Gopal Radha, Monin Leticia, Slight Samantha, Uche Uzodinma, Blanchard Emmeline, Fallert Junecko Beth A, Ramos-Payan Rosalio, Stallings Christina L, Reinhart Todd A, Kolls Jay K, Kaushal Deepak, Nagarajan Uma, Rangel-Moreno Javier, Khader Shabaana A
Department of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
PLoS Pathog. 2014 May 15;10(5):e1004099. doi: 10.1371/journal.ppat.1004099. eCollection 2014 May.
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), infects one third of the world's population. Among these infections, clinical isolates belonging to the W-Beijing appear to be emerging, representing about 50% of Mtb isolates in East Asia, and about 13% of all Mtb isolates worldwide. In animal models, infection with W-Beijing strain, Mtb HN878, is considered "hypervirulent" as it results in increased mortality and causes exacerbated immunopathology in infected animals. We had previously shown the Interleukin (IL) -17 pathway is dispensable for primary immunity against infection with the lab adapted Mtb H37Rv strain. However, it is not known whether IL-17 has any role to play in protective immunity against infection with clinical Mtb isolates. We report here that lab adapted Mtb strains, such as H37Rv, or less virulent Mtb clinical isolates, such as Mtb CDC1551, do not require IL-17 for protective immunity against infection while infection with Mtb HN878 requires IL-17 for early protective immunity. Unexpectedly, Mtb HN878 induces robust production of IL-1β through a TLR-2-dependent mechanism, which supports potent IL-17 responses. We also show that the role for IL-17 in mediating protective immunity against Mtb HN878 is through IL-17 Receptor signaling in non-hematopoietic cells, mediating the induction of the chemokine, CXCL-13, which is required for localization of T cells within lung lymphoid follicles. Correct T cell localization within lymphoid follicles in the lung is required for maximal macrophage activation and Mtb control. Since IL-17 has a critical role in vaccine-induced immunity against TB, our results have far reaching implications for the design of vaccines and therapies to prevent and treat emerging Mtb strains. In addition, our data changes the existing paradigm that IL-17 is dispensable for primary immunity against Mtb infection, and instead suggests a differential role for IL-17 in early protective immunity against emerging Mtb strains.
结核分枝杆菌（Mtb）是结核病（TB）的病原体，感染了世界三分之一的人口。在这些感染中，属于W-Beijing家族的临床分离株似乎正在出现，占东亚Mtb分离株的约50%，占全球所有Mtb分离株的约13%。在动物模型中，感染W-Beijing菌株Mtb HN878被认为是“高毒力的”，因为它会导致死亡率增加，并在受感染动物中引起加剧的免疫病理学。我们之前已经表明，白细胞介素（IL）-17途径对于针对实验室适应的Mtb H37Rv菌株感染的初级免疫是可有可无的。然而，尚不清楚IL-17在针对临床Mtb分离株感染的保护性免疫中是否发挥任何作用。我们在此报告，实验室适应的Mtb菌株，如H37Rv，或毒力较低的Mtb临床分离株，如Mtb CDC1551，在针对感染的保护性免疫中不需要IL-17，而感染Mtb HN878则需要IL-17进行早期保护性免疫。出乎意料的是，Mtb HN878通过依赖TLR-2的机制诱导强大的IL-1β产生，这支持了有效的IL-17反应。我们还表明，IL-17在介导针对Mtb HN878的保护性免疫中的作用是通过非造血细胞中的IL-17受体信号传导，介导趋化因子CXCL-13的诱导，这是T细胞在肺淋巴滤泡中定位所必需的。T细胞在肺淋巴滤泡中的正确定位是最大程度激活巨噬细胞和控制Mtb所必需的。由于IL-17在疫苗诱导的抗结核免疫中起关键作用，我们的结果对预防和治疗新出现的Mtb菌株的疫苗和疗法设计具有深远影响。此外，我们的数据改变了现有的范式，即IL-17对于针对Mtb感染的初级免疫是可有可无的，相反，表明IL-17在针对新出现的Mtb菌株的早期保护性免疫中具有不同的作用。
