title: The porin OmpD from nontyphoidal Salmonella is a key target for a protective B1b cell antibody response.
abstract: Invasive nontyphoidal Salmonella (NTS), including Salmonella typhimurium (STm), are major yet poorly-recognized killers of infants in sub-Saharan Africa. Death in these children is usually associated with bacteremia, commonly in the absence of gastrointestinal symptoms. Evidence from humans and animal studies suggest that severe infection and bacteremia occur when specific Ab is lacking. Understanding how Ab responses to Salmonella are regulated will help develop vaccines against these devastating infections. STm induces atypical Ab responses characterized by prominent, accelerated, extrafollicular T-independent (TI) Ab against a range of surface antigens. These responses develop without concomitant germinal centers, which only appear as infection resolves. Here, we show STm rapidly induces a population of TI B220(+)CD5(-) B1b cells during infection and TI Ab from B1b cells targets the outer membrane protein (Omp) porins OmpC, OmpD and OmpF but not flagellin. When porins are used as immunogens they can ablate bacteremia and provide equivalent protection against STm as killed bacterial vaccine and this is wholly B cell-dependent. Furthermore Ab from porin-immunized chimeras, that have B1b cells, is sufficient to impair infection. Infecting with porin-deficient bacteria identifies OmpD, a protein absent from Salmonella Typhi, as a key target of Ab in these infections. This work broadens the recognized repertoire of TI protein antigens and highlights the importance of Ab from different B cell subsets in controlling STm infection. OmpD is a strong candidate vaccine target and may, in part, explain the lack of cross-protection between Salmonella Typhi and STm infections.
authors.affiliation: School of Immunity and Infection and Medical Research Council Centre for Immune Regulation, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gil-Cruz
authors.forename: Saeeda
authors.initials: S
authors.lastname: Bobat
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Marshall
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kingsley
authors.forename: Ewan A
authors.initials: EA
authors.lastname: Ross
authors.forename: Ian R
authors.initials: IR
authors.lastname: Henderson
authors.forename: Denisse L
authors.initials: DL
authors.lastname: Leyton
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Coughlan
authors.forename: Mahmood
authors.initials: M
authors.lastname: Khan
authors.forename: Karina T
authors.initials: KT
authors.lastname: Jensen
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.forename: Ian C M
authors.initials: IC
authors.lastname: MacLennan
authors.forename: Constantino
authors.initials: C
authors.lastname: López-Macías
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000166:cytology; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051379:Mice; D010529:Peritoneal Cavity / Q000166:cytology; D018272:Porins / Q000276:immunology*; D012475:Salmonella / Q000276:immunology / Q000378:metabolism*
chemical_list: D000907:Antibodies, Bacterial; D017931:DNA Primers; C470933:OmpD protein, Salmonella typhimurium; D018272:Porins