Person:

Stefanetti, Giuseppe

Although maternal antibodies protect newborns from infection, little is known about how protective antibodies are induced without prior pathogen exposure. Here we show that neonatal mice lacking the capacity to produce IgG are protected by maternal natural IgG antibodies to the enteric pathogen enterotoxigenic Escherichia coli (ETEC) when antibodies are delivered either trans-placentally or through milk. By challenging pups fostered on either maternal antibody¬–sufficient or –deficient dams, we found that milk-derived IgG was critical for protection against ETEC-induced disease. Pups utilize the neonatal Fc receptor (FcRn) to transfer IgG from milk into serum, and this IgG provides protection against systemic and mucosal E. coli infection. The maternal commensal microbiota can induce antibodies that recognize antigens expressed by ETEC and other Enterobacteriaceae species. Induction of maternal antibodies against a commensal Pantoea species confers ETEC protection in pups. The surprising role of the microbiota in eliciting protective antibodies to a specific neonatal pathogen represents an important host defense mechanism against neonatal infection.

Francisella tularensis is the causative agent of tularemia, a category A bioterrorism agent. The lipopolysaccharide (LPS) O antigen (OAg) of F. tularensis has been considered for use in a glycoconjugate vaccine, but conjugate vaccines tested so far have failed to confer protection necessary against aerosolized pulmonary bacterial challenge. When F. tularensis OAg was purified under standard conditions, the antigen had a small molecular size [25 kDa, low molecular weight (LMW)]. Using milder extraction conditions, we found the native OAg had a larger molecular size [80 kDa, high molecular weight (HMW)], and in a mouse model of tularemia, a glycoconjugate vaccine made with the HMW polysaccharide coupled to tetanus toxoid (HMW-TT) conferred better protection against intranasal challenge than a conjugate made with the LMW polysaccharide (LMW-TT). To further investigate the role of OAg size in protection, we created an F. tularensis live vaccine strain (LVS) mutant with a significantly increased OAg size [220 kDa, very high molecular weight (VHMW)] by expressing in F. tularensis a heterologous chain-length regulator gene (wzz) from the related species Francisella novicida. Immunization with VHMW-TT provided markedly increased protection over that obtained with TT glycoconjugates made using smaller OAgs. We found that protective antibodies recognize a length-dependent epitope better expressed on HMW and VHMW antigens, which bind with higher affinity to the organism.