Immune subversion by Mycobacterium tuberculosis through CCR5 mediated signaling: involvement of IL-10.
Tuberculosis is characterized by severe immunosuppression of the host macrophages, resulting in the loss of the host protective immune responses. During Mycobacterium tuberculosis infection, the pathogen modulates C-C Chemokine Receptor 5 (CCR5) to enhance IL-10 production, indicating the possible involvement of CCR5 in regulation of the host immune response. Here, we found that Mycobacterium infection significantly increased CCR5 expression in macrophages there by facilitating the activation of its downstream signaling. These events culminated in up-regulation of the immunosuppressive cytokine IL-10 production, which was further associated with the down-regulation of macrophage MHC-II expression along with the up-regulation of CCR5 expression via engagement of STAT-3 in a positive feedback loop. Treatment of macrophages with CCR5 specific siRNA abrogated the IL-10 production and restored MHCII expression. While, in vivo CCR5 silencing was also effective for the restoration of host immune responses against tuberculosis. This study demonstrated that CCR5 played a very critical role for the immune subversion mechanism employed by the pathogen.
Division of Molecular Medicine, Bose Institute, Kolkata, India.
Shibali
S
Das
Division of Molecular Medicine, Bose Institute, Kolkata, India.
Sayantan
S
Banerjee
Division of Molecular Medicine, Bose Institute, Kolkata, India.
Saikat
S
Majumder
Division of Molecular Medicine, Bose Institute, Kolkata, India.
Bidisha Paul
BP
Chowdhury
Department of Microbiology, Institute of Post Graduate Medical Education and Research, Kolkata, India.
Avranil
A
Goswami
Division of Molecular Medicine, Bose Institute, Kolkata, India.
Kuntal
K
Halder
Department of Microbiology, Institute of Post Graduate Medical Education and Research, Kolkata, India.
Urmita
U
Chakraborty
Department of Microbiology, Institute of Post Graduate Medical Education and Research, Kolkata, India; Department of Microbiology, Malda Medical College, Malda, India.
Nishith K
NK
Pal
Division of Molecular Medicine, Bose Institute, Kolkata, India.
Subrata
S
Majumdar
D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D057131:Immune Evasion; D016753:Interleukin-10 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D019713:Receptors, CCR5 / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology*
C000592874:CCR5 protein, mouse; D000949:Histocompatibility Antigens Class II; C556062:IL10 protein, mouse; D019713:Receptors, CCR5; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016753:Interleukin-10