title: Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis.
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.
authors.affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
authors.forename: Shashank
authors.initials: S
authors.lastname: Gupta
authors.forename: Nasir
authors.initials: N
authors.lastname: Salam
authors.forename: Varsha
authors.initials: V
authors.lastname: Srivastava
authors.forename: Rupak
authors.initials: R
authors.lastname: Singla
authors.forename: Digamber
authors.initials: D
authors.lastname: Behera
authors.forename: Khalid U
authors.initials: KU
authors.lastname: Khayyam
authors.forename: Reshma
authors.initials: R
authors.lastname: Korde
authors.forename: Pawan
authors.initials: P
authors.lastname: Malhotra
authors.forename: Rajiv
authors.initials: R
authors.lastname: Saxena
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Natarajan
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity; D014162:Transfection; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D015220:Calcium Channels