title: Suppression of Protective Responses upon Activation of L-Type Voltage Gated Calcium Channel in Macrophages during Mycobacterium bovis BCG Infection.
abstract: The prevalence of Mycobacterium tuberculosis (M. tb) strains eliciting drug resistance has necessitated the need for understanding the complexities of host pathogen interactions. The regulation of calcium homeostasis by Voltage Gated Calcium Channel (VGCCs) upon M. tb infection has recently assumed importance in this area. We previously showed a suppressor role of VGCC during M. tb infections and recently reported the mechanisms of its regulation by M. tb. Here in this report, we further characterize the role of VGCC in mediating defence responses of macrophages during mycobacterial infection. We report that activation of VGCC during infection synergistically downmodulates the generation of oxidative burst (ROS) by macrophages. This attenuation of ROS is regulated in a manner which is dependent on Toll like Receptor (TLR) and also on the route of calcium influx, Protein Kinase C (PKC) and by Mitogen Activation Protein Kinase (MAPK) pathways. VGCC activation during infection increases cell survival and downmodulates autophagy. Concomitantly, pro-inflammatory responses such as IL-12 and IFN-γ secretion and the levels of their receptors on cell surface are inhibited. Finally, the ability of phagosomes to fuse with lysosomes in M. bovis BCG and M. tb H37Rv infected macrophages is also compromised when VGCC activation occurs during infection. The results point towards a well-orchestrated strategy adopted by mycobacteria to supress protective responses mounted by the host. This begins with the increase in the surface levels of VGCCs by mycobacteria and their antigens by well-controlled and regulated mechanisms. Subsequent activation of the upregulated VGCC following tweaking of calcium levels by molecular sensors in turn mediates suppressor responses and prepare the macrophages for long term persistent infection.
authors.affiliation: Infectious Disease Immunology Lab, Dr. B R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Deepika
authors.initials: D
authors.lastname: Sharma
authors.affiliation: Infectious Disease Immunology Lab, Dr. B R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Brijendra Kumar
authors.initials: BK
authors.lastname: Tiwari
authors.affiliation: Infectious Disease Immunology Lab, Dr. B R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Subhash
authors.initials: S
authors.lastname: Mehto
authors.affiliation: Infectious Disease Immunology Lab, Dr. B R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Cecil
authors.initials: C
authors.lastname: Antony
authors.affiliation: Infectious Disease Immunology Lab, Dr. B R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Gunjan
authors.initials: G
authors.lastname: Kak
authors.affiliation: Department of Zoology, University of Delhi, Delhi, India.
authors.forename: Yogendra
authors.initials: Y
authors.lastname: Singh
authors.affiliation: Infectious Disease Immunology Lab, Dr. B R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Natarajan
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000276:immunology*; D020013:Calcium Signaling / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009164:Mycobacterium Infections / Q000276:immunology*; D009163:Mycobacterium bovis / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology
chemical_list: D020746:Calcium Channels, L-Type; C573415:IFNG protein, human; C000611649:IFNG protein, mouse; D017382:Reactive Oxygen Species; D018664:Interleukin-12; D007371:Interferon-gamma