Research Article: Evidence That Rhesus Macaques Self-Cure from a Schistosoma japonicum Infection by Disrupting Worm Esophageal Function: A New Route to an Effective Vaccine?

Date Published: July 10, 2015

Publisher: Public Library of Science

Author(s): Xiao-Hong Li, Yu-Xin Xu, Gill Vance, Yun Wang, Long-Bao Lv, Govert J. van Dam, Jian-Ping Cao, R. Alan Wilson, John Pius Dalton.

Abstract: BackgroundRhesus macaques are unusual among schistosome hosts, self-curing from an established infection and thereafter manifesting solid immunity against a challenge, an ideal model for vaccine development. Previously, the immunological basis of self-cure was confirmed; surviving worms had ceased feeding but how immunological pressure achieved this was unclear. The schistosome esophagus is not simply a conduit for blood but plays a central role in its processing. Secretions from the anterior and posterior esophageal glands mix with incoming blood causing erythrocyte lysis and tethering and killing of leucocytes.Methodology/Principal FindingsWe have analysed the self-cure process in rhesus macaques infected with Schistosoma japonicum. Faecal egg output and circulating antigen levels were used to chart the establishment of a mature worm population and its subsequent demise. The physiological stress of surviving females at perfusion was especially evident from their pale, shrunken appearance, while changes in the structure and function of the esophagus were observed in both sexes. In the anterior region electron microscopy revealed that the vesicle secretory process was disrupted, the tips of lining corrugations being swollen by greatly enlarged vesicles and the putative sites of vesicle release obscured by intense deposits of IgG. The lumen of the posterior esophagus in starving worms was occluded by cellular debris and the lining cytoplasmic plates were closely adherent, also potentially preventing secretion. Seven proteins secreted by the posterior gland were identified and IgG responses were detected to some or all of them. Intrinsic rhesus IgG colocalized with secreted SjMEGs 4.1, 8.2, 9, 11 and VAL-7 on cryosections, suggesting they are potential targets for disruption of function.Conclusions/SignificanceOur data suggest that rhesus macaques self-cure by blocking esophagus function with antibody; the protein products of the glands provide a new class of potential vaccine targets.

Partial Text: Schistosomiasis is one of the most important parasitic diseases in tropical and sub-tropical regions of the world, with about 800 million people at risk and more than 200 million infected [1,2]. With intense efforts over six decades, great progress has been made in combating this disease in China [3], nevertheless zoonotic schistosomiasis japonica remains a major public health problem. Although comprehensive measures, including mass treatment, snail control and environmental modifications have proved effective in reducing the prevalence and morbidity in endemic areas, none of them can prevent re-infection. Furthermore, unlike other schistosome species, Schistosoma japonicum has a wide range of reservoir hosts in China [4]; 42 species in 28 genera within seven orders of mammals can harbor the infection naturally, adding considerably to the complexity of disease control and prevention. A vaccine with long-term efficacy would augment efforts to control and ultimately eradicate the disease and hence has received wide attention but so far has proved to be an elusive goal.

Initially, the rhesus macaque behaves as a permissive host for S. japonicum, with approximately 75% of applied cercariae being recovered as mature adults six weeks post infection, worm bodies of both genders being even longer than those from the permissive rabbit host [7]. Viable eggs are laid in large numbers and granulomatous liver pathology ensues [7]. However, unlike most other hosts of this zoonotic parasite, the monkeys develop a self-cure response, so that by 20 weeks or so only a small fraction of the original worm population remains [7]. In our study, the data on faecal egg output showed that a robust infection was established in all animals after cercarial exposure. The CAA level also provided good evidence for establishment of a considerable worm population. The body weight reductions that followed oviposition plus the diarrhea and inappetence at week 8 (typical clinical symptoms of acute schistosomiasis) were independent evidence for the magnitude of infection, whilst the subsequent increase in weight revealed that by week 12 the impact of the infection was waning. The coincident reduced egg output while CAA levels remained high, showed that worms were still present but already manifesting impaired reproductive capacity. Indeed, females recovered from rhesus macaques and permissive hosts clearly fell into two distinct populations, the former being shorter and having fewer eggs, whilst the latter were longer with more eggs.



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