Research Papers: Immunology:

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

Ricardo Calderon-Gonzalez, Elisabet Frande-Cabanes, Hector Teran-Navarro, José María Marimon, Javier Freire, David Salcines-Cuevas, M. Carmen Fariñas, Claudia Gonzalez-Rico, Marco Marradi, Isabel Garcia, Mirian Alkorta-Gurrutxaga, Aida San Nicolas-Gomez, Ana Castañeda-Sampedro, Sonsoles Yañez-Diaz, Soledad Penades, Carmen Punzon, Javier Gomez-Roman, Fernando Rivera, Manuel Fresno and Carmen Alvarez-Dominguez _

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Oncotarget. 2017; 8:53916-53934. https://doi.org/10.18632/oncotarget.19405

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Ricardo Calderon-Gonzalez1,*, Elisabet Frande-Cabanes1,*, Hector Teran-Navarro1,*, José María Marimon2, Javier Freire3, David Salcines-Cuevas1, M. Carmen Fariñas4, Claudia Gonzalez-Rico4, Marco Marradi5, Isabel Garcia5, Mirian Alkorta-Gurrutxaga2, Aida San Nicolas-Gomez1, Ana Castañeda-Sampedro1, Sonsoles Yañez-Diaz6, Soledad Penades5, Carmen Punzon7, Javier Gomez-Roman3, Fernando Rivera8, Manuel Fresno7 and Carmen Alvarez-Dominguez1

1 Grupo de Nanovacunas y vacunas celulares basadas en Listeria y sus aplicaciones en biomedicina, Instituto de Investigación Marqués de Valdecilla, Santander, Spain

2 Servicio de Microbiología, Instituto de Investigación Sanitaria Biodonostia, Hospital Universitario Donostia, San Sebastián, Gipuzkoa y CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain

3 Servicio de Anatomía Patológica, Hospital Universitario Marqués de Valdecilla, Santander, Spain

4 Seccion de Enfermedades Infecciosas, Hospital Universitario Marqués de Valdecilla, Santander, Spain

5 CIC biomaGUNE, and Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Paseo Miramón 182, Donostia-San Sebastián, Spain

6 Servicio de Dermatología, Hospital Universitario Marqués de Valdecilla, Santander, Spain

7 Diomune S.L. Parque Científico de Madrid, Madrid, Spain; Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, Spain

8 Servicio de Oncología Médica, Hospital Universitario Marqués de Valdecilla, Santander, Spain

* These authors have contributed equally to this study


Carmen Alvarez-Dominguez, email:

Keywords: neonatal listeriosis, microglia, apoptosis, tumor necrosis factor signaling, nanovaccines, Immunology and Microbiology Section, Immune response, Immunity

Received: November 09, 2016 Accepted: July 01, 2017 Published: July 20, 2017


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.

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