Characterization of Protective Immunity to MTB in a Setting of HIV Coinfection

抽象的。 活动性结核病由结核分枝杆菌(Mtb)生产性感染引起，造成约150万人死亡 每年一次。结核分枝杆菌/艾滋病毒混合感染大大加重了全球结核病负担。结核病控制的失败源于 由于缺乏有效的疫苗。因此迫切需要新的疫苗。我们并没有完全 了解与保护相关的免疫反应的身份。 我们最近的工作表明，MTBΔSIGH，一个缺乏应激反应调节因子的突变体，完全是 在猕猴肺中存活而减弱，并引起深刻和有效的肺部免疫反应。气雾剂 用该突变株免疫猕猴可完全保护猕猴免受致死性肺结核病的侵袭，两种反应 而且保护作用远远超过卡介苗接种。似乎接种Δ感叹疫苗有保护作用 通过招募对肺的保护性记忆T细胞反应来对抗结核分枝杆菌的致命挑战。因此，我们 有前所未有的机会更好地了解预防结核分枝杆菌感染的相关因素 研究在这些猕猴身上引起的反应。此外，我们现在表明，非致病性感染 带有结核分枝杆菌Δ叹息的猕猴肺不会因为与SIV混合感染而重新激活，这是结核分枝杆菌特异性肺结核病的情况。 然而，大多数感染结核分枝杆菌的动物在合并感染SIV时会重新激活感染。因此 在SIV(因此可能是艾滋病毒)混合感染的情况下似乎是安全的。 作为这项应用的一部分，我们试图识别与保护相关的T细胞特异性免疫相关性。 接种Δ疫苗的猕猴感叹，相对于接种卡介苗或未接种卡介苗的动物，无论是接种前后 MTB挑战赛。此外，我们还将研究这些与保护相关的反应是否保留在 SIV合并感染的设置。我们将进一步关注B细胞特异性反应，根据初步和 公布的数据表明，含有这些细胞的集群在受保护动物的肉芽肿中积累。 好了！

Abstract. Active TB disease, resulting from productive infection with M. tuberculosis (Mtb), causes ~1.5 million deaths annually. Mtb/HIV co-infections contribute significantly to the global TB burden. The failure to control TB stems from the lack of an effective vaccine. New vaccines are therefore urgently needed. We do not completely understand the identity of protection-associated immune responses. Our recent work has shown that MtbΔsigH, a mutant lacking the stress-response regulator SigH, is completely attenuated for survival in macaque lungs, and elicits profound and productive lung immune responses. Aerosol vaccination with this mutant completely protects macaques from lethal pulmonary TB and both the responses and protection far exceed that observed for BCG vaccination. It appears that ΔsigH-vaccination protects against lethal challenge with Mtb by a recruiting a protective memory T cell response to the lung. Therefore, we have an unprecedented opportunity to better understand the correlates of protection from Mtb infection by studying responses elicited in these macaques. Furthermore, we now show that the nonpathogenic infection of macaque lungs with MtbΔsigH is not reactivated by co-infection with SIV, as is the case for Mtb-specific LTBI. A majority of Mtb infected animals with LTBI however reactivate infection when co-infected with SIV. Therefore appears to be safe in the setting of SIV (hence possibly HIV) co-infection. As part of this application we seek to identify protection-associated T cell specific correlates of immunity in macaques vaccinated with ΔsigH, relative to BCG vaccinated or unvaccinated animals, both prior to and after Mtb challenge. Furthermore, we will also study if these protection-associated responses are retained in the setting of SIV co-infection. We will further focus on B cell specific responses in the light of preliminary and published data that clusters containing these cells accumulate in granulomas of protected animals. !