Granzyme A Produced by gamma(9)delta(2) T Cells Activates ER Stress Responses and ATP Production, and Protects Against Intracellular Mycobacterial Replication Independent of Enzymatic Activity
Rasi, Valerio; Wood, David C; Eickhoff, Christopher S; Xia, Mei; Pozzi, Nicola; Edwards, Rachel L; Walch, Michael; Bovenschen, Niels; Hoft, Daniel F
(2021) Frontiers in Immunology, volume 12, pp. 1 - 12
(Article)
Abstract
Mycobacterium tuberculosis (Mtb), the pathological agent that causes tuberculosis (TB) is the number one infectious killer worldwide with one fourth of the world's population currently infected. Data indicate that γ9δ2 T cells secrete Granzyme A (GzmA) in the extracellular space triggering the infected monocyte to inhibit growth of intracellular mycobacteria.
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Accordingly, deletion of GZMA from γ9δ2 T cells reverses their inhibitory capacity. Through mechanistic studies, GzmA's action was investigated in monocytes from human PBMCs. The use of recombinant human GzmA expressed in a mammalian system induced inhibition of intracellular mycobacteria to the same degree as previous human native protein findings. Our data indicate that: 1) GzmA is internalized within mycobacteria-infected cells, suggesting that GzmA uptake could prevent infection and 2) that the active site is not required to inhibit intracellular replication. Global proteomic analysis demonstrated that the ER stress response and ATP producing proteins were upregulated after GzmA treatment, and these proteins abundancies were confirmed by examining their expression in an independent set of patient samples. Our data suggest that immunotherapeutic host interventions of these pathways may contribute to better control of the current TB epidemic.
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Keywords: 2D-DIGE, ATP production, BCG, ER stress response, Granzyme A, GZMA, human monocyte, Mycobacterium tuberculosis, Immunology and Allergy, Immunology, Journal Article
ISSN: 1664-3224
Publisher: Frontiers Media S. A.
Note: Funding Information: Research reported in this publication was supported by the National Heart, Lung, And Blood Institute under Award Number F30HL151136 to VR and National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R01AI048391 to DH. NP was in part supported by a grant (R01 HL150146) from the National Heart, Lung and Blood Institute. Funding Information: We would like to thank Dr. Grant R. Kolar from the Saint Louis University Research Microscopy Core for help in obtaining the images from the confocal microscopy experiments. Publisher Copyright: © Copyright © 2021 Rasi, Wood, Eickhoff, Xia, Pozzi, Edwards, Walch, Bovenschen and Hoft.
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