期刊
JOURNAL OF CONTROLLED RELEASE
卷 349, 期 -, 页码 796-811出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2022.07.040
关键词
CD44; Host-defense; Tuberculosis; Macrophages; Immunity; Thioaptamers; Liposomes; Mycobacterium tuberculosis; CD4 T cells; Host-directed therapy
资金
- NIH [R21 7R21AI137533-02]
- HMRI
- Houston Methodist Research Institute
This study describes the role of CD44-mediated signaling in host-defense against tuberculosis (TB). CD44-targeting liposomes were designed and tested as a new vaccine to enhance host immunity in TB. The results showed that CD44TA-LIP enhanced the killing of Mtb in human macrophages and increased the production of pro-inflammatory cytokines. It also activated antigen presentation to CD4 T-cells and exhibited antimicrobial effects. In Mtb-infected mice, CD44TA-LIP led to reduced colony forming units of Mtb and increased IFN-gamma + CD4 T cells. Biodistribution studies showed that CD44TA-LIP accumulated in the lungs and were associated with CD11b+ cells.
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 (MCYRILLIC CAPITAL LETTER EF). 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 MCYRILLIC CAPITAL LETTER EF, which correlated with an increased production of pro -inflammatory cytokines IL-1 beta, TNF-alpha and IL-12. CD44TA-LIP activated MCYRILLIC CAPITAL LETTER EF showed an enhanced MHC-II dependent antigen presentation to CD4 T-cells. Inhibition of cellular proliferation and cytoskeleton rearrange-ment pathways downstream of CD44 signaling abrogated CD44TA-LIP-induced antimicrobial effects. Blockade of inflammatory pathways also reduced antigen presentation by MCYRILLIC CAPITAL LETTER EF and activation of CD4 T cells. Mtb infected MCYRILLIC CAPITAL LETTER EF treated with CD44TA-LIP exhibited increased nitric oxide and H beta D2 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-gamma + 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据