Date Published: October 10, 2013
Publisher: Public Library of Science
Author(s): Diana K. Riner, Christine E. Ferragine, Sean K. Maynard, Stephen J. Davies, Christoph G. Grevelding.
Blood flukes of the genus Schistosoma infect over 200 million people, causing granulomatous pathology with accompanying morbidity and mortality. As a consequence of extensive host-parasite co-evolution, schistosomes exhibit a complex relationship with their hosts, in which immunological factors are intimately linked with parasite development. Schistosomes fail to develop normally in immunodeficient mice, an outcome specifically dependent on the absence of CD4+ T cells. The role of CD4+ T cells in parasite development is indirect and mediated by interaction with innate cells, as repeated toll-like receptor 4 stimulation is sufficient to restore parasite development in immunodeficient mice in the absence of CD4+ T cells. Here we show that repeated stimulation of innate immunity by an endogenous danger signal can also restore parasite development and that both these stimuli, when administered repeatedly, lead to the regulation of innate responses. Supporting a role for regulation of innate responses in parasite development, we show that regulation of inflammation by neutralizing anti-TNF antibodies also restores parasite development in immunodeficient mice. Finally, we show that administration of IL-4 to immunodeficient mice to regulate inflammation by induction of type 2 responses also restores parasite development. These findings suggest that the type 2 response driven by CD4+ T cells during pre-patent infection of immunocompetent hosts is exploited by schistosomes to complete their development to reproductively mature adult parasites.
As a result of extensive host-parasite co-evolution, helminths exploit resources within their hosts to complete their development and ensure transmission to new hosts. Indeed, most helminths are obligate parasites, requiring the intra-host environment for successful life cycle completion. However, for the most part, the precise host factors that helminths require or utilize, in terms of host cells or molecules, are poorly defined. Previously, CD4+ T cells were shown to play a fundamental role in schistosome development –, as significant impairment of parasite growth and reproductive activity occurred in mice that lack CD4+ T cells. While the precise mechanism by which CD4+ T cells mediate this effect is unclear, the mechanism is indirect, as chronic stimulation of innate immune responses with lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) agonist, during pre-patent infection was able to restore parasite development in the absence of CD4+ T cells . Thus, all the host factors necessary for schistosome development are present, or at least can be induced, independently of CD4+ T cells. However, whether the mechanisms by which CD4+ T cells and chronic LPS stimulation restore schistosome development share any common elements has remained an open question.
Numerous lines of evidence indicate that type 2 responses are beneficial in schistosome infection, not because these responses mediate immunity against schistosomes but because they limit potentially damaging pro-inflammatory responses. For example, in mice deficient in IL-4, IL-4 and IL-10, IL-4 and IL-13 or IL-4 receptor, decreased host survival is observed during acute schistosome infection due to excessive pro-inflammatory cytokine expression and increased liver and intestinal pathology , , , . Likewise, in schistosomiasis patients, severe disease is correlated with decreased production of type 2 cytokines and elevated levels of IFN-γ, TNF and nitric oxide . However, there is also evidence that type 2 responses ultimately benefit schistosomes, and that this benefit extends beyond the obvious relationship between extended host survival and the increased likelihood of transmission to snail intermediate hosts. For example, it has long been recognized that egress of schistosome eggs across the bowel wall is immune-dependent . Subsequent macrophage-specific ablation of IL-4R expression showed that IL-4/IL-13-responsive macrophages are specifically required for egg passage into the intestinal lumen . These observations suggest that host-parasite co-evolution has not only selected for immune responses that prolong host survival, but also for parasites that are able to take advantage of the resulting immunological milieu. The data we present here support the hypothesis that control of pro-inflammatory signals may also be intimately linked to parasite development before the onset of egg production.