Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis.

Mycobacterium tuberculosis modulates levels and activity of key intracellular second messengers to evade protective immune responses. Calcium release from voltage gated calcium channels (VGCC) regulates immune responses to pathogens. In this study, we investigated the roles of VGCC in regulating pro...

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Main Authors: Shashank Gupta, Nasir Salam, Varsha Srivastava, Rupak Singla, Digamber Behera, Khalid U Khayyam, Reshma Korde, Pawan Malhotra, Rajiv Saxena, Krishnamurthy Natarajan
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2009-01-01
Series:PLoS ONE
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19390594/pdf/?tool=EBI
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spelling doaj-5ff101c6cf15425e9fdbd7552a1bffc42021-03-03T22:39:58ZengPublic Library of Science (PLoS)PLoS ONE1932-62032009-01-0144e530510.1371/journal.pone.0005305Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis.Shashank GuptaNasir SalamVarsha SrivastavaRupak SinglaDigamber BeheraKhalid U KhayyamReshma KordePawan MalhotraRajiv SaxenaKrishnamurthy NatarajanMycobacterium tuberculosis modulates levels and activity of key intracellular second messengers to evade protective immune responses. Calcium release from voltage gated calcium channels (VGCC) regulates immune responses to pathogens. In this study, we investigated the roles of VGCC in regulating protective immunity to mycobacteria in vitro and in vivo. Inhibiting L-type or R-type VGCC in dendritic cells (DCs) either using antibodies or by siRNA increased calcium influx in an inositol 1,4,5-phosphate and calcium release calcium activated channel dependent mechanism that resulted in increased expression of genes favoring pro-inflammatory responses. Further, VGCC-blocked DCs activated T cells that in turn mediated killing of M. tuberculosis inside macrophages. Likewise, inhibiting VGCC in infected macrophages and PBMCs induced calcium influx, upregulated the expression of pro-inflammatory genes and resulted in enhanced killing of intracellular M. tuberculosis. Importantly, compared to healthy controls, PBMCs of tuberculosis patients expressed higher levels of both VGCC, which were significantly reduced following chemotherapy. Finally, blocking VGCC in vivo in M. tuberculosis infected mice using specific antibodies increased intracellular calcium and significantly reduced bacterial loads. These results indicate that L-type and R-type VGCC play a negative role in M. tuberculosis infection by regulating calcium mobilization in cells that determine protective immunity.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19390594/pdf/?tool=EBI
collection DOAJ
language English
format Article
sources DOAJ
author Shashank Gupta
Nasir Salam
Varsha Srivastava
Rupak Singla
Digamber Behera
Khalid U Khayyam
Reshma Korde
Pawan Malhotra
Rajiv Saxena
Krishnamurthy Natarajan
spellingShingle Shashank Gupta
Nasir Salam
Varsha Srivastava
Rupak Singla
Digamber Behera
Khalid U Khayyam
Reshma Korde
Pawan Malhotra
Rajiv Saxena
Krishnamurthy Natarajan
Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis.
PLoS ONE
author_facet Shashank Gupta
Nasir Salam
Varsha Srivastava
Rupak Singla
Digamber Behera
Khalid U Khayyam
Reshma Korde
Pawan Malhotra
Rajiv Saxena
Krishnamurthy Natarajan
author_sort Shashank Gupta
title Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis.
title_short Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis.
title_full Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis.
title_fullStr Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis.
title_full_unstemmed Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis.
title_sort voltage gated calcium channels negatively regulate protective immunity to mycobacterium tuberculosis.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2009-01-01
description Mycobacterium tuberculosis modulates levels and activity of key intracellular second messengers to evade protective immune responses. Calcium release from voltage gated calcium channels (VGCC) regulates immune responses to pathogens. In this study, we investigated the roles of VGCC in regulating protective immunity to mycobacteria in vitro and in vivo. Inhibiting L-type or R-type VGCC in dendritic cells (DCs) either using antibodies or by siRNA increased calcium influx in an inositol 1,4,5-phosphate and calcium release calcium activated channel dependent mechanism that resulted in increased expression of genes favoring pro-inflammatory responses. Further, VGCC-blocked DCs activated T cells that in turn mediated killing of M. tuberculosis inside macrophages. Likewise, inhibiting VGCC in infected macrophages and PBMCs induced calcium influx, upregulated the expression of pro-inflammatory genes and resulted in enhanced killing of intracellular M. tuberculosis. Importantly, compared to healthy controls, PBMCs of tuberculosis patients expressed higher levels of both VGCC, which were significantly reduced following chemotherapy. Finally, blocking VGCC in vivo in M. tuberculosis infected mice using specific antibodies increased intracellular calcium and significantly reduced bacterial loads. These results indicate that L-type and R-type VGCC play a negative role in M. tuberculosis infection by regulating calcium mobilization in cells that determine protective immunity.
url https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19390594/pdf/?tool=EBI
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