Humanized nonobese diabetic-scid IL2rgammanull mice are susceptible to lethal Salmonella Typhi infection
Salmonella enterica serovar Typhi, the cause of typhoid fever, is host-adapted to humans and unable to cause disease in mice. Here, we show that S. Typhi can replicate in vivo in nonobese diabetic (NOD)-scid IL2rgamma(null) mice engrafted with human hematopoietic stem cells (hu-SRC-SCID mice) to cau...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2010-08, Vol.107 (35), p.15589-15594 |
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| creator | Libby, Stephen J Brehm, Michael A Greiner, Dale L Shultz, Leonard D McClelland, Michael Smith, Kelly D Cookson, Brad T Karlinsey, Joyce E Kinkel, Traci L Porwollik, Steffen Canals, Rocio Cummings, Lisa A Fang, Ferric C |
| description | Salmonella enterica serovar Typhi, the cause of typhoid fever, is host-adapted to humans and unable to cause disease in mice. Here, we show that S. Typhi can replicate in vivo in nonobese diabetic (NOD)-scid IL2rgamma(null) mice engrafted with human hematopoietic stem cells (hu-SRC-SCID mice) to cause a lethal infection with pathological and inflammatory cytokine responses resembling human typhoid. In contrast, S. Typhi does not exhibit net replication or cause illness in nonengrafted or immunocompetent control animals. Screening of transposon pools in hu-SRC-SCID mice revealed both known and previously unknown Salmonella virulence determinants, including Salmonella Pathogenicity Islands 1, 2, 3, 4, and 6. Our observations indicate that the presence of human immune cells allows the in vivo replication of S. Typhi in mice. The hu-SRC-SCID mouse provides an unprecedented opportunity to gain insights into S. Typhi pathogenesis and devise strategies for the prevention of typhoid fever. |
| doi_str_mv | 10.1073/pnas.1005566107 |
| format | Article |
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Here, we show that S. Typhi can replicate in vivo in nonobese diabetic (NOD)-scid IL2rgamma(null) mice engrafted with human hematopoietic stem cells (hu-SRC-SCID mice) to cause a lethal infection with pathological and inflammatory cytokine responses resembling human typhoid. In contrast, S. Typhi does not exhibit net replication or cause illness in nonengrafted or immunocompetent control animals. Screening of transposon pools in hu-SRC-SCID mice revealed both known and previously unknown Salmonella virulence determinants, including Salmonella Pathogenicity Islands 1, 2, 3, 4, and 6. Our observations indicate that the presence of human immune cells allows the in vivo replication of S. Typhi in mice. The hu-SRC-SCID mouse provides an unprecedented opportunity to gain insights into S. Typhi pathogenesis and devise strategies for the prevention of typhoid fever.</description><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1005566107</identifier><identifier>PMID: 20713716</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Animals, Newborn ; Cytokines - metabolism ; Female ; Flow Cytometry ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells - metabolism ; Humans ; Interferon-gamma - metabolism ; Interleukin Receptor Common gamma Subunit - genetics ; Interleukin Receptor Common gamma Subunit - metabolism ; Leukocyte Common Antigens - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Salmonella typhi - genetics ; Salmonella typhi - pathogenicity ; Tumor Necrosis Factor-alpha - metabolism ; Typhoid Fever - genetics ; Typhoid Fever - metabolism ; Typhoid Fever - pathology ; Virulence - genetics</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2010-08, Vol.107 (35), p.15589-15594</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20713716$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Libby, Stephen J</creatorcontrib><creatorcontrib>Brehm, Michael A</creatorcontrib><creatorcontrib>Greiner, Dale L</creatorcontrib><creatorcontrib>Shultz, Leonard D</creatorcontrib><creatorcontrib>McClelland, Michael</creatorcontrib><creatorcontrib>Smith, Kelly D</creatorcontrib><creatorcontrib>Cookson, Brad T</creatorcontrib><creatorcontrib>Karlinsey, Joyce E</creatorcontrib><creatorcontrib>Kinkel, Traci L</creatorcontrib><creatorcontrib>Porwollik, Steffen</creatorcontrib><creatorcontrib>Canals, Rocio</creatorcontrib><creatorcontrib>Cummings, Lisa A</creatorcontrib><creatorcontrib>Fang, Ferric C</creatorcontrib><title>Humanized nonobese diabetic-scid IL2rgammanull mice are susceptible to lethal Salmonella Typhi infection</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Salmonella enterica serovar Typhi, the cause of typhoid fever, is host-adapted to humans and unable to cause disease in mice. Here, we show that S. Typhi can replicate in vivo in nonobese diabetic (NOD)-scid IL2rgamma(null) mice engrafted with human hematopoietic stem cells (hu-SRC-SCID mice) to cause a lethal infection with pathological and inflammatory cytokine responses resembling human typhoid. In contrast, S. Typhi does not exhibit net replication or cause illness in nonengrafted or immunocompetent control animals. Screening of transposon pools in hu-SRC-SCID mice revealed both known and previously unknown Salmonella virulence determinants, including Salmonella Pathogenicity Islands 1, 2, 3, 4, and 6. Our observations indicate that the presence of human immune cells allows the in vivo replication of S. Typhi in mice. The hu-SRC-SCID mouse provides an unprecedented opportunity to gain insights into S. Typhi pathogenesis and devise strategies for the prevention of typhoid fever.</description><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Cytokines - metabolism</subject><subject>Female</subject><subject>Flow Cytometry</subject><subject>Hematopoietic Stem Cell Transplantation</subject><subject>Hematopoietic Stem Cells - metabolism</subject><subject>Humans</subject><subject>Interferon-gamma - metabolism</subject><subject>Interleukin Receptor Common gamma Subunit - genetics</subject><subject>Interleukin Receptor Common gamma Subunit - metabolism</subject><subject>Leukocyte Common Antigens - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred NOD</subject><subject>Mice, Knockout</subject><subject>Mice, SCID</subject><subject>Salmonella typhi - genetics</subject><subject>Salmonella typhi - pathogenicity</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Typhoid Fever - genetics</subject><subject>Typhoid Fever - metabolism</subject><subject>Typhoid Fever - pathology</subject><subject>Virulence - genetics</subject><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kDFPwzAQRi0kREthZkPemALnOLHjEVVAK0VioHtkOxdq5DghToby67FEme7T6en0viPkjsEjA8mfxqBjSlCWQqTFBVkzUCwThYIVuY7xCwBUWcEVWeUgGZdMrMlxt_Q6uB9saRjCYDAibZ02ODubRetauq_z6VP3iVq8p72zSPWENC7R4jg745HOA_U4H7WnH9r3Q0DvNT2cxqOjLnRoZzeEG3LZaR_x9jw35PD6ctjusvr9bb99rrMxeWdMAlelLUUrDC9Y6gGyU8rmvBCyzRlURgqh86LDvJSi5bpjhTLWWF1VBdN8Qx7-zo7T8L1gnJveJdEkFHBYYiPLAoAJVSXy_kwupse2GSfX6-nU_P-G_wKltmTs</recordid><startdate>20100831</startdate><enddate>20100831</enddate><creator>Libby, Stephen J</creator><creator>Brehm, Michael A</creator><creator>Greiner, Dale L</creator><creator>Shultz, Leonard D</creator><creator>McClelland, Michael</creator><creator>Smith, Kelly D</creator><creator>Cookson, Brad T</creator><creator>Karlinsey, Joyce E</creator><creator>Kinkel, Traci L</creator><creator>Porwollik, Steffen</creator><creator>Canals, Rocio</creator><creator>Cummings, Lisa A</creator><creator>Fang, Ferric C</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20100831</creationdate><title>Humanized nonobese diabetic-scid IL2rgammanull mice are susceptible to lethal Salmonella Typhi infection</title><author>Libby, Stephen J ; 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| subjects | Animals Animals, Newborn Cytokines - metabolism Female Flow Cytometry Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells - metabolism Humans Interferon-gamma - metabolism Interleukin Receptor Common gamma Subunit - genetics Interleukin Receptor Common gamma Subunit - metabolism Leukocyte Common Antigens - metabolism Male Mice Mice, Inbred C57BL Mice, Inbred NOD Mice, Knockout Mice, SCID Salmonella typhi - genetics Salmonella typhi - pathogenicity Tumor Necrosis Factor-alpha - metabolism Typhoid Fever - genetics Typhoid Fever - metabolism Typhoid Fever - pathology Virulence - genetics |
| title | Humanized nonobese diabetic-scid IL2rgammanull mice are susceptible to lethal Salmonella Typhi infection |
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