Blood fluke exploitation of non-cognate CD4+ T cell help to facilitate parasite development.

Schistosoma blood flukes, which infect over 200 million people globally, co-opt CD4+ T cell-dependent mechanisms to facilitate parasite development and egg excretion. The latter requires Th2 responses, while the mechanism underpinning the former has remained obscure. Using mice that are either defective in T cell receptor (TCR) signaling or that lack TCRs that can respond to schistosomes, we show that naïve CD4+ T cells facilitate schistosome development in the absence of T cell receptor signaling. Concurrently, the presence of naïve CD4+ T cells correlates with both steady-state changes in the expression of genes that are critical for the development of monocytes and macrophages and with significant changes in the composition of peripheral mononuclear phagocyte populations. Finally, we show that direct stimulation of the mononuclear phagocyte system restores blood fluke development in the absence of CD4+ T cells. Thus we conclude that schistosomes co-opt innate immune signals to facilitate their development and that the role of CD4+ T cells in this process may be limited to the provision of non-cognate help for mononuclear phagocyte function. Our findings have significance for understanding interactions between schistosomiasis and other co-infections, such as bacterial infections and human immunodeficiency virus infection, which potently stimulate innate responses or interfere with T cell help, respectively. An understanding of immunological factors that either promote or inhibit schistosome development may be valuable in guiding the development of efficacious new therapies and vaccines for schistosomiasis.

Rapid induction of IgE responses to a worm cysteine protease during murine pre-patent schistosome infection.

BACKGROUND: During the pre-patent stage of infection, juvenile Schistosoma blood flukes co-opt signals from the adaptive immune system to facilitate parasite development, but the types of responses that are induced at this early stage of infection, and the parasite antigens they target, have not been characterized. RESULTS: Through analysis of experimental pre-patent infections, we show that the S. mansoni cysteine protease SmCB1 is rapidly targeted by an antigen-specific IgE response. The induction of this response is independent of schistosome eggs as infection with male or female worms alone also induced SmCB1-specific IgE. We also show that the SmCB1-specific IgE response is dependent on cognate CD4+ T cell help and IL-4, suggesting that pre-patent Th2 responses provide T cell help for the SmCB1-specific IgE response. Finally, exposed human subjects also produced IgE against SmCB1. CONCLUSIONS: Our data demonstrate that, like eggs, schistosome worms also induce functional type 2 responses and that a parasite cysteine protease is an inducer of type 2 responses during the early stages of schistosome infection.

Conservation of CD4+ T cell-dependent developmental mechanisms in the blood fluke pathogens of humans.

Schistosoma blood flukes are trematode parasites with a cosmopolitan distribution that infect over 200 million people globally. We previously showed that Schistosoma mansoni growth and development in the mammalian host is dependent on signals from host CD4+ T cells. To gain insight into the mechanisms that underlie this dependence, we sought to determine the evolutionary origins and limits of this aspect of the host-pathogen relationship. By infecting RAG-1-/- mice with a range of different schistosome species and strains, we tested several hypotheses concerning the time during Schistosoma evolution at which this dependence arose, and whether this dependence is specific to Schistosoma or is also found in other blood flukes. Our data indicate that the developmental dependence on CD4+ T cells previously described for S. mansoni is conserved in the evolutionarily basal species Schistosoma japonicum, suggesting this developmental adaptation arose early in Schistosoma evolution. We also demonstrate that the development of the more evolutionarily derived species Schistosoma haematobium and Schistosoma intercalatum are dependent on adaptive immune signals. Together, these data suggest that the blood fluke parasites of humans utilise common mechanisms to infect their hosts and to co-opt immune signals in the coordination of parasite development. Thus, exploitation of host-schistosome interactions to impair or prevent parasite development may represent a novel approach to combating all of the schistosome pathogens of humans.

The common gamma chain cytokines interleukin (IL)-2 and IL-7 indirectly modulate blood fluke development via effects on CD4+ T cells.

The human pathogen Schistosoma mansoni exhibits a highly evolved and intricate relationship with its host, evading immune destruction while co-opting CD4(+) T cell-driven mechanisms to facilitate parasite development and egg excretion. Because the common gamma ( gamma (c)) chain cytokine interleukin (IL)-7 is also implicated in modulating schistosome development, we investigated whether this effect is mediated indirectly through the essential role that IL-7 plays in CD4(+) T cell growth and survival. We demonstrate that attenuated schistosome development in the absence of IL-7 results from dysregulated T cell homeostasis and not from disruption of direct interactions between schistosomes and IL-7. We also identify an indirect role that another gamma (c) chain cytokine plays in schistosome development, demonstrating that IL-2 expression by CD4(+) T cells is essential for normal parasite development. Thus, cytokines critical for CD4(+) T cell survival and function can mediate indirect but potent effects on developing schistosomes and underscore the importance of CD4(+) T cells in facilitating schistosome development.