Abstract
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.
Original language | English (US) |
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Pages (from-to) | 796-811 |
Number of pages | 16 |
Journal | Journal of Controlled Release |
Volume | 349 |
DOIs | |
State | Published - Sep 2022 |
Keywords
- CD4 T cells
- CD44
- Host-defense
- Host-directed therapy
- Immunity
- Liposomes
- Macrophages
- Mycobacterium tuberculosis
- Thioaptamers
- Tuberculosis
- Humans
- Interleukin-12
- Hyaluronan Receptors/metabolism
- Nitric Oxide
- Tuberculosis/drug therapy
- Tumor Necrosis Factor-alpha
- Anti-Infective Agents
- Macrophage-1 Antigen
- Nanoparticles
- Tissue Distribution
- Defensins
ASJC Scopus subject areas
- Pharmaceutical Science