The long-term goal of the research proposed in this grant application is to understand the role of calcium influx in cells of the immune system for immunity to infection and as a cause of immunodeficiency. Our central hypothesis is that calcium influx through so-called CRAC channels is required for the function of T cells and thus immunity to infection. We will study patients with inherited defects in CRAC channel function and use mice with genetic deletion of CRAC channel genes in animal models of infection. We previously showed that patients with inherited defects in CRAC channel function suffer from recurrent, life-threatening infections early in life. CRAC channels are encoded by members of the ORAI and STIM family of genes. We identified the first patients with mutations in ORAI1 and STIM1 genes. They suffer from a unique immunodeficiency syndrome that is characterized by severe infections, autoimmunity, muscular hypotonia and defects in tooth formation and sweat gland function. The immunodeficiency in CRAC channel-deficient patients has been attributed to the impaired function of T cells, white blood cells whose activation is dependent on CRAC channels. Mutations in ORAI1 and STIM1 genes abolish calcium influx in immune cells and impair their function including the production of important immune regulatory proteins. Despite these insights gained from studying the function of CRAC channel-deficient immune cells in cell culture systems, we are lacking a deeper mechanistic understanding of how CRAC channels enable T cells and other immune cells to fight infections in living organisms. In addition to studying patients with inherited mutations in CRAC channel genes, we therefore generated genetically engineered mice that lack expression of STIM and ORAI genes in T cells. Using these mice we recently showed that CRAC channels are important for the ability of T cells to mediate autoimmune diseases and to provide immunity to infection. These mice will therefore be ideal tools to study the mechanisms by which CRAC channels provide host defense to infection with viruses as well as fungal and mycobacterial pathogens. Our lab is in a unique position to translate findings made in animal models into patients by investigating if defects in the calcium-dependent immunoregulatory mechanisms found in mice contribute to the immunodeficiency in patients with mutations in CRAC channels.
The specific aims of this proposal are as follows: (1). We will analyze the genetic defects in immunodeficient patients with suspected CRAC channel dysfunction and investigate how mutations interfere with CRAC channel function at a molecular level. (2) We will determine the mechanisms by which CRAC channels in T cells control immunity against acute and chronic viral infections as well as intracellular bacteria. (3) We will investigate the role of CRAC channels in host defense against fungal infections and in regulating the function of T cells that provide antifungal immunity. Furthermore, we will determine how CRAC channels in T cells control immune responses to chronic mycobacterial infections and provide protection against tuberculosis.

Public Health Relevance

The goal of this proposal is to understand the molecular and immunological mechanisms by which calcium influx through CRAC channels in immune cells controls immune responses to infections with viruses, mycobacteria and fungal pathogens. The results from our studies will provide important insights into how calcium influx in immune cells enables them to protect the human host against acute and chronic infection. Since calcium influx is also required for the ability of immune cells to cause autoimmunity, inflammation and allergic responses, CRAC channels have become an attractive drug target to treat these diseases;a better understanding of the role of calcium influx for immunity to infection, however, is required to properly assess the benefits and risks associated with therapeutic CRAC channel inhibition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI097302-02S2
Application #
8820394
Study Section
Program Officer
Johnson, David R
Project Start
2014-08-15
Project End
2015-05-31
Budget Start
2014-08-15
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$89,528
Indirect Cost
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Concepcion, Axel R; Vaeth, Martin; Wagner 2nd, Larry E et al. (2016) Store-operated Ca2+ entry regulates Ca2+-activated chloride channels and eccrine sweat gland function. J Clin Invest 126:4303-4318
Kaufmann, Ulrike; Shaw, Patrick J; Kozhaya, Lina et al. (2016) Selective ORAI1 Inhibition Ameliorates Autoimmune Central Nervous System Inflammation by Suppressing Effector but Not Regulatory T Cell Function. J Immunol 196:573-85
Vaeth, Martin; Eckstein, Miriam; Shaw, Patrick J et al. (2016) Store-Operated Ca(2+) Entry in Follicular T Cells Controls Humoral Immune Responses and Autoimmunity. Immunity 44:1350-64
Elling, Roland; Keller, Baerbel; Weidinger, Carl et al. (2016) Preserved effector functions of human ORAI1- and STIM1-deficient neutrophils. J Allergy Clin Immunol 137:1587-1591.e7
Feske, Stefan; Wulff, Heike; Skolnik, Edward Y (2015) Ion channels in innate and adaptive immunity. Annu Rev Immunol 33:291-353
Maus, Mate; Jairaman, Amit; Stathopulos, Peter B et al. (2015) Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation. Proc Natl Acad Sci U S A 112:6206-11
Desvignes, Ludovic; Weidinger, Carl; Shaw, Patrick et al. (2015) STIM1 controls T cell-mediated immune regulation and inflammation in chronic infection. J Clin Invest 125:2347-62
Nurbaeva, Meerim K; Eckstein, Miriam; Concepcion, Axel R et al. (2015) Dental enamel cells express functional SOCE channels. Sci Rep 5:15803
Vaeth, Martin; Zee, Isabelle; Concepcion, Axel R et al. (2015) Ca2+ Signaling but Not Store-Operated Ca2+ Entry Is Required for the Function of Macrophages and Dendritic Cells. J Immunol 195:1202-17
Lacruz, Rodrigo S; Feske, Stefan (2015) Diseases caused by mutations in ORAI1 and STIM1. Ann N Y Acad Sci 1356:45-79

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