CD44 receptor targeted nanoparticles augment immunity against tuberculosis in mice

Vipul K. Singh, Eric Chau, Abhishek Mishra, Alexandro DeAnda, Venkatesh L Hegde, Jagannadha K. Sastry, David Haviland, Chinnaswamy Jagannath, Biana Godin, Arshad Khan

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)796-811
Number of pages16
JournalJournal of Controlled Release
Volume349
DOIs
StatePublished - Sep 2022

Keywords

  • CD4 T cells
  • CD44
  • Host-defense
  • Host-directed therapy
  • Immunity
  • Liposomes
  • Macrophages
  • Mycobacterium tuberculosis
  • Thioaptamers
  • Tuberculosis

ASJC Scopus subject areas

  • Pharmaceutical Science

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