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-1ß and interferon-α/ß. 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.
ABSTRACT
BACKGROUND: The objective of this study was to identify the risk factors associated with the nosocomial sepsis syndrome according to the criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. PATIENTS AND METHOD: A 1-year prospective case-control study matched for sex, age (+/- 5 years), and pre-infection hospital stay (+/- 1 day) was performed in a 1,200-bed university hospital. Cases were selected according to the above criteria. Controls were randomly selected from the daily list of hospitalized patients. Crude and adjusted odds ratios (OR) were determined. RESULTS: 346 cases and 346 controls were included. Multivariate analysis identified the following intrinsic risk factors: coma in the 48 hours before sepsis (OR: 15.1; CI 95%, 5.6-41.2), renal failure (OR: 3.4; CI 95%; 1.5-10.8), neoplasm (OR: 2.4; CI 95%, 1.1-5.1), prosthesis material (OR: 2.7; CI 95%, 1.0-7.8), and serum albumin concentration at admission lower than 3.1 g/dl (OR: 5.3; CI 95%, 2.3-12.4). Main extrinsic risk factors were: previous nosocomial infection (OR: 12.5; CI 95%, 1.61-96.3), intensive care unit (ICU) stay (OR: 10.6; CI 95%, 3.1-36.2), naso-gastric tube (OR: 8.4; CI 95%, 2.3-31.3), indwelling urinary catheter (OR: 5.0; CI 95%, 1.4-18.9), H2 blockers treatment (OR: 5.0; CI 95%, 1.6-15.2), and IV central line (OR: 4.1; CI 95%, 1.2-14.0). CONCLUSION: In our study, main risk factors for development of nosocomial sepsis were presence of coma in the 48 hours before sepsis, ICU stay, and prior cross infection during hospitalization.
