Evolution of antigenic diversity in the zoonotic multi-host parasite Schistosoma japonicum: implications for vaccine design

The multi-host zoonotic transmission of the blood fluke Schistosoma japonicum is complex, presenting challenges for China's schistosomiasis elimination strategy. How multi-host transmission impacts the genetic diversity of S. japonicum populations is poorly understood and the extent of Schistosoma japonicum antigen coding gene (SjACG) variability remains unknown despite the implications for parasite survival, vaccine development and disease control. To address this, we sequenced the host-interacting domains of three functionally significant SjACGs previously identified as promising vaccine targets (tetraspanin 23 (TSP-23), venom allergen-like protein 7 (VAL-7), and tegument allergen-like protein 1 (TAL-1)) from FTA-archived S. japonicum miracidia sampled from natural infections amongst different definitive host species in mainland China. This work represents the first known analysis of SjACG variation among different host species. SjACGs were genetically diverse across host species, with 10-20 SjACG haplotypes identified from 60 to 81 sequences. Host-derived immune selection pressures may be driving this variation, impacting antigen protein structure, function, and antigenic propensity. Antigen haplotypes were broadly shared across host species, supporting prior suggestions of gene flow and underscoring the importance of zoonotic transmission in disseminating diversity. Some host adaptation was inferred through identification of host species-specific variation. Parasites sampled from humans displayed the greatest overall diversity of SjACGs, and humans shared haplotypes with all other host species. SjACG diversification appears to have occurred rapidly, and before modern humans arrived in China (∼1.7-0.66 million years ago (MYA)), suggesting that animal hosts have been important in the evolutionary history of these antigens. Collectively, the results expand our understanding of the impact of zoonotic transmission on the co-evolutionary processes driving antigenic variability and provide possible evidence of adaptive molecular evolution of certain antigen haplotypes to specific host species. Our findings have implications for the development of anti-schistosome vaccines and, ultimately, for control of zoonotic schistosomiasis.