Skip to main content
Article thumbnail
Location of Repository

Voltage Gated Calcium Channels Negatively Regulate Protective Immunity to Mycobacterium tuberculosis

By Shashank Gupta, Nasir Salam, Varsha Srivastava, Rupak Singla, Digamber Behera, Khalid U. Khayyam, Reshma Korde, Pawan Malhotra, Rajiv Saxena and Krishnamurthy Natarajan

Abstract

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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:2669286
Provided by: PubMed Central

Suggested articles

Citations

  1. (2008). A scaffold protein, AHNAK1 is required for calcium signaling during T cell activation.
  2. (1997). Activation of human dendritic cells following infection with Mycobacterium tuberculosis.
  3. (2007). Calcium signaling in lymphocyte activation and disease.
  4. (1993). Cell signaling. A tale of two messengers.
  5. (2003). DCSIGN is the major Mycobacteterium tuberculosis receptor on human dendritic cells.
  6. (1998). Dendritic cells and the control of immunity.
  7. (2001). Dendritic cells as sensors of infection.
  8. (2004). Dominance of CD86, TGF-b and Interleukin-10 from Mycobacterium tuberculosis secretory antigen activated dendritic cells regulate T helper 1 responses to mycobacterial antigens.
  9. (2006). Efficient intracellular multiplication of Legionella pneumophila in human monocytes requires functional host cell L-type calcium channels.
  10. (2005). Functional analysis of early secreted antigenic target-6, the dominant T-cell antigen of Mycobacterium tuberculosis, reveals key residues involved in secretion, complex formation, virulence, and immunogenecity.
  11. (2001). Fundamental Ca 2+ signaling mechanisms in mouse dendritic cells: CRAC is the major Ca 2+ entry pathway.
  12. (2002). Geneva, Switzerland: World Health Organization Fact Sheet.
  13. (1997). Identification and characterization of a novel Ets-2-related nuclear complex implicated in the activation of the human interleukin-12p40 gene promoter.
  14. (2001). Immnuology of Tuberculosis.
  15. (2004). Immunology of tuberculosis and implications in vaccine development.
  16. (2006). Impaired generation of reactive oxygen species during differentiation of Dendritic cells (DCs) by Mycobacterium tuberculosis secretory antigen (MTSA) and subsequent activation of MTSA-DCs by mycobacteria results in increased intracellular survival.
  17. (2004). Intracellular calcium release is required for caspase-3 and -9 activation.
  18. (1998). Involvement of dihydropyridinesensitive calcium channels in human dendritic cells function: competition with HIV-1 TAT.
  19. (2000). Is the development of a new tuberculosis vaccine possible?
  20. (2000). L-type Ca 2+ channel activation regulates induction of c-fos transcription by hypoxia.
  21. (1999). Ltype Ca 2+ channels are essential for glutamate-mediated CREB phosphorylation and c-fos gene expression in striatal neurons.
  22. (1999). Mediating immunity to mycobacteria.
  23. (2000). Modulation by dihydropyridine-type calcium channel anagonists of cytokine-inducible gene expression in vascular smooth muscle cells.
  24. (2007). Modulation of gamma interferon receptor 1 by Mycobacterium tuberculosis: a potential immune evasive mechanism.
  25. (2004). Molecular properties of voltage-gated calcium channels. In: Zamponi G, ed (2004) Voltage-gated calcium channels.
  26. (2002). Mycobacterium tuberculosis antigens induce the differentiation of dendritic cells from bone marrow.
  27. (2003). Mycobacterium tuberculosis blocks Ca 2+ signaling and phagosome maturation inhuman macrophages via specific inhibition of sphingosine kinase.
  28. (2003). Mycobacterium tuberculosis exerts gene-selective inhibition of transcriptional responses to IFN-c without inhibiting STAT1 function.
  29. (1999). N-acetyl-L-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-kB inhibition.
  30. (2006). Neely A
  31. (2004). Prolonged Toll-like receptor signaling by Mycobacterium tuberculosis and its 19-kilodalton lipoprotein inhibits gamma interferon-induced regulation of selected genes in macrophages.
  32. (2008). Protective immunity to Mycobacterium tuberculosis infection by chemokine and cytokine conditioned CFP-10 differentiated dendritic cells.
  33. (2005). Regulation of immune responses to Mycobacterium tuberculosis secretory antigens by Dendritic cells.
  34. (2004). Removal of Ca 2+ channel b3 subunit enhances Ca 2+ oscillation frequency and insulin exocytosis.
  35. (2005). response to Mycobacterium tuberculosis and exacerbates outcome of infection.
  36. (2000). Structure and regulation of voltage-gated Ca 2+ channels.
  37. (2007). Survival of mycobacteria in macrophages is mediated by coronin-1-dependent activation of calcineurin.
  38. (1993). T cell antigen receptor signal pathways.
  39. (2000). The balance of protein kinase C and calcium signaling directs T cell subset development.
  40. (2007). The molecular choreography of a store-operated calcium channel.
  41. (2003). Tuberculosis toxin blocking phagosome maturation inhibits a novel Ca 2+/calmodulin-PI3K hVPS34 cascade.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.