Helminth infections, including Trichinella spiralis, infect approximately 2 billion people worldwide and represent a significant public health concern. To combat these parasites the mammalian immune system has evolved mechanisms to maintain a delicate balance between promoting beneficial inflammation needed to reduce parasitic burdens and limiting pathologic inflammation in order to maintain tissue integrity. The importance of maintaining this balance is evident by the severe pathology that presents in patients exhibiting dysregulated immune responses to helminthes. Despite the importance of balancing protective and pathologic responses in the context of helminth infections, the cellular and molecular events that regulate these pathways remain unknown. It is well established that type 2 responses, characteristic of helminth-induced immune responses in humans and mice, are required to both promote worm clearance and limit infection- induced tissue damage. Our recent studies have demonstrated that specialized helminth-induced hematopoietic stem/progenitor cells (HSPCs) enter peripheral tissues, develop into mast cells and promote TH2 cytokine-dependent immunity to Trichinella spiralis. In addition, our novel preliminary data reveal that helminth-induced HSPCs upregulate Carbonic anhydrase enzymes, a family of enzymes that regulate pH and are targeted therapeutically to treat epilepsy and glaucoma. Further, blocking Car enzyme activity via treatment with FDA approved pan Car inhibitors was sufficient to prevent murine and human mast cell development in vitro and mast cell responses, TH2 cytokine production and protective immunity to Trichinella in vivo. Moreover, our preliminary studies indicate that Car-dependent mast cells promote monocyte responses and the presence of intestinal alternatively activated macrophage populations. These data indicate that pharmacologic manipulation of Car enzyme activation could be employed to regulate mast cell development, TH2 cytokine- mediated inflammation and wound healing responses in the context of helminth infections. Based on our new data, two specific aims will address the following questions: (i) Can pharmacologic inhibition or activation of specific Car enzyme family members be employed to regulate Trichinella-induced mast cell responses and TH2 cytokine-mediated inflammation? (ii) Do monocytes cooperate with Car-dependent mast cells to promote intestinal wound healing responses following Trichinella infection? Collectively, these studies will interrogate novel aspects of innate immune mechanisms through which TH2 cytokine-mediated immunity and inflammation are initiated. We anticipate that defining the mechanisms through which Car enzymes regulate helminth- induced mast cell responses, Th2 cytokine production and intestinal pathology will significantly inform new immune therapeutic strategies to treat helminth infections and their associated morbidities.

Public Health Relevance

Helminth parasites infect approximately 2 billion people worldwide and represent a significant public health and economic challenge. While multiple studies have demonstrated an essential role for adaptive immune cells in promoting protective immunity to helminths, the innate immune mechanisms that contribute to these pathways remain unknown. This proposal will investigate how specific enzymatic pathways activated in progenitor cell populations promote mast cell development, monocytes responses and protective immunity to helminth parasites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI123224-02
Application #
9199205
Study Section
Immunity and Host Defense (IHD)
Program Officer
Wali, Tonu M
Project Start
2016-01-01
Project End
2020-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Rutgers University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
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Henry, Everett K; Sy, Chandler B; Inclan-Rico, Juan M et al. (2016) Carbonic anhydrase enzymes regulate mast cell-mediated inflammation. J Exp Med 213:1663-73