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 many types of immune 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 ORAI and STIM family genes and we identified the first patients with mutations in ORAI1 and STIM1 genes. These mutations, which abolish calcium influx and impair immune cell function, cause a unique immunodeficiency syndrome that is characterized by severe infections, autoimmunity, muscular hypotonia and defects in tooth formation and sweat gland function. Immunodeficiency in CRAC deficient patients has been attributed largely to the impaired function of T cells, white blood cells whose activation is dependent on CRAC channels. The important role of CRAC channels in T cells is emphasized by our finding that disruption of STIM1 and ORAI1 genes in mice prevents T-cell driven autoimmune disease in animal models of multiple sclerosis and inflammatory bowel disease. CRAC channel genes are emerging to play a role for the function of other immune cells as well but their importance for immune responses to infection in vivo is not well understood. My lab is in a unique position to study the mechanisms by which CRAC channels contribute to host defense against pathogens because we are studying patients with inherited mutations in CRAC channel genes. In addition, we generated genetically engineered mice that lack expression of STIM and ORAI genes in defined populations of immune cells. These mice are ideal tools to study the role of CRAC channels for immunity to infection.
The specific aims of this proposal describe the following areas of research that we will focus on. (1) We will analyze the genetic defects in immunodeficient patients with suspected defects in CRAC channel function. One goal of these studies is to quantify the minimal Ca2+ influx that is required for normal immune function and protection from infection. (2) We will determine how CRAC channels in T cells and NK cells control immunity against viral and bacterial infections to which patients with impaired CRAC channel function are susceptible. (3) We will investigate if CRAC channels are required to control infection with (mycobacterium) tuberculosis and fungal pathogens and determine how CRAC channels regulate the function of cells in the innate immune system. Taken together, our studies will determine how CRAC channels control immunity to infection. Understanding the role of calcium influx for immune responses is essential to assess the therapeutic potential of CRAC channel inhibition as a treatment for autoimmune and allergic diseases in the future.
: Calcium influx across the plasma membrane of cells in the immune system is required for their function and proper immune responses to infection. This is best illustrated by a small but very instructive group of human patients with inherited immunodeficiency who suffers from recurrent, severe infections due to mutations in the genes ORAI1 and STIM1. These genes encode the main calcium channel in immune cells, the so-called CRAC channel. The goal of this proposal is to understand how calcium influx mediated by CRAC channels controls immune function and which microbial pathogens may exploit defects in calcium influx to cause infections. Since calcium influx is required for the ability of immune cells to cause autoimmunity and potentially also 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 CRAC channel inhibition.
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