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

4 Scopus citations

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
  • 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

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