GNP-GAPDH1-22 nanovaccines prevent neonatal listeriosis by blocking microglial apoptosis and bacterial dissemination

Ricardo Calderon-Gonzalez, Elisabet Frande-Cabanes, Hector Teran-Navarro, Jose Maria Marimon, Javier Freire, David Salcines-Cuevas, Maria del Carmen Fariñas, Claudia Gonzalez-Rico, Marco Marradi, Isabel Garcia, Miriam Alkorta-Gurrutxaga, Aida San Nicolas-Gomez, Ana Castañeda-San Pedro, Sonsoles Yañez-Diaz, Soledad Penades, Carmen Punzon, Jose Javier Gomez-Roman, Fernando Rivera, Manuel Fresno, Carmen Alvarez-Dominguez

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Abstract

Clinical cases of neonatal listeriosis are associated with brain disease and fetal loss due to complications in early or late pregnancy, which suggests that microglial function is altered. This is believed to be the first study to link microglial apoptosis with neonatal listeriosis and listeriosis-associated brain disease, and to propose a new nanovaccine formulation that reverses all effects of listeriosis and confers Listeria monocytogenes (LM)-specific immunity. We examined clinical cases of neonatal listeriosis in 2013-2015 and defined two useful prognostic immune biomarkers to design listeriosis vaccines: high anti-GAPDH1-22 titres and tumor necrosis factor (TNF)/interleukin (IL)-6 ratios. Therefore, we developed a nanovaccine with gold glyco-nanoparticles conjugated to LM peptide 1-22 of GAPDH (Lmo2459), GNP-GAPDH1-22 nanovaccinesformulated with a pro-inflammatory Toll-like receptor 2/4-targeted adjuvant. Neonates born to non-vaccinated pregnant mice with listeriosis, showed brain and vascular diseases and significant microglial dysfunction by induction of TNF-α-mediated apoptosis. This programmed TNF-mediated suicide explains LM dissemination in brains and livers and blocks production of early pro-inflammatory cytokines such as IL-1β and interferon-α/β. In contrast, neonates born to GNP-GAPDH1-22-vaccinated mothers before LM infection, did not develop listeriosis or brain diseases and had functional microglia. In nanovaccinated mothers, immune responses shifted towards Th1/IL-12 pro-inflammatory cytokine profiles and high production of anti-GAPDH1-22 antibodies, suggesting good induction of LM-specific memory.
Original languageEnglish
Pages (from-to)53916-53934
Number of pages19
JournalOncotarget
Volume8
Issue number33
DOIs
Publication statusPublished - 20 Jul 2017
Externally publishedYes

Keywords

  • Neonatal listeriosis
  • Microglia
  • Apoptosis
  • Tumor necrosis factor signaling
  • Nanovaccines
  • Immunology and Microbiology Section
  • Immune response
  • Immunity

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