A rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants

The ability of gut bacterial pathogens to escape immunity by antigenic variation—particularly via changes to surface-exposed antigens—is a major barrier to immune clearance 1 . However, not all variants are equally fit in all environments 2 , 3 . It should therefore be possible to exploit such immun...

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Veröffentlicht in:Nature microbiology 2021-07, Vol.6 (7), p.830-841
Hauptverfasser: Diard, Médéric, Bakkeren, Erik, Lentsch, Verena, Rocker, Andrea, Bekele, Nahimi Amare, Hoces, Daniel, Aslani, Selma, Arnoldini, Markus, Böhi, Flurina, Schumann-Moor, Kathrin, Adamcik, Jozef, Piccoli, Luca, Lanzavecchia, Antonio, Stadtmueller, Beth M., Donohue, Nicholas, van der Woude, Marjan W., Hockenberry, Alyson, Viollier, Patrick H., Falquet, Laurent, Wüthrich, Daniel, Bonfiglio, Ferdinando, Loverdo, Claude, Egli, Adrian, Zandomeneghi, Giorgia, Mezzenga, Raffaele, Holst, Otto, Meier, Beat H., Hardt, Wolf-Dietrich, Slack, Emma
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container_issue 7
container_start_page 830
container_title Nature microbiology
container_volume 6
creator Diard, Médéric
Bakkeren, Erik
Lentsch, Verena
Rocker, Andrea
Bekele, Nahimi Amare
Hoces, Daniel
Aslani, Selma
Arnoldini, Markus
Böhi, Flurina
Schumann-Moor, Kathrin
Adamcik, Jozef
Piccoli, Luca
Lanzavecchia, Antonio
Stadtmueller, Beth M.
Donohue, Nicholas
van der Woude, Marjan W.
Hockenberry, Alyson
Viollier, Patrick H.
Falquet, Laurent
Wüthrich, Daniel
Bonfiglio, Ferdinando
Loverdo, Claude
Egli, Adrian
Zandomeneghi, Giorgia
Mezzenga, Raffaele
Holst, Otto
Meier, Beat H.
Hardt, Wolf-Dietrich
Slack, Emma
description The ability of gut bacterial pathogens to escape immunity by antigenic variation—particularly via changes to surface-exposed antigens—is a major barrier to immune clearance 1 . However, not all variants are equally fit in all environments 2 , 3 . It should therefore be possible to exploit such immune escape mechanisms to direct an evolutionary trade-off. Here, we demonstrate this phenomenon using Salmonella enterica subspecies enterica serovar Typhimurium ( S .Tm). A dominant surface antigen of S .Tm is its O-antigen: a long, repetitive glycan that can be rapidly varied by mutations in biosynthetic pathways or by phase variation 4 , 5 . We quantified the selective advantage of O-antigen variants in the presence and absence of O-antigen-specific immunoglobulin A and identified a set of evolutionary trajectories allowing immune escape without an associated fitness cost in naive mice. Through the use of rationally designed oral vaccines, we induced immunoglobulin A responses blocking all of these trajectories. This selected for Salmonella mutants carrying deletions of the O-antigen polymerase gene wzyB . Due to their short O-antigen, these evolved mutants were more susceptible to environmental stressors (detergents or complement) and predation (bacteriophages) and were impaired in gut colonization and virulence in mice. Therefore, a rationally induced cocktail of intestinal antibodies can direct an evolutionary trade-off in S .Tm. This lays the foundations for the exploration of mucosal vaccines capable of setting evolutionary traps as a prophylactic strategy. Salmonella mutants with reduced ability to colonize the mouse gut and cause disease are selected for by vaccine-induced intestinal antibody responses in mice.
doi_str_mv 10.1038/s41564-021-00911-1
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However, not all variants are equally fit in all environments 2 , 3 . It should therefore be possible to exploit such immune escape mechanisms to direct an evolutionary trade-off. Here, we demonstrate this phenomenon using Salmonella enterica subspecies enterica serovar Typhimurium ( S .Tm). A dominant surface antigen of S .Tm is its O-antigen: a long, repetitive glycan that can be rapidly varied by mutations in biosynthetic pathways or by phase variation 4 , 5 . We quantified the selective advantage of O-antigen variants in the presence and absence of O-antigen-specific immunoglobulin A and identified a set of evolutionary trajectories allowing immune escape without an associated fitness cost in naive mice. Through the use of rationally designed oral vaccines, we induced immunoglobulin A responses blocking all of these trajectories. This selected for Salmonella mutants carrying deletions of the O-antigen polymerase gene wzyB . Due to their short O-antigen, these evolved mutants were more susceptible to environmental stressors (detergents or complement) and predation (bacteriophages) and were impaired in gut colonization and virulence in mice. Therefore, a rationally induced cocktail of intestinal antibodies can direct an evolutionary trade-off in S .Tm. This lays the foundations for the exploration of mucosal vaccines capable of setting evolutionary traps as a prophylactic strategy. 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Immunoglobulins ; Immunology ; Infectious Diseases ; Intestine ; Intestines - immunology ; Intestines - microbiology ; Letter ; Life Sciences ; Medical Microbiology ; Mice ; Microbiology ; Microbiology and Parasitology ; Mucosa ; Mutants ; Mutation ; O Antigens - genetics ; O Antigens - immunology ; Parasitology ; Phages ; Predation ; Salmonella ; Salmonella Infections - microbiology ; Salmonella Infections - prevention &amp; control ; Salmonella typhimurium - genetics ; Salmonella typhimurium - immunology ; Salmonella typhimurium - pathogenicity ; Salmonella Vaccines - administration &amp; dosage ; Salmonella Vaccines - immunology ; Vaccines ; Vaccines, Attenuated - administration &amp; dosage ; Vaccines, Attenuated - immunology ; Vaccinology ; Virology ; Virulence</subject><ispartof>Nature microbiology, 2021-07, Vol.6 (7), p.830-841</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-b30cd3c0b22fddca249a29d21bc31690d750e6c3c54d59df92d8c4352cf197f03</citedby><cites>FETCH-LOGICAL-c508t-b30cd3c0b22fddca249a29d21bc31690d750e6c3c54d59df92d8c4352cf197f03</cites><orcidid>0000-0002-0055-640X ; 0000-0002-3041-7240 ; 0000-0002-5739-2610 ; 0000-0002-1451-5166 ; 0000-0001-8102-7579 ; 0000-0002-9892-6420 ; 0000-0002-0446-8829 ; 0000-0002-2473-1145 ; 0000-0002-5249-9910 ; 0000-0002-0888-1717 ; 0000-0002-4545-3826 ; 0000-0002-9107-4464 ; 0000-0001-5914-8059 ; 0000-0001-9452-8751 ; 0000-0001-7440-4604</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34045711$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-03395327$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Diard, Médéric</creatorcontrib><creatorcontrib>Bakkeren, Erik</creatorcontrib><creatorcontrib>Lentsch, Verena</creatorcontrib><creatorcontrib>Rocker, Andrea</creatorcontrib><creatorcontrib>Bekele, Nahimi Amare</creatorcontrib><creatorcontrib>Hoces, Daniel</creatorcontrib><creatorcontrib>Aslani, Selma</creatorcontrib><creatorcontrib>Arnoldini, Markus</creatorcontrib><creatorcontrib>Böhi, Flurina</creatorcontrib><creatorcontrib>Schumann-Moor, Kathrin</creatorcontrib><creatorcontrib>Adamcik, Jozef</creatorcontrib><creatorcontrib>Piccoli, Luca</creatorcontrib><creatorcontrib>Lanzavecchia, Antonio</creatorcontrib><creatorcontrib>Stadtmueller, Beth M.</creatorcontrib><creatorcontrib>Donohue, Nicholas</creatorcontrib><creatorcontrib>van der Woude, Marjan W.</creatorcontrib><creatorcontrib>Hockenberry, Alyson</creatorcontrib><creatorcontrib>Viollier, Patrick H.</creatorcontrib><creatorcontrib>Falquet, Laurent</creatorcontrib><creatorcontrib>Wüthrich, Daniel</creatorcontrib><creatorcontrib>Bonfiglio, Ferdinando</creatorcontrib><creatorcontrib>Loverdo, Claude</creatorcontrib><creatorcontrib>Egli, Adrian</creatorcontrib><creatorcontrib>Zandomeneghi, Giorgia</creatorcontrib><creatorcontrib>Mezzenga, Raffaele</creatorcontrib><creatorcontrib>Holst, Otto</creatorcontrib><creatorcontrib>Meier, Beat H.</creatorcontrib><creatorcontrib>Hardt, Wolf-Dietrich</creatorcontrib><creatorcontrib>Slack, Emma</creatorcontrib><title>A rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants</title><title>Nature microbiology</title><addtitle>Nat Microbiol</addtitle><addtitle>Nat Microbiol</addtitle><description>The ability of gut bacterial pathogens to escape immunity by antigenic variation—particularly via changes to surface-exposed antigens—is a major barrier to immune clearance 1 . However, not all variants are equally fit in all environments 2 , 3 . It should therefore be possible to exploit such immune escape mechanisms to direct an evolutionary trade-off. Here, we demonstrate this phenomenon using Salmonella enterica subspecies enterica serovar Typhimurium ( S .Tm). A dominant surface antigen of S .Tm is its O-antigen: a long, repetitive glycan that can be rapidly varied by mutations in biosynthetic pathways or by phase variation 4 , 5 . We quantified the selective advantage of O-antigen variants in the presence and absence of O-antigen-specific immunoglobulin A and identified a set of evolutionary trajectories allowing immune escape without an associated fitness cost in naive mice. Through the use of rationally designed oral vaccines, we induced immunoglobulin A responses blocking all of these trajectories. This selected for Salmonella mutants carrying deletions of the O-antigen polymerase gene wzyB . Due to their short O-antigen, these evolved mutants were more susceptible to environmental stressors (detergents or complement) and predation (bacteriophages) and were impaired in gut colonization and virulence in mice. Therefore, a rationally induced cocktail of intestinal antibodies can direct an evolutionary trade-off in S .Tm. This lays the foundations for the exploration of mucosal vaccines capable of setting evolutionary traps as a prophylactic strategy. Salmonella mutants with reduced ability to colonize the mouse gut and cause disease are selected for by vaccine-induced intestinal antibody responses in mice.</description><subject>101/6</subject><subject>13/1</subject><subject>13/31</subject><subject>42/41</subject><subject>45/23</subject><subject>45/29</subject><subject>45/77</subject><subject>631/181/2475</subject><subject>631/250/347</subject><subject>631/326/41/2531</subject><subject>631/326/421</subject><subject>64/60</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antibodies, Bacterial - immunology</subject><subject>Antigenic Variation</subject><subject>Antigens</subject><subject>Bacterial Proteins - genetics</subject><subject>Bacteriology</subject><subject>Biomedical and Life Sciences</subject><subject>Colonization</subject><subject>Detergents</subject><subject>Digestive system</subject><subject>Evolution</subject><subject>Evolution, Molecular</subject><subject>Gastrointestinal tract</subject><subject>Genetic Fitness</subject><subject>Hexosyltransferases - genetics</subject><subject>Human health and pathology</subject><subject>Immune Evasion</subject><subject>Immunity, Mucosal</subject><subject>Immunoglobulin A</subject><subject>Immunoglobulin A - immunology</subject><subject>Immunoglobulins</subject><subject>Immunology</subject><subject>Infectious Diseases</subject><subject>Intestine</subject><subject>Intestines - immunology</subject><subject>Intestines - microbiology</subject><subject>Letter</subject><subject>Life Sciences</subject><subject>Medical Microbiology</subject><subject>Mice</subject><subject>Microbiology</subject><subject>Microbiology and Parasitology</subject><subject>Mucosa</subject><subject>Mutants</subject><subject>Mutation</subject><subject>O Antigens - genetics</subject><subject>O Antigens - immunology</subject><subject>Parasitology</subject><subject>Phages</subject><subject>Predation</subject><subject>Salmonella</subject><subject>Salmonella Infections - microbiology</subject><subject>Salmonella Infections - prevention &amp; control</subject><subject>Salmonella typhimurium - genetics</subject><subject>Salmonella typhimurium - immunology</subject><subject>Salmonella typhimurium - pathogenicity</subject><subject>Salmonella Vaccines - administration &amp; dosage</subject><subject>Salmonella Vaccines - immunology</subject><subject>Vaccines</subject><subject>Vaccines, Attenuated - administration &amp; dosage</subject><subject>Vaccines, Attenuated - immunology</subject><subject>Vaccinology</subject><subject>Virology</subject><subject>Virulence</subject><issn>2058-5276</issn><issn>2058-5276</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kctu1TAURSMEolXpDzBAlhgxSPEjduIJ0lUFLdKVGABjy7GdXFeOXfy4Un-Br8ZpSikM8MSPs8_aOt5N8xrBCwTJ8D51iLKuhRi1EHKEWvSsOcWQDi3FPXv-5HzSnKd0AyFEDDM2sJfNCelgR3uETpufOxBltsFL5-6ANsnO3mgQonTgKJWy3gDrdVEmAbssxYfZhbE468GuFkA-GLCUuMrmkutVZqBtNCqn-5o5BldWPggTkDkbX2SuBl-lW4I3zslqE630Ob1qXkzSJXP-sJ813z99_HZ53e6_XH2-3O1bReGQ25FApYmCI8aT1krijkvMNUajIohxqHsKDVNE0U5TrieO9aA6QrGaEO8nSM6aDxv3toyL0cr4XKcVt9EuMt6JIK34u-LtQczhKHqG6iIV8G4DHP5pu97txfoGCeGU4P6Iqvbtg1kMP4pJWdyEEutvJ4FpxwjnjOCqwptKxZBSNNMjFkGxxi22uEWNW9zHLVb0m6dzPLb8DrcKyCZIteRnE_94_wf7C-XCuGQ</recordid><startdate>20210701</startdate><enddate>20210701</enddate><creator>Diard, Médéric</creator><creator>Bakkeren, Erik</creator><creator>Lentsch, Verena</creator><creator>Rocker, Andrea</creator><creator>Bekele, Nahimi Amare</creator><creator>Hoces, Daniel</creator><creator>Aslani, Selma</creator><creator>Arnoldini, Markus</creator><creator>Böhi, Flurina</creator><creator>Schumann-Moor, Kathrin</creator><creator>Adamcik, Jozef</creator><creator>Piccoli, Luca</creator><creator>Lanzavecchia, Antonio</creator><creator>Stadtmueller, Beth M.</creator><creator>Donohue, Nicholas</creator><creator>van der Woude, Marjan W.</creator><creator>Hockenberry, Alyson</creator><creator>Viollier, Patrick H.</creator><creator>Falquet, Laurent</creator><creator>Wüthrich, Daniel</creator><creator>Bonfiglio, Ferdinando</creator><creator>Loverdo, Claude</creator><creator>Egli, Adrian</creator><creator>Zandomeneghi, Giorgia</creator><creator>Mezzenga, Raffaele</creator><creator>Holst, Otto</creator><creator>Meier, Beat H.</creator><creator>Hardt, Wolf-Dietrich</creator><creator>Slack, Emma</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FE</scope><scope>8FH</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0055-640X</orcidid><orcidid>https://orcid.org/0000-0002-3041-7240</orcidid><orcidid>https://orcid.org/0000-0002-5739-2610</orcidid><orcidid>https://orcid.org/0000-0002-1451-5166</orcidid><orcidid>https://orcid.org/0000-0001-8102-7579</orcidid><orcidid>https://orcid.org/0000-0002-9892-6420</orcidid><orcidid>https://orcid.org/0000-0002-0446-8829</orcidid><orcidid>https://orcid.org/0000-0002-2473-1145</orcidid><orcidid>https://orcid.org/0000-0002-5249-9910</orcidid><orcidid>https://orcid.org/0000-0002-0888-1717</orcidid><orcidid>https://orcid.org/0000-0002-4545-3826</orcidid><orcidid>https://orcid.org/0000-0002-9107-4464</orcidid><orcidid>https://orcid.org/0000-0001-5914-8059</orcidid><orcidid>https://orcid.org/0000-0001-9452-8751</orcidid><orcidid>https://orcid.org/0000-0001-7440-4604</orcidid></search><sort><creationdate>20210701</creationdate><title>A rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants</title><author>Diard, Médéric ; Bakkeren, Erik ; Lentsch, Verena ; Rocker, Andrea ; Bekele, Nahimi Amare ; Hoces, Daniel ; Aslani, Selma ; Arnoldini, Markus ; Böhi, Flurina ; Schumann-Moor, Kathrin ; Adamcik, Jozef ; Piccoli, Luca ; Lanzavecchia, Antonio ; Stadtmueller, Beth M. ; Donohue, Nicholas ; van der Woude, Marjan W. ; Hockenberry, Alyson ; Viollier, Patrick H. ; Falquet, Laurent ; Wüthrich, Daniel ; Bonfiglio, Ferdinando ; Loverdo, Claude ; Egli, Adrian ; Zandomeneghi, Giorgia ; Mezzenga, Raffaele ; Holst, Otto ; Meier, Beat H. ; Hardt, Wolf-Dietrich ; Slack, Emma</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c508t-b30cd3c0b22fddca249a29d21bc31690d750e6c3c54d59df92d8c4352cf197f03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>101/6</topic><topic>13/1</topic><topic>13/31</topic><topic>42/41</topic><topic>45/23</topic><topic>45/29</topic><topic>45/77</topic><topic>631/181/2475</topic><topic>631/250/347</topic><topic>631/326/41/2531</topic><topic>631/326/421</topic><topic>64/60</topic><topic>Administration, Oral</topic><topic>Animals</topic><topic>Antibodies, Bacterial - immunology</topic><topic>Antigenic Variation</topic><topic>Antigens</topic><topic>Bacterial Proteins - genetics</topic><topic>Bacteriology</topic><topic>Biomedical and Life Sciences</topic><topic>Colonization</topic><topic>Detergents</topic><topic>Digestive system</topic><topic>Evolution</topic><topic>Evolution, Molecular</topic><topic>Gastrointestinal tract</topic><topic>Genetic Fitness</topic><topic>Hexosyltransferases - genetics</topic><topic>Human health and pathology</topic><topic>Immune Evasion</topic><topic>Immunity, Mucosal</topic><topic>Immunoglobulin A</topic><topic>Immunoglobulin A - immunology</topic><topic>Immunoglobulins</topic><topic>Immunology</topic><topic>Infectious Diseases</topic><topic>Intestine</topic><topic>Intestines - immunology</topic><topic>Intestines - microbiology</topic><topic>Letter</topic><topic>Life Sciences</topic><topic>Medical Microbiology</topic><topic>Mice</topic><topic>Microbiology</topic><topic>Microbiology and Parasitology</topic><topic>Mucosa</topic><topic>Mutants</topic><topic>Mutation</topic><topic>O Antigens - genetics</topic><topic>O Antigens - immunology</topic><topic>Parasitology</topic><topic>Phages</topic><topic>Predation</topic><topic>Salmonella</topic><topic>Salmonella Infections - microbiology</topic><topic>Salmonella Infections - prevention &amp; control</topic><topic>Salmonella typhimurium - genetics</topic><topic>Salmonella typhimurium - immunology</topic><topic>Salmonella typhimurium - pathogenicity</topic><topic>Salmonella Vaccines - administration &amp; dosage</topic><topic>Salmonella Vaccines - immunology</topic><topic>Vaccines</topic><topic>Vaccines, Attenuated - administration &amp; dosage</topic><topic>Vaccines, Attenuated - immunology</topic><topic>Vaccinology</topic><topic>Virology</topic><topic>Virulence</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Diard, Médéric</creatorcontrib><creatorcontrib>Bakkeren, Erik</creatorcontrib><creatorcontrib>Lentsch, Verena</creatorcontrib><creatorcontrib>Rocker, Andrea</creatorcontrib><creatorcontrib>Bekele, Nahimi Amare</creatorcontrib><creatorcontrib>Hoces, Daniel</creatorcontrib><creatorcontrib>Aslani, Selma</creatorcontrib><creatorcontrib>Arnoldini, Markus</creatorcontrib><creatorcontrib>Böhi, Flurina</creatorcontrib><creatorcontrib>Schumann-Moor, Kathrin</creatorcontrib><creatorcontrib>Adamcik, Jozef</creatorcontrib><creatorcontrib>Piccoli, Luca</creatorcontrib><creatorcontrib>Lanzavecchia, Antonio</creatorcontrib><creatorcontrib>Stadtmueller, Beth M.</creatorcontrib><creatorcontrib>Donohue, Nicholas</creatorcontrib><creatorcontrib>van der Woude, Marjan W.</creatorcontrib><creatorcontrib>Hockenberry, Alyson</creatorcontrib><creatorcontrib>Viollier, Patrick H.</creatorcontrib><creatorcontrib>Falquet, Laurent</creatorcontrib><creatorcontrib>Wüthrich, Daniel</creatorcontrib><creatorcontrib>Bonfiglio, Ferdinando</creatorcontrib><creatorcontrib>Loverdo, Claude</creatorcontrib><creatorcontrib>Egli, Adrian</creatorcontrib><creatorcontrib>Zandomeneghi, Giorgia</creatorcontrib><creatorcontrib>Mezzenga, Raffaele</creatorcontrib><creatorcontrib>Holst, Otto</creatorcontrib><creatorcontrib>Meier, Beat H.</creatorcontrib><creatorcontrib>Hardt, Wolf-Dietrich</creatorcontrib><creatorcontrib>Slack, Emma</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature microbiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Diard, Médéric</au><au>Bakkeren, Erik</au><au>Lentsch, Verena</au><au>Rocker, Andrea</au><au>Bekele, Nahimi Amare</au><au>Hoces, Daniel</au><au>Aslani, Selma</au><au>Arnoldini, Markus</au><au>Böhi, Flurina</au><au>Schumann-Moor, Kathrin</au><au>Adamcik, Jozef</au><au>Piccoli, Luca</au><au>Lanzavecchia, Antonio</au><au>Stadtmueller, Beth M.</au><au>Donohue, Nicholas</au><au>van der Woude, Marjan W.</au><au>Hockenberry, Alyson</au><au>Viollier, Patrick H.</au><au>Falquet, Laurent</au><au>Wüthrich, Daniel</au><au>Bonfiglio, Ferdinando</au><au>Loverdo, Claude</au><au>Egli, Adrian</au><au>Zandomeneghi, Giorgia</au><au>Mezzenga, Raffaele</au><au>Holst, Otto</au><au>Meier, Beat H.</au><au>Hardt, Wolf-Dietrich</au><au>Slack, Emma</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants</atitle><jtitle>Nature microbiology</jtitle><stitle>Nat Microbiol</stitle><addtitle>Nat Microbiol</addtitle><date>2021-07-01</date><risdate>2021</risdate><volume>6</volume><issue>7</issue><spage>830</spage><epage>841</epage><pages>830-841</pages><issn>2058-5276</issn><eissn>2058-5276</eissn><abstract>The ability of gut bacterial pathogens to escape immunity by antigenic variation—particularly via changes to surface-exposed antigens—is a major barrier to immune clearance 1 . However, not all variants are equally fit in all environments 2 , 3 . It should therefore be possible to exploit such immune escape mechanisms to direct an evolutionary trade-off. Here, we demonstrate this phenomenon using Salmonella enterica subspecies enterica serovar Typhimurium ( S .Tm). A dominant surface antigen of S .Tm is its O-antigen: a long, repetitive glycan that can be rapidly varied by mutations in biosynthetic pathways or by phase variation 4 , 5 . We quantified the selective advantage of O-antigen variants in the presence and absence of O-antigen-specific immunoglobulin A and identified a set of evolutionary trajectories allowing immune escape without an associated fitness cost in naive mice. Through the use of rationally designed oral vaccines, we induced immunoglobulin A responses blocking all of these trajectories. This selected for Salmonella mutants carrying deletions of the O-antigen polymerase gene wzyB . Due to their short O-antigen, these evolved mutants were more susceptible to environmental stressors (detergents or complement) and predation (bacteriophages) and were impaired in gut colonization and virulence in mice. Therefore, a rationally induced cocktail of intestinal antibodies can direct an evolutionary trade-off in S .Tm. This lays the foundations for the exploration of mucosal vaccines capable of setting evolutionary traps as a prophylactic strategy. Salmonella mutants with reduced ability to colonize the mouse gut and cause disease are selected for by vaccine-induced intestinal antibody responses in mice.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34045711</pmid><doi>10.1038/s41564-021-00911-1</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-0055-640X</orcidid><orcidid>https://orcid.org/0000-0002-3041-7240</orcidid><orcidid>https://orcid.org/0000-0002-5739-2610</orcidid><orcidid>https://orcid.org/0000-0002-1451-5166</orcidid><orcidid>https://orcid.org/0000-0001-8102-7579</orcidid><orcidid>https://orcid.org/0000-0002-9892-6420</orcidid><orcidid>https://orcid.org/0000-0002-0446-8829</orcidid><orcidid>https://orcid.org/0000-0002-2473-1145</orcidid><orcidid>https://orcid.org/0000-0002-5249-9910</orcidid><orcidid>https://orcid.org/0000-0002-0888-1717</orcidid><orcidid>https://orcid.org/0000-0002-4545-3826</orcidid><orcidid>https://orcid.org/0000-0002-9107-4464</orcidid><orcidid>https://orcid.org/0000-0001-5914-8059</orcidid><orcidid>https://orcid.org/0000-0001-9452-8751</orcidid><orcidid>https://orcid.org/0000-0001-7440-4604</orcidid><oa>free_for_read</oa></addata></record>
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language eng
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subjects 101/6
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13/31
42/41
45/23
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45/77
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631/326/41/2531
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Administration, Oral
Animals
Antibodies, Bacterial - immunology
Antigenic Variation
Antigens
Bacterial Proteins - genetics
Bacteriology
Biomedical and Life Sciences
Colonization
Detergents
Digestive system
Evolution
Evolution, Molecular
Gastrointestinal tract
Genetic Fitness
Hexosyltransferases - genetics
Human health and pathology
Immune Evasion
Immunity, Mucosal
Immunoglobulin A
Immunoglobulin A - immunology
Immunoglobulins
Immunology
Infectious Diseases
Intestine
Intestines - immunology
Intestines - microbiology
Letter
Life Sciences
Medical Microbiology
Mice
Microbiology
Microbiology and Parasitology
Mucosa
Mutants
Mutation
O Antigens - genetics
O Antigens - immunology
Parasitology
Phages
Predation
Salmonella
Salmonella Infections - microbiology
Salmonella Infections - prevention & control
Salmonella typhimurium - genetics
Salmonella typhimurium - immunology
Salmonella typhimurium - pathogenicity
Salmonella Vaccines - administration & dosage
Salmonella Vaccines - immunology
Vaccines
Vaccines, Attenuated - administration & dosage
Vaccines, Attenuated - immunology
Vaccinology
Virology
Virulence
title A rationally designed oral vaccine induces immunoglobulin A in the murine gut that directs the evolution of attenuated Salmonella variants
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