ABSTRACT
Preterm birth is currently the leading cause of neonatal morbidity and mortality. Genetic, immunological and infectious causes are suspected. Preterm infants have a higher risk of severe bacterial neonatal infections, most of which are caused by Escherichia coli an in particular E. coli K1strains. Women with history of preterm delivery have a high risk of recurrence and therefore constitute a target population for the development of vaccine against E. coli neonatal infections. Here, we characterize the immunological, microbiological and protective properties of a live attenuated vaccine candidate in adult female mice and their pups against after a challenge by K1 and non-K1 strains of E. coli. Our results show that the E. coli K1 E11 ∆aroA vaccine induces strong immunity, driven by polyclonal bactericidal antibodies. In our model of meningitis, mothers immunized prior to mating transfer maternal antibodies to pups, which protect newborn mice against various K1 and non-K1 strains of E. coli. Given the very high mortality rate and the neurological sequalae associated with neonatal E. coli K1 meningitis, our results constitute preclinical proof of concept for the development of a live attenuated vaccine against severe E. coli infections in women at risk of preterm delivery.
Subject(s)
Escherichia coli Infections , Infant, Newborn, Diseases , Meningitis , Premature Birth , Infant , Adult , Infant, Newborn , Female , Animals , Mice , Humans , Escherichia coli/genetics , Vaccines, Attenuated , Premature Birth/prevention & control , Infant, Premature , Escherichia coli Infections/prevention & control , Infant, Newborn, Diseases/etiology , Antibodies , Meningitis/etiologyABSTRACT
BACKGROUND: T cell-mediated graft rejection is mostly correlated with potent Th1 responses. However, because IFNγ mice reject their graft as efficiently as wild-type (WT) mice, the exact contribution of IFNγ and its transcription factor T-bet remains a matter of debate. Here, we address this question in the context of pancreatic islet allograft to better inform the molecular pathways that hampers islet survival in vivo. METHODS: Pancreatic islets from BALB/c mice were transplanted in WT, IFNγ, or T-bet C57BL/6 mice. Graft survival and the induction of effector and cytotoxic T-cell responses were monitored. RESULTS: Rejection of fully mismatched islet allografts correlated with high expression of both IFNγ and T-bet in WT recipients. However, allogeneic islets were permanently accepted in T-bet mice, in contrast to IFNγ hosts. Long-term survival correlated with decreased CD4 and CD8 T-cell infiltrates, drastically reduced donor-specific IFNγ and tumor necrosis factor tumor necrosis factor α responses and very low expression of the cytotoxic markers granzyme B, perforin, and FasLigand. In addition, in vitro and in vivo data pointed to an increased susceptibility of T-bet CD8 T cell to apoptosis. These observations were not reported in IFNγ mice, which have set up compensatory effector mechanisms comprising an increased expression of the transcription factor Eomes and cytolytic molecules as well as tumor necrosis factor α-mediated but not IL-4 nor IL-17-mediated allogeneic responses. CONCLUSIONS: Anti-islet T-cell responses require T-bet but not IFNγ-dependent programs. Our results provide new clues on the mechanisms dictating islet rejection and may help refine the therapeutic/immunosuppressive regimens applied in diabetic patients receiving islets or pancreas allografts.
