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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Johnson, David R
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New York University
Schools of Medicine
New York
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Saint Fleur-Lominy, Shella; Maus, Mate; Vaeth, Martin et al. (2018) STIM1 and STIM2 Mediate Cancer-Induced Inflammation in T Cell Acute Lymphoblastic Leukemia. Cell Rep 24:3045-3060.e5
Vaeth, Martin; Feske, Stefan (2018) Ion channelopathies of the immune system. Curr Opin Immunol 52:39-50
Lian, Jayson; Cuk, Mario; Kahlfuss, Sascha et al. (2018) ORAI1 mutations abolishing store-operated Ca2+ entry cause anhidrotic ectodermal dysplasia with immunodeficiency. J Allergy Clin Immunol 142:1297-1310.e11
Maus, Mate; Cuk, Mario; Patel, Bindi et al. (2017) Store-Operated Ca2+ Entry Controls Induction of Lipolysis and the Transcriptional Reprogramming to Lipid Metabolism. Cell Metab 25:698-712
Concepcion, Axel R; Feske, Stefan (2017) Regulation of epithelial ion transport in exocrine glands by store-operated Ca2+entry. Cell Calcium 63:53-59
Vaeth, Martin; Yang, Jun; Yamashita, Megumi et al. (2017) ORAI2 modulates store-operated calcium entry and T cell-mediated immunity. Nat Commun 8:14714
Vaeth, Martin; Maus, Mate; Klein-Hessling, Stefan et al. (2017) Store-Operated Ca2+ Entry Controls Clonal Expansion of T Cells through Metabolic Reprogramming. Immunity 47:664-679.e6
Eckstein, Miriam; Vaeth, Martin; Fornai, Cinzia et al. (2017) Store-operated Ca2+entry controls ameloblast cell function and enamel development. JCI Insight 2:e91166
Nurbaeva, Meerim K; Eckstein, Miriam; Feske, Stefan et al. (2017) Ca2+ transport and signalling in enamel cells. J Physiol 595:3015-3039
Klemann, Christian; Ammann, Sandra; Heizmann, Miriam et al. (2017) Hemophagocytic lymphohistiocytosis as presenting manifestation of profound combined immunodeficiency due to an ORAI1 mutation. J Allergy Clin Immunol 140:1721-1724

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