title: Over-expression of superoxide dismutase obliterates the protective effect of BCG against tuberculosis by modulating innate and adaptive immune responses.
abstract: An efficient global control of tuberculosis requires development of alternative vaccination strategies that can enhance the efficacy of existing BCG vaccine. In this study, we evaluated the protective efficacy of a recombinant BCG (rBCG) vaccine over-expressing iron-cofactored superoxide dismutase (SOD-A), one of the prominent oxidative stress response proteins of Mycobacterium tuberculosis. Contrary to our expectations, over-expression of SOD-A resulted in the abrogation of BCG's ability to confer protection in guinea pig as well as in murine model. Analysis of immune responses revealed that over-expression of SOD-A by rBCG has pleiotropic effects on innate and adaptive immune responses. Macrophages infected in vitro with rBCG exhibited a marked reduction in apoptosis and microbicidal potential. In addition, rBCG vaccination of mice resulted in a reduced IFNγ and increased IL10 production when compared with the BCG vaccination. Further, we show that rBCG vaccination failed to generate an effective multi-functional CD4 T cell response. Altogether, our findings suggest that over-expression of SOD-A in BCG enhances the immuno-suppressive properties of BCG, characterized by skewing of immune responses towards Th2 type, an inefficient multi-functional T cell response and reduced apoptosis and microbicidal potential of macrophages leading to abolishment of BCG's protective efficacy.
authors.affiliation: Department of Biochemistry, University of Delhi South Campus, New Delhi 110021, India.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Jain
authors.forename: Bappaditya
authors.initials: B
authors.lastname: Dey
authors.forename: Aparna
authors.initials: A
authors.lastname: Khera
authors.forename: Priyadarshani
authors.initials: P
authors.lastname: Srivastav
authors.forename: Umesh D
authors.initials: UD
authors.lastname: Gupta
authors.forename: V M
authors.initials: VM
authors.lastname: Katoch
authors.forename: V D
authors.initials: VD
authors.lastname: Ramanathan
authors.forename: Anil K
authors.initials: AK
authors.lastname: Tyagi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001500:BCG Vaccine / Q000008:administration & dosage / Q000276:immunology*; D001426:Bacterial Proteins / Q000096:biosynthesis*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D015870:Gene Expression; D006168:Guinea Pigs; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D013482:Superoxide Dismutase / Q000096:biosynthesis*; D014376:Tuberculosis / Q000517:prevention & control*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D001500:BCG Vaccine; D001426:Bacterial Proteins; D014614:Vaccines, Synthetic; D016753:Interleukin-10; D007371:Interferon-gamma; C095500:SodA protein, Bacteria; D013482:Superoxide Dismutase