Rv2299c, a novel dendritic cell-activating antigen ofMycobacterium tuberculosis, fused-ESAT-6 subunit vaccine confers improved and durable protection against the hypervirulent strain HN878 in mice

// Han-Gyu Choi 1 , Seunga Choi 1 , Yong Woo Back 1 , Seungwha Paik 1 , Hye-Soo Park 1 , Woo Sik Kim 2 , Hongmin Kim 2 , Seung Bin Cha 2 , Chul Hee Choi 1 , Sung Jae Shin 2 , Hwa-Jung Kim 1 1 Department of Microbiology, and Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea 2 Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea Correspondence to: Hwa-Jung Kim, email: hjukim@cnu.ac.kr Sung Jae Shin, email: sjshin@yuhs.ac Keywords: tuberculosis, DC maturation, toll-like receptor 4, multifunctional T cell, subunit vaccine Received: June 08, 2016     Accepted: December 16, 2016     Published: February 10, 2017 ABSTRACT Understanding functional interactions between DCs and antigens is necessary for achieving an optimal and desired immune response during vaccine development. Here, we identified and characterized protein Rv2299c (heat-shock protein 90 family), which effectively induced DC maturation. The Rv2299c-maturated DCs showed increased expression of surface molecules and production of proinflammatory cytokines. Rv2299c induced these effects by binding to TLR4 and stimulating the downstream MyD88-, MAPK- and NF-κB-dependent signaling pathways. The Rv2299c-maturated DCs also showed an induced Th1 cell response with bactericidal activity and expansion of effector/memory T cells. The Rv2299c-ESAT-6 fused protein had greater immunoreactivity than ESAT-6. Furthermore, boosting BCG with the fused protein significantly reduced hypervirulent Mycobacterium tuberculosis HN878 burdens post-challenge. The pathological study of the lung from the challenged mice assured the efficacy of the fused protein. The fused protein boosting also induced Rv2299c-ESAT-6-specific multifunctional CD4 + T-cell response in the lungs of the challenged mice. Our findings suggest that Rv2299c is an excellent candidate for the rational design of an effective multiantigenic TB vaccine.