Helminths such as Schistosoma mansoni are remarkably efficient at establishing chronic infections with limited inflammatory pathology in some of their hosts, while in other infected people they can cause severe morbidity and they are a major health problem worldwide. Our long-term goal is to understand how liver and intestinal inflammation is regulated during S. mansoni infection. Perhaps the balance between pathogenesis and symbiosis is dependent on the nutritional status of infected individuals. However, we have a very limited understanding of the molecular mechanisms that underpin the relationship between helminth infections, nutritional status and inflammatory responses. Micronutrients such as vitamin A may play a critical role in regulating the inflammatory immune response during helminth infection. Recently, vitamin A metabolism and retinoic acid (RA) has emerged to be important in regulating mucosal immunity. Aldh1a2 is the major enzyme regulating RA production by antigen presenting cells in the gut. Alternatively activated macrophages (AAM) induced by IL-4 have been shown to play an important role in regulating liver and intestinal inflammation during S. mansoni infection, although the mechanism of regulation is not known. Here, we hypothesize that RA production via Aldh1a2 activity in AAM plays an important role in promoting Th2 responses and hence regulating liver and intestinal inflammation during S. mansoni infection. We have preliminary results showing that Aldh1a2 is upregulated by AAM in vitro and in vivo during helminth infection. By infecting vitamin A deficient mice with S. mansoni, we have found that Th2 responses are strikingly reduced, whereas surprisingly, we see an increase in regulatory T cells. We have previously shown that AAMs could bias T helper cell differentiation pathways from Th1 to Th2 cells and RA might therefore provide a mechanism. Since the Aldh1a2 deficient mice are embryonically lethal, we have also designed and generated a transgenic reporter mouse with an inducible deletion system. We are also generating mice with cell type specific (macrophage and dendritic cell) deletions of the Aldh1a2 gene. In this proposal, our specific aims are: (1) to determine if RA production by AAM plays a role in enhancing Th2 responses during in vivo S. mansoni infection; (2) to determine if AAM can influence T helper cell differentiation and function through RA in vitro; (3) to characterize new mouse strains that will provide genetic loss of function evidence for cell specific roles of Aldh1a2 in promoting Th2 responses during S. mansoni infection. The results of these studies will provide us with a framework to devise new ways of regulating inflammation through manipulating the capacity of macrophages to control vitamin A metabolism.

Public Health Relevance

Schistosomiasis affects 200 million people worldwide and is associated with serious morbidity and mortality, causing more than 200,000 deaths annually. Many of these people also suffer from Vitamin A deficiency, which has important effects on the immune response. The goals of this proposal are to understand how Vitamin A metabolites are regulated during infection and apply this knowledge towards designing better interventional strategies to reduce the pathogenesis of schistosomiasis and other inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093811-04
Application #
8604128
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
2011-02-15
Project End
2015-11-30
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Gundra, Uma Mahesh; Girgis, Natasha M; Gonzalez, Michael A et al. (2017) Vitamin A mediates conversion of monocyte-derived macrophages into tissue-resident macrophages during alternative activation. Nat Immunol 18:642-653
Harris, Nicola L; Loke, P'ng (2017) Recent Advances in Type-2-Cell-Mediated Immunity: Insights from Helminth Infection. Immunity 47:1024-1036
Tang, Mei San; Bowcutt, Rowann; Leung, Jacqueline M et al. (2017) Integrated Analysis of Biopsies from Inflammatory Bowel Disease Patients Identifies SAA1 as a Link Between Mucosal Microbes with TH17 and TH22 Cells. Inflamm Bowel Dis 23:1544-1554
Rahman, Karishma; Vengrenyuk, Yuliya; Ramsey, Stephen A et al. (2017) Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression. J Clin Invest 127:2904-2915
Loke, P'ng; Niewold, Timothy B (2017) By CyTOF: Heterogeneity of Human Monocytes. Arterioscler Thromb Vasc Biol 37:1423-1424
Ramanan, Deepshika; Bowcutt, Rowann; Lee, Soo Ching et al. (2016) Helminth infection promotes colonization resistance via type 2 immunity. Science 352:608-12
Loke, P; Lim, Y A L (2015) Helminths and the microbiota: parts of the hygiene hypothesis. Parasite Immunol 37:314-23
Ouimet, Mireille; Ediriweera, Hasini N; Gundra, U Mahesh et al. (2015) MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J Clin Invest 125:4334-48
Tang, Mei San; Poles, Jordan; Leung, Jacqueline M et al. (2015) Inferred metagenomic comparison of mucosal and fecal microbiota from individuals undergoing routine screening colonoscopy reveals similar differences observed during active inflammation. Gut Microbes 6:48-56
Lauvau, Grégoire; Loke, P'ng; Hohl, Tobias M (2015) Monocyte-mediated defense against bacteria, fungi, and parasites. Semin Immunol 27:397-409

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