Department of Microbiology, Mycobacteria Research Laboratories, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682, USA.
Immunol Cell Biol. 2012 Nov;90(10):945-54. doi: 10.1038/icb.2012.34. Epub 2012 Jul 17.
New approaches consisting of 'multistage' vaccines against (TB) are emerging that combine early antigenic proteins with latency-associated antigens. In this study, HspX was tested for its potential to elicit both short- and long-term protective immune responses. HspX is a logical component in vaccine strategies targeting protective immune responses against primary infection, as well as against reactivation of latent infection, because as previously shown, it is produced during latency, and as our studies show, it elicits protection within 30 days of infection. Recent studies have shown that the current TB vaccine, bacilli Calmette-Guerin (BCG), does not induce strong interferon-γ T-cell responses to latency-associated antigens like HspX, which may be in part why BCG fails to protect against reactivation disease. We therefore tested HspX protein alone as a prophylactic vaccine and as a boost to BCG vaccination, and found that HspX purified from M. tuberculosis cell lysates protected mice against aerosol challenge and improved the protective efficacy of BCG when used as a booster vaccine. Native HspX was highly immunogenic and protective, in a dose-dependent manner, in both short- and long-term infection models. Based on these promising findings, HspX was produced as a recombinant protein in E. coli, as this would enable facile purification; however, recombinant HspX (rHspX) alone consistently failed to protect against aerosol challenge. Incubation of rHspX with mycobacterial cell lysate and re-purification following incubation restored the capacity of the protein to confer protection. These data suggest the possibility that the native form may chaperone an immunogenic and protective antigen that is mycobacteria-specific.
新的方法包括针对（TB）的“多阶段”疫苗，这些疫苗将早期抗原蛋白与潜伏相关抗原结合在一起。在这项研究中，测试了 HspX 激发短期和长期保护性免疫反应的潜力。HspX 是针对原发性感染和潜伏感染再激活的保护性免疫反应的疫苗策略的逻辑组成部分，因为如前所述，它在潜伏期产生，并且正如我们的研究所示，它在感染后 30 天内引发保护。最近的研究表明，目前的结核病疫苗卡介苗（BCG）不会诱导针对潜伏相关抗原（如 HspX）的强烈干扰素-γ T 细胞反应，这可能部分解释了为什么 BCG 不能预防再激活疾病。因此，我们单独测试了 HspX 蛋白作为预防性疫苗和 BCG 疫苗的加强剂，并发现从结核分枝杆菌细胞裂解物中纯化的 HspX 可保护小鼠免受气溶胶挑战，并在用作加强疫苗时提高了 BCG 的保护效力。天然 HspX 在短期和长期感染模型中均具有高度免疫原性和保护作用，呈剂量依赖性。基于这些有希望的发现，HspX 作为重组蛋白在大肠杆菌中生产，因为这将使其易于纯化；然而，单独的重组 HspX（rHspX）始终不能防止气溶胶挑战。rHspX 与分枝杆菌细胞裂解物孵育并在孵育后重新纯化恢复了该蛋白赋予保护的能力。这些数据表明，天然形式可能伴侣一种免疫原性和保护性抗原，该抗原是分枝杆菌特异性的。
