We describe a role of CD44-mediated signaling during host-defense against tuberculosis (TB) using a mouse model of TB and studies in M. tuberculosis (Mtb) infected human macrophage (MФ). Liposomes targeting CD44 using thioaptamers (CD44TA-LIP) were designed and tested as new vaccines to boost host immunity in TB. CD44TA-LIP enhanced killing of Mtb in human MФ, which correlated with an increased production of pro-inflammatory cytokines IL-1β, TNF-α and IL-12. CD44TA-LIP activated MФ showed an enhanced MHC-II dependent antigen presentation to CD4 T-cells. Inhibition of cellular proliferation and cytoskeleton rearrangement pathways downstream of CD44 signaling abrogated CD44TA-LIP-induced antimicrobial effects. Blockade of inflammatory pathways also reduced antigen presentation by MФ and activation of CD4 T cells. Mtb infected MФ treated with CD44TA-LIP exhibited increased nitric oxide and HβD2 defensin peptide production. Among Mtb infected mice with increased lung and spleen loads of organisms, intranasal administration of CD44TA-LIP led to a ten-fold reduction of colony forming units of Mtb and elevated IFN-γ + CD4, effector, central and resident memory T cells. Biodistribution studies demonstrated that CD44TA-LIP preferentially accumulated in the lungs and were associated with CD11b + cells. CD44TA-LIP treated mice showed no weight loss or increased liver LDH levels. This study highlights the importance of CD44-mediated signaling in host-defense during TB and the therapeutic potential of CD44TA-LIP.

我们使用结核病小鼠模型和对结核分枝杆菌（Mtb）感染的人巨噬细胞（MФ）的研究描述了CD44介导的信号在宿主防御结核病（TB）过程中的作用。使用硫适体 (CD44TA-LIP) 靶向 CD44 的脂质体被设计和测试为新疫苗，以增强结核病宿主的免疫力。CD44TA-LIP 增强了人 MФ 中Mtb的杀灭，这与促炎细胞因子 IL-1β、TNF-α 和 IL-12 的产生增加相关。CD44TA-LIP 激活的 MФ 表现出增强的 MHC-II 依赖性抗原向 CD4 T 细胞的呈递。CD44 信号下游的细胞增殖和细胞骨架重排途径的抑制消除了 CD44TA-LIP 诱导的抗菌作用。炎症途径的阻断也减少了 MФ 的抗原呈递和 CD4 T 细胞的激活。用 CD44TA-LIP 处理的感染Mtb 的MФ 表现出一氧化氮和 HβD2 防御素肽的产生增加。在肺部和脾脏生物体负荷增加的Mtb感染小鼠中，鼻内给予 CD44TA-LIP 导致Mtb集落形成单位减少十倍，并升高 IFN-γ + CD4、效应细胞、中枢和常驻记忆 T 细胞。生物分布研究表明，CD44TA-LIP 优先在肺部积聚，并与 CD11b + 细胞相关。CD44TA-LIP 治疗的小鼠没有表现出体重减轻或肝脏 LDH 水平增加。这项研究强调了 CD44 介导的信号传导在结核病期间宿主防御中的重要性以及 CD44TA-LIP 的治疗潜力。