NIH grant: Calcium signaling in MR1-dependent presentation of Mycobacterium tuberculosis antigens (1R01AI189489-01A1)

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NIH grant 1R01AI189489-01A1: Calcium signaling in MR1-dependent presentation of Mycobacterium tuberculosis antigens
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Elham  Karamooz. Award: $582845.
Start: 2026-06-18T00:00:00.
Project Summary
The fundamental role of the immune system is to detect self from non-self. The detection and elimination of
microbial infection is critical for human survival. One challenge to the immune system is infection from an
intracellular microbe because the microbe masks its presence in a host cell. One strategy of the immune system
to detect microbes is the sampling of different kinds of antigens, such as peptides, lipids and glycolipids, by
antigen presenting molecules. A fundamentally unique arm of the immune system is MR1, which is an antigen
presenting molecule that is intracellular, ubiquitously expressed across tissues, and detects small molecules
derived from microbial metabolism. These features suggest that MR1 is poised to detect intracellular microbes.
MR1 presents antigens to MR1-restricted T cells. These T cells are highly prevalent in the lungs and can kill
infected cells. Because MR1 presents small molecule antigens and adopts an intracellular distribution, the
mechanisms governing MR1 sampling of the intracellular environment are distinct from other antigen presenting
molecules. These mechanisms remain unknown. Our over-arching hypothesis is that intracellular calcium
signaling is important for MR1 antigen presentation. We use Mycobacterium tuberculosis (Mtb) as a model for
intracellular infection and have identified calcium-sensitive trafficking proteins and calcium channels important
for MR1 antigen presentation. Aim 1 of this study will determine the mechanism of two-pore channel 1 in MR1-
dependent antigen presentation, with a focus on endoplasmic reticulum-endosome contact sites. Aim 2 will
determine the role of specific calcium-sensitive Synaptotagmins and their binding partners. Aim 3 will determine
the mechanism behind augmented MR1 antigen presentation following modulation of the of the cystic fibrosis
transmembrane conductance regulator. Successful completion of these Aims has the potential to lead to new
MR1-based immunotherapies.

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