The porin OmpD from nontyphoidal Salmonella is a key target for a protective B1b cell antibody response

Cristina Gil-Cruz, Saeeda Bobat, Jennifer L. Marshall, Robert A. Kingsley, Ewan A. Ross, Ian R. Henderson, Denisse L. Leyton, Ruth E. Coughlan, Mahmood Khan, Karina T. Jensen, Christopher D. Buckley, Gordon Dougan, Ian C.M. MacLennan, Constantino López-Macías, Adam F. Cunningham

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)9803-9808
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number24
DOIs
Publication statusPublished - 16 Jun 2009

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Porins
Salmonella typhimurium
Salmonella
Antibody Formation
Bacteremia
Infection
Salmonella typhi
Salmonella Infections
Vaccines
T Independent Antigens
Cross Protection
Bacterial Vaccines
B-Lymphocyte Subsets
Flagellin
Inactivated Vaccines
Germinal Center
Africa South of the Sahara
Surface Antigens
Membrane Proteins
Proteins

Keywords

  • B cells
  • Vaccines

Cite this

Gil-Cruz, Cristina ; Bobat, Saeeda ; Marshall, Jennifer L. ; Kingsley, Robert A. ; Ross, Ewan A. ; Henderson, Ian R. ; Leyton, Denisse L. ; Coughlan, Ruth E. ; Khan, Mahmood ; Jensen, Karina T. ; Buckley, Christopher D. ; Dougan, Gordon ; MacLennan, Ian C.M. ; López-Macías, Constantino ; Cunningham, Adam F. / The porin OmpD from nontyphoidal Salmonella is a key target for a protective B1b cell antibody response. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 24. pp. 9803-9808.
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Gil-Cruz, C, Bobat, S, Marshall, JL, Kingsley, RA, Ross, EA, Henderson, IR, Leyton, DL, Coughlan, RE, Khan, M, Jensen, KT, Buckley, CD, Dougan, G, MacLennan, ICM, López-Macías, C & Cunningham, AF 2009, 'The porin OmpD from nontyphoidal Salmonella is a key target for a protective B1b cell antibody response', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 24, pp. 9803-9808. https://doi.org/10.1073/pnas.0812431106

The porin OmpD from nontyphoidal Salmonella is a key target for a protective B1b cell antibody response. / Gil-Cruz, Cristina; Bobat, Saeeda; Marshall, Jennifer L.; Kingsley, Robert A.; Ross, Ewan A.; Henderson, Ian R.; Leyton, Denisse L.; Coughlan, Ruth E.; Khan, Mahmood; Jensen, Karina T.; Buckley, Christopher D.; Dougan, Gordon; MacLennan, Ian C.M.; López-Macías, Constantino; Cunningham, Adam F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 24, 16.06.2009, p. 9803-9808.

Research output: Contribution to journalArticle

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T1 - The porin OmpD from nontyphoidal Salmonella is a key target for a protective B1b cell antibody response

AU - Gil-Cruz, Cristina

AU - Bobat, Saeeda

AU - Marshall, Jennifer L.

AU - Kingsley, Robert A.

AU - Ross, Ewan A.

AU - Henderson, Ian R.

AU - Leyton, Denisse L.

AU - Coughlan, Ruth E.

AU - Khan, Mahmood

AU - Jensen, Karina T.

AU - Buckley, Christopher D.

AU - Dougan, Gordon

AU - MacLennan, Ian C.M.

AU - López-Macías, Constantino

AU - Cunningham, Adam F.

PY - 2009/6/16

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N2 - 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.

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KW - Vaccines

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