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.

Background: TNF receptor-associated factor 2 (TRAF2) is a key adaptor molecule in the TNF receptor (TNFR) signaling pathway. Results: TRAF-interacting protein (TRIP) inhibits Lys63 -linked TRAF2 ubiquitination by blocking the binding of the cofactor sphingosine 1-phosphate (S1P) to the TRAF2 RING domain. Conclusion: TRIP negatively regulates the TRAF2 ubiquitin-dependent pathway by modulating the TRAF2-S1P interaction. Significance: TRIP is an important cellular regulator of the TNFR-mediated inflammatory response.

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Background: Genetic defects in the OSTM1 (osteopetrosis-associated transmembrane protein 1) gene cause autosomal recessive osteopetrosis. Results:The loss of the transmembrane domain in the OSTM1 gene produces a secreted form of truncated OSTM1 that inhibits osteoclast differentiation and survival. Conclusion: Extracellular secretion of a truncated OSTM1 is negatively involved in osteoclastogenesis. Significance: We identified a novel function for the secreted form of truncated OSTM1 in osteoclastogenesis.

Macrophages constitute the first line of defense against Mycobacterium tuberculosis and are critical in linking innate and adaptive immunity. Therefore, the identification and characterization of mycobacterial proteins that modulate macrophage function are essential for understanding tuberculosis pathogenesis. In this study, we identified the novel macrophage-activating protein, Rv2882c, from M. tuberculosis culture filtrate proteins. Recombinant Rv2882c protein activated macrophages to secrete pro-inflammatory cytokines and express co-stimulatory and major histocompatibility complex molecules via Toll-like receptor 4, myeloid differentiation primary response protein 88, and Toll/IL-1 receptor-domain-containing adaptor inducing IFN-beta. Mitogen-activated protein kinases and NF-κB signaling pathways were involved in Rv2882c-induced macrophage activation. Further, Rv2882c-treated macrophages induced expansion of the effector/memory T cell population and Th1 immune responses. In addition, boosting Bacillus Calmette-Guerin vaccination with Rv2882c improved protective efficacy against M. tuberculosis in our model system. These results suggest that Rv2882c is an antigen that could be used for tuberculosis vaccine development.