Despite the advent of mass chemotherapy programs, schistosomiasis remains a very significant cause of human disease in Africa, The Middle East, Asia and South America. Our long-term goal is to understand the protective mechanisms that allow host survival in the face of extensive tissue damage associated with chronic schistosomiasis. Work over the last 15 years has revealed that the nature of the CD4+ T cell response induced by egg antigens is critical in determining the death or survival outcome of infection. The infection induces a Th2 response, and the Th2 bias is critical, since in the absence of IL-4, a major product of Th2 cells, infected mice die rapidly after eggs begin to be produced by the parasites, due to an immunopathologic response in which NO and TNF? (products of classically activated, M1 macrophages) are implicated. In contrast, infected wild type mice survive over long periods of time, thereby modeling the chronic nature of the disease in humans. In this model, as in humans, infection severity is linked to parasite burden (the more worm pairs a mouse is infected with, the more eggs it is exposed to, and the sicker it will be), and over time the repeated cycles of inflammation and resolution can lead to severe liver fibrosis, which again mirrors the most serious disease manifestation of human schistosomiasis. There is evidence that the protective mechanisms that permit host survival during schistosomiasis are mediated by cells that that can be categorized as alternatively activated (M2) macrophages, and that IgG1, which is made by B cells that have been helped by IL-4 producing T follicular helper (Tfh) cells, plays a role in this process during the later stages of disease. However, we have surprisingly little understanding of how these macrophage- and B cell-dependent mechanisms operate, and it is on these areas that our proposal focuses. We have two aims.
Specific Aim 1 is to understand the role of the Tfh/B cell axis during infection. Here we will determine the evolution of the T cell and B cell responses over time during infection, incorporating a detailed study of Th2 cells, Tfh cells and plasma cells. We will ask whether both Th2 and Tfh responses are modulated over time, and whether increasing the relative output of Tfh cells vs. Th2 effector cells improves the prognosis during chronic schistosomiasis. We will ask how B cells get into the liver during schistosomiasis and explore the fate and function of the cells once they have infiltrated this organ.
Specific Aim 2 is to establish the origin and function of hepatic macrophages during chronic infection. For this aim we will use new tools to explore the origin and role of macrophages in the hepatic tissues of chronically infected mice. We will ask whether the primary role of antibody is (in the form of immune complexes) to bind to Fc?RIIB on monocytes/macrophages and thereby inhibit inflammation during chronic schistosomiasis. We will determine how the absence of B cells influences the hepatic macrophage population and determine whether dysregulated thromboxane-A2 production by macrophages underlies the development of severe portal hypertension during chronic schistosomiasis in the absence of antibody.

Public Health Relevance

Schistosomiasis is a chronic Neglected Tropical Disease caused by infection with parasitic flatworms of the genus Schistosoma, that despite the availability of an excellent drug, and ongoing treatment programs, remains as prevalent as it was 20 years ago and continues to represent a cause of severe morbidity in millions of people. Infection causes a complex multi-organ disease characterized by marked inflammation in the liver, intestine and, in the most severe ceases, lungs. Survival with infection requires an appropriately regulated Th2 response. Understanding the intrinsic regulatory mechanisms that permit survival with chronic schistosome infection has broad therapeutic implications for not only schistosomiasis, but also other helminth infections, allergy/asthma and autoimmunity.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI032573-23
Application #
8663821
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
Project End
Budget Start
Budget End
Support Year
23
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Everts, Bart; Tussiwand, Roxane; Dreesen, Leentje et al. (2016) Migratory CD103+ dendritic cells suppress helminth-driven type 2 immunity through constitutive expression of IL-12. J Exp Med 213:35-51
Fairfax, Keke C; Everts, Bart; Amiel, Eyal et al. (2015) IL-4-secreting secondary T follicular helper (Tfh) cells arise from memory T cells, not persisting Tfh cells, through a B cell-dependent mechanism. J Immunol 194:2999-3010
Pearce, Edward J; Huang, Stanley Ching-Cheng (2015) The metabolic control of schistosome egg production. Cell Microbiol 17:796-801
Chang, Chih-Hao; Qiu, Jing; O'Sullivan, David et al. (2015) Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell 162:1229-41
Monin, Leticia; Griffiths, Kristin L; Lam, Wing Y et al. (2015) Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis. J Clin Invest 125:4699-713
Tussiwand, Roxane; Everts, Bart; Grajales-Reyes, Gary E et al. (2015) Klf4 expression in conventional dendritic cells is required for T helper 2 cell responses. Immunity 42:916-28
Nascimento, Marcia; Huang, Stanley C; Smith, Amber et al. (2014) Ly6Chi monocyte recruitment is responsible for Th2 associated host-protective macrophage accumulation in liver inflammation due to schistosomiasis. PLoS Pathog 10:e1004282
Huang, Stanley Ching-Cheng; Everts, Bart; Ivanova, Yulia et al. (2014) Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol 15:846-55
Reese, T A; Wakeman, B S; Choi, H S et al. (2014) Helminth infection reactivates latent γ-herpesvirus via cytokine competition at a viral promoter. Science 345:573-7
Fairfax, Keke C; Everts, Bart; Smith, Amber M et al. (2013) Regulation of the development of the hepatic B cell compartment during Schistosoma mansoni infection. J Immunol 191:4202-10

Showing the most recent 10 out of 23 publications