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

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.

A Cross-Protective Vaccine Against 4b and 1/2b Listeria monocytogenes

“…Vaccine immunization is one of the most effective strategy to prevent listeriosis infections. Researchers have developed a diverse array of Listeria vaccine platforms, e.g., Listeria live attenuated vaccine (McLaughlin et al, 2013), live vector vaccine (Yin et al, 2017;Zeng et al, 2020), inactivated vaccine (Jazani et al, 2010), inactivated but metabolically active (KBMA) vaccine (Lauer et al, 2008), irradiated vaccine (Dong et al, 2009), Bacterial ghosts (BGs) (Wu et al, 2017), subunit vaccine (Ansari et al, 2012;Rodriguez-Del Rio et al, 2015), nanovaccine (Calderon-Gonzalez et al, 2017), and peptides-loaded DC vaccine (Kono et al, 2012;Jensen et al, 2013). However, there is not yet a Listeria vaccine that has been approved by the FDA department on the market (Cory and Chu, 2014).…”

“…Listeriosis is associated with miscarriage, gastroenteritis, sepsis, and meningitis, with a mortality rate of 20-30% (Hernandez-Milian and Payeras-Cifre, 2014; Schutte et al, 2019). Listeriosis has remained a problem in recent years, listeriosis outbreaks were reported in South Africa (Smith et al, 2019), the United States (Angelo et al, 2017), the European Union (Calderon-Gonzalez et al, 2017;Duranti et al, 2018), and other countries and regions.…”

Glyceraldehyde-3-phosphate Dehydrogenase Common Peptides of Listeria monocytogenes, Mycobacterium marinum and Streptococcus pneumoniae as Universal Vaccines

“…DC are cultured in DMEM complete medium with 10% FCS to a density of 10 10 cells/mL and homogenized on Hepes-saline-EDTA buffer to obtain cytosol for ADP-ribosylation assays as reported [ 24 , 25 ]. DIO-1 is a TLR2/4 targeted molecule that we used as adjuvant [ 26 , 27 ].…”

Listeria Monocytogenes: A Model Pathogen Continues to Refine Our Knowledge of the CD8 T Cell Response

“…Therefore, although phagocytic cells can present non-secreted antigens to CD8 T cells to prime them, CD8 T cells specific for non-secreted antigens do not recognize infected non-phagocytic cells and are unable to control listeriosis [ 135 ]. As maternal Lm infection can cause serious fetal or neonatal complications, developing prophylactic and therapeutic vaccines against listeriosis is an ongoing interest [ 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 ]. When designing CD8 T cell-based vaccines against listeriosis, it is important to keep it in mind that non-secreted antigens may not be relevant targets.…”