled human infection model; Gastrointestinal/hepatosplenic schistosomiasis; Schistosoma; Schistosomiasis; Schistosomiasis vaccine; Urogenital schistosomiasis.

Fig. 1

Life cycle of human schistosomes. Adult schistosome worms parasitise the blood vessels of humans and other vertebrates which act as definitive hosts, but their life cycle necessitates a phase of asexual multiplication and development within a freshwater snail. Infective larvae (cercariae) are periodically released from the snail, and these actively seek and penetrate the skin of the human definitive host; in zoonotic schistosomiasis (caused by S. japonicum), other mammals, especially bovines, can also be involved. Following penetration of the skin, the cercarial tails drop off in the skin and the parasites transform into schistosomula which enter the venous blood vessels and are transported to the lungs via the right heart, before reaching the left side of the heart to eventually enter the arterial circulation. The schistosomula migrate to, and live in, the mesenteric veins of the bowel (S. mansoni, S. japonicum) or the pelvic venous plexus (S. haematobium). There they mature into female or male adult worms with the females ending up in the male’s gynaecophoral canal and ultimately producing eggs over a period that in extreme cases may be as long as 20 years. The eggs are aimed at passing from the lumen of the blood vessels through the intestinal or bladder mucosa and are shed in the faeces (S. mansoni and S. japonicum) or urine (S. haematobium), but as many as 50% of them wind up in adjacent tissues or are flushed into the liver (mainly S. mansoni and S. japonicum) but can in rare cases find more remote organs. Eggs failing to be excreted from the host are trapped in the tissues inducing inflammatory responses and resulting in pathological lesions that are ultimately revealed as clinical disease. The life cycle is completed when the eggs hatch, releasing free-swimming ciliated miracidia which, in turn, locate and infect specific freshwater snails (Biomphalaria spp. for S. mansoni; Oncomelania spp. for S. japonicum, Bulinus spp. for S. haematobium). Cercariae are released after two generations of primary sporocysts and then daughter sporocysts within the snail. From Reference : Ross AG, Bartley PB, Sleigh AC, Olds GR, Li Y, Williams GM, McManus DP (2002) Schistosomiasis New Engl J Med 346: 1212–1220; Massachusetts Medical Society. Reprinted with permission.

Fig. 2

Features of schistosome-induced granuloma formation. Adult schistosome worm pairs residing in mesenteric veins produce eggs some of which become entrapped in the host’s liver (or other organs) tissue where they evoke a dominant CD4(+) T_H2 immune response mediated by IL-4 and IL-13. This leads to the development of granulomas and fibrosis with hepatic stellate cells, macrophages, lymphocytes, neutrophils, and eosinophils, all identified as major cellular contributors to these events. a Major cellular populations located within and adjacent to the hepatic granuloma induced in either S. japonicum or S. mansoni infection. Whereas a dense population of eosinophils are present at the core of a S. mansoni-induced hepatic granuloma, the core in a S. japonicum infection is comprised chiefly of neutrophils. Chemokine-binding proteins secreted by the eggs of S. mansoni eggs bind neutrophil chemoattractant C-X-C-motif chemokine ligand 8 (CXCL8), thereby blocking the infiltration of neutrophils to the granuloma. In contrast, these proteins do not bind to eosinophil chemoattractant CC-chemokine ligand 11 (CCL11) and, therefore, do not inhibit the recruitment of eosinophils. b A granuloma in the liver of a S. mansoni-infected mouse with hepatic stellate cells (HSCs). Part a adapted with permission from Chuah, C., Jones, M. K., Burke, M. L., McManus, D. P. & Gobert, G. N. Cellular and chemokine-mediated regulation in schistosome-induced hepatic pathology. Trends Parasitol. 30, 141–150 (2014), Elsevier. Part b courtesy of A. M. O. Kildemoes, University of Copenhagen, Denmark