title: Immunotherapeutic efficacy of recombinant Mycobacterium smegmatis expressing Ag85B-ESAT6 fusion protein against persistent tuberculosis infection in mice.
abstract: The application of immunotherapy in combination with chemotherapy is considered an effective treatment strategy against persistent Mycobacterium tuberculosis (Mtb) infection. In this study, we constructed a novel recombinant Mycobacterium smegmatis (rMS) strain that expresses Ag85B and ESAT6 fusion protein (AE-rMS). Immunization of C57BL/6 mice with AE-rMS generated mainly Th1-type immune responses by strongly stimulating IFN-γ- and IL-2-producing splenocytes and increasing antigen-specific cytotoxic T lymphocyte (CTL) activity. To test the immunotherapeutic efficacy of AE-rMS, a persistent tuberculosis infection (PTBI) model was established via tail-vein injection of C57BL/6 mice with 1×10(4) colony forming units (CFU) of Mtb strain H37Rv in combination with concurrent chemotherapy drugs isoniazid (INH) and pyrazinamide (PZA). PTBI mice immunized with AE-rMS showed high levels of IFN-γ secreted by splenocytes and decreased bacteria loads in lung. Treatment with only the anti-tuberculosis (anti-TB) drugs RFP and INH (RI), decreased bacteria loads to low levels, with the Th1-type immune response further attenuated. Moreover, AE-rMS, when combined with RI treatment, further reduced the bacteria load as well as the pathological tissue damage in lung. Together, these results demonstrated the essential roles of AE-rMS-induced Th1-type responses, providing an effective treatment strategy by combining AE-rMS and RI for persistent TB.
authors: Department of Microbiology; the Fourth Military Medical University; Xi'an, Shaanxi Province, PR China; Department of Pathology and Clinical Laboratory; Luoyang, Henan Province, PR China.
authors: Ping
authors: P
authors: Wang
authors: Department of Microbiology; the Fourth Military Medical University; Xi'an, Shaanxi Province, PR China.
authors: Limei
authors: L
authors: Wang
authors: Department of Microbiology; the Fourth Military Medical University; Xi'an, Shaanxi Province, PR China.
authors: Wei
authors: W
authors: Zhang
authors: Department of Microbiology; the Fourth Military Medical University; Xi'an, Shaanxi Province, PR China.
authors: Yinlan
authors: Y
authors: Bai
authors: Department of Microbiology; the Fourth Military Medical University; Xi'an, Shaanxi Province, PR China.
authors: Jian
authors: J
authors: Kang
authors: Department of Microbiology; the Fourth Military Medical University; Xi'an, Shaanxi Province, PR China.
authors: Yanfei
authors: Y
authors: Hao
authors: Department of Microbiology; the Fourth Military Medical University; Xi'an, Shaanxi Province, PR China.
authors: Tailai
authors: T
authors: Luo
authors: Division of Infection and Immunology; Laboratory Animals Center; the Fourth Military Medical University; Xi'an, Shaanxi Province, PR China.
authors: Changhong
authors: C
authors: Shi
authors: Department of Microbiology; the Fourth Military Medical University; Xi'an, Shaanxi Province, PR China.
authors: Zhikai
authors: Z
authors: Xu
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D000995:Antitubercular Agents / Q000008:administration & dosage*; D001419:Bacteria; D058491:Bacterial Load; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D003131:Combined Modality Therapy / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007538:Isoniazid / Q000008:administration & dosage; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008810:Mice, Inbred C57BL; D020102:Mycobacterium smegmatis / Q000235:genetics / Q000276:immunology*; D011718:Pyrazinamide / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016896:Treatment Outcome; D014376:Tuberculosis / Q000628:therapy*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D000995:Antitubercular Agents; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D032581:Tuberculosis Vaccines; D014614:Vaccines, Synthetic; D011718:Pyrazinamide; D007371:Interferon-gamma; D000217:Acyltransferases; C121433:antigen 85B, Mycobacterium tuberculosis; D007538:Isoniazid
keywords: Ag85B; ESAT6; Mycobacterium tuberculosis; immunotherapy; recombinant Mycobacterium smegmatis
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