Schistosomiasis - Immune Response & Immunopathology
Our laboratory studies the host immune response and immunopathology associated with schistosomiasis, a serious potentially fatal parasitic disease currently afflicting more than 200 million people in tropical regions of the world. Schistosomiasis is contracted by exposure to bodies of fresh water contaminated with parasitic helminths of the genus Schistosoma. The immunopathology in schistosomiasis consists of granulomatous and fibrosing inflammation against tissue-lodged parasite eggs. Our goal is to gain a better understanding of the cellular and molecular mechanisms that regulate the immunopathological host response.
The intensity of egg-induced immunopathology is determined by the predominance of a net pro- vs. anti-inflammatory host cytokine environment orchestrated by CD4 T cells specific for schistosome egg antigens. We found that the novel subset of CD4 T cells producing interleukin (IL)-17 (Th17 cells) is a major force that drives severe inflammation. Current efforts are directed at determining the mechanisms responsible for the preferential development of Th17 cells in certain mouse strains, such as CBA, which are genetically prone to high pathology. These studies focus on analyzing live parasite egg interactions with dendritic cells (DCs) that prime and activate the pathogenic Th17 cells (Figure 1).
We recently discovered that DCs from high-pathology CBA mice express strikingly higher levels of the C-type lectin receptor (CLR) CD209a (SIGNR5), a murine homologue of human CD209 (DC-SIGN), in comparison with low-pathology BL/6 mice. Indeed, knock-down of CD209a abolishes the ability of egg-stimulated CBA DCs to produce IL-1β and IL-23, which are necessary to activate pathogenic Th17 cells, suggesting that CD209a by itself can control the magnitude of egg-induced inflammation (Figure 1). Current efforts in the lab are aimed at elucidating the key signaling pathways downstream of CD209a conducive to Th17 cell development and severe immunopathology.
Upper panels: Macroscopic and histologic depiction of granulomatous lesions around parasite eggs in livers from 7 week-infected mice. Left, large egg granulomas as seen in CBA mice; right, small granulomas as seen in BL/6 mice. Lower panels: Immune cell and cytokine profiles in 7 week schistosome-infected mice. Left: Egg-stimulated, CD209a-expressing CBA antigen-presenting cells (APCs) generate a strong proinflammatory cytokine milieu resulting in the activation of mainly proinflammatory T cell subsets that mediate severe immunopathology. Right: Egg-stimulated BL/6 APCs, devoid of CD209a, generate a largely anti-inflammatory cytokine milieu resulting in the activation of anti-inflammatory and regulatory T (T reg) cells and mild immunopathology. DC I: type I or classically activated dendritic cell; DC II: type II or alternatively activated dendritic cell; M I: type I or classically activated macrophage; M II: type II or alternatively activated macrophage. Others: other APCs including granulocytes, B cells and innate lymphoid cells. PRRs: pattern recognition receptors.
Additional focus in the lab is directed towards identifying the sensitizing egg antigens/glycans, and further ascertaining the genetic base of disease heterogeneity. Our goal is to understand the innate and adaptive immunopathogenic mechanisms operating in genetically diverse host populations that develop dissimilar forms of schistosomiasis with the idea of designing strategies for prevention and/or amelioration of severe disease. Our research has strong connections with, and obvious implications for global health, as close collaborators have recently demonstrated that an increase in Th17 responses is also associated with pathology in the human disease.