Susceptibility to Anthrax Lethal Toxin Is Controlled by Three Linked Quantitative Trait Loci
Anthrax lethal toxin (LT) is the principal virulence factor associated with lethal pathologies following infection with Bacillus anthracis . Macrophages are the primary effector cells mediating lethality since macrophage-depleted mice are resistant to LT challenge. Recently, Ltxs1 , the gene control...
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| Veröffentlicht in: | The American journal of pathology 2003-11, Vol.163 (5), p.1735-1741 |
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| creator | McAllister, Ryan D. Singh, Yogendra du Bois, Wendy D. Potter, Michael Boehm, Thomas Meeker, Nathan D. Fillmore, Parley D. Anderson, Lisa M. Poynter, Matthew E. Teuscher, Cory |
| description | Anthrax lethal toxin (LT) is the principal virulence factor associated with lethal pathologies following infection with
Bacillus anthracis
. Macrophages are the primary effector cells mediating lethality since macrophage-depleted mice are resistant to LT challenge. Recently,
Ltxs1
, the gene controlling differential susceptibility of murine macrophages to cytolysis following
in vitro
exposure to LT, was identified as
Kif1c
. To directly assess the
in vivo
role of
Kif1c
alleles in mortality, we studied a panel of interval-specific recombinant congenic lines carrying various segments of central chromosome 11 derived from LT-resistant DBA/2 mice on the LT-susceptible BALB/c background. The results of this study reveal that mortality is controlled by three linked quantitative trait loci (QTL):
Ltxs1/Kif1c
(42–43 cM),
Ltxs2
(35–37 cM), and
Ltxs3
(45–47 cM). The
Ltxs3
interval encompasses
Nos2
, which is an attractive candidate gene for
Ltxs3
. In this regard, we demonstrate that selective, pharmacologically based inhibition of Nos2 activity
in vivo
partially overrides genetic resistance to LT and that
Nos2
expression as determined by reverse transcription-polymerase chain reaction differs significantly between DBA/2 and BALB/c macrophages. Additionally, to recapitulate dominant resistance to mortality as seen in (BALB/c × DBA/2) F
1 hybrids, DBA/2 alleles are required at all three QTL. |
| doi_str_mv | 10.1016/S0002-9440(10)63532-8 |
| format | Article |
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Bacillus anthracis
. Macrophages are the primary effector cells mediating lethality since macrophage-depleted mice are resistant to LT challenge. Recently,
Ltxs1
, the gene controlling differential susceptibility of murine macrophages to cytolysis following
in vitro
exposure to LT, was identified as
Kif1c
. To directly assess the
in vivo
role of
Kif1c
alleles in mortality, we studied a panel of interval-specific recombinant congenic lines carrying various segments of central chromosome 11 derived from LT-resistant DBA/2 mice on the LT-susceptible BALB/c background. The results of this study reveal that mortality is controlled by three linked quantitative trait loci (QTL):
Ltxs1/Kif1c
(42–43 cM),
Ltxs2
(35–37 cM), and
Ltxs3
(45–47 cM). The
Ltxs3
interval encompasses
Nos2
, which is an attractive candidate gene for
Ltxs3
. In this regard, we demonstrate that selective, pharmacologically based inhibition of Nos2 activity
in vivo
partially overrides genetic resistance to LT and that
Nos2
expression as determined by reverse transcription-polymerase chain reaction differs significantly between DBA/2 and BALB/c macrophages. Additionally, to recapitulate dominant resistance to mortality as seen in (BALB/c × DBA/2) F
1 hybrids, DBA/2 alleles are required at all three QTL.</description><identifier>ISSN: 0002-9440</identifier><identifier>EISSN: 1525-2191</identifier><identifier>DOI: 10.1016/S0002-9440(10)63532-8</identifier><identifier>PMID: 14578173</identifier><identifier>CODEN: AJPAA4</identifier><language>eng</language><publisher>Bethesda, MD: Elsevier Inc</publisher><subject>Animals ; Antigens, Bacterial ; Bacterial diseases ; Bacterial Toxins - genetics ; Bacterial Toxins - pharmacology ; Biological and medical sciences ; Experimental bacterial diseases and models ; Female ; Genetic Predisposition to Disease ; Genotype ; Infectious diseases ; Kinesin - genetics ; Male ; Medical sciences ; Mice ; Mice, Congenic ; Nitric Oxide Synthase - genetics ; Nitric Oxide Synthase Type II ; Quantitative Trait Loci - genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Short Communication ; Species Specificity</subject><ispartof>The American journal of pathology, 2003-11, Vol.163 (5), p.1735-1741</ispartof><rights>2003 American Society for Investigative Pathology</rights><rights>2004 INIST-CNRS</rights><rights>Copyright © 2003, American Society for Investigative Pathology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c525t-d7ba8df8d68808a347947c19fd5f99bd595a392f95178aaf794edc836f36b6d73</citedby><cites>FETCH-LOGICAL-c525t-d7ba8df8d68808a347947c19fd5f99bd595a392f95178aaf794edc836f36b6d73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1892420/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0002944010635328$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,3537,27901,27902,53766,53768,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15227838$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14578173$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McAllister, Ryan D.</creatorcontrib><creatorcontrib>Singh, Yogendra</creatorcontrib><creatorcontrib>du Bois, Wendy D.</creatorcontrib><creatorcontrib>Potter, Michael</creatorcontrib><creatorcontrib>Boehm, Thomas</creatorcontrib><creatorcontrib>Meeker, Nathan D.</creatorcontrib><creatorcontrib>Fillmore, Parley D.</creatorcontrib><creatorcontrib>Anderson, Lisa M.</creatorcontrib><creatorcontrib>Poynter, Matthew E.</creatorcontrib><creatorcontrib>Teuscher, Cory</creatorcontrib><title>Susceptibility to Anthrax Lethal Toxin Is Controlled by Three Linked Quantitative Trait Loci</title><title>The American journal of pathology</title><addtitle>Am J Pathol</addtitle><description>Anthrax lethal toxin (LT) is the principal virulence factor associated with lethal pathologies following infection with
Bacillus anthracis
. Macrophages are the primary effector cells mediating lethality since macrophage-depleted mice are resistant to LT challenge. Recently,
Ltxs1
, the gene controlling differential susceptibility of murine macrophages to cytolysis following
in vitro
exposure to LT, was identified as
Kif1c
. To directly assess the
in vivo
role of
Kif1c
alleles in mortality, we studied a panel of interval-specific recombinant congenic lines carrying various segments of central chromosome 11 derived from LT-resistant DBA/2 mice on the LT-susceptible BALB/c background. The results of this study reveal that mortality is controlled by three linked quantitative trait loci (QTL):
Ltxs1/Kif1c
(42–43 cM),
Ltxs2
(35–37 cM), and
Ltxs3
(45–47 cM). The
Ltxs3
interval encompasses
Nos2
, which is an attractive candidate gene for
Ltxs3
. In this regard, we demonstrate that selective, pharmacologically based inhibition of Nos2 activity
in vivo
partially overrides genetic resistance to LT and that
Nos2
expression as determined by reverse transcription-polymerase chain reaction differs significantly between DBA/2 and BALB/c macrophages. Additionally, to recapitulate dominant resistance to mortality as seen in (BALB/c × DBA/2) F
1 hybrids, DBA/2 alleles are required at all three QTL.</description><subject>Animals</subject><subject>Antigens, Bacterial</subject><subject>Bacterial diseases</subject><subject>Bacterial Toxins - genetics</subject><subject>Bacterial Toxins - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Experimental bacterial diseases and models</subject><subject>Female</subject><subject>Genetic Predisposition to Disease</subject><subject>Genotype</subject><subject>Infectious diseases</subject><subject>Kinesin - genetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Congenic</subject><subject>Nitric Oxide Synthase - genetics</subject><subject>Nitric Oxide Synthase Type II</subject><subject>Quantitative Trait Loci - genetics</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Short Communication</subject><subject>Species Specificity</subject><issn>0002-9440</issn><issn>1525-2191</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhi0EokvhJ4B84esQsOM4sS-gasVHpZUQ6nJDsiaO07h4463tLN1_j9NdtXDiZI3nmXdezYvQc0reUULr9xeEkLKQVUXeUPK2ZpyVhXiAFpSXvCippA_R4g45QU9ivMplzQR5jE5oxRtBG7ZAPy-mqM022dY6m_Y4eXw2piHADV6ZNIDDa39jR3we8dKPKXjnTIfbPV4PwRi8suOvXH-fYEw2QbI7g9cBbMIrr-1T9KgHF82z43uKfnz-tF5-LVbfvpwvz1aFzmZT0TUtiK4XXS0EEcCqRlaNprLveC9l23HJgcmyl5w2AqDPbdNpweqe1W3dNewUfTjobqd2k1smGwWntsFuIOyVB6v-7Yx2UJd-p6iQZVWSLPDqKBD89WRiUhubz-IcjMZPUTWUEV7TeRM_gDr4GIPp75ZQouZc1G0uaj76_HWbixJ57sXfDu-njkFk4OURgKjB9QFGbeM9x8uyEWwWen3gBns5_LbBqLgB57IsVXC1pTVTXGVBnsmPB9Lky--sCSpqa0Ztujylk-q8_Y_pPybtuMc</recordid><startdate>20031101</startdate><enddate>20031101</enddate><creator>McAllister, Ryan D.</creator><creator>Singh, Yogendra</creator><creator>du Bois, Wendy D.</creator><creator>Potter, Michael</creator><creator>Boehm, Thomas</creator><creator>Meeker, Nathan D.</creator><creator>Fillmore, Parley D.</creator><creator>Anderson, Lisa M.</creator><creator>Poynter, Matthew E.</creator><creator>Teuscher, Cory</creator><general>Elsevier Inc</general><general>ASIP</general><general>American Society for Investigative Pathology</general><scope>IQODW</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20031101</creationdate><title>Susceptibility to Anthrax Lethal Toxin Is Controlled by Three Linked Quantitative Trait Loci</title><author>McAllister, Ryan D. ; Singh, Yogendra ; du Bois, Wendy D. ; Potter, Michael ; Boehm, Thomas ; Meeker, Nathan D. ; Fillmore, Parley D. ; Anderson, Lisa M. ; Poynter, Matthew E. ; Teuscher, Cory</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c525t-d7ba8df8d68808a347947c19fd5f99bd595a392f95178aaf794edc836f36b6d73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Antigens, Bacterial</topic><topic>Bacterial diseases</topic><topic>Bacterial Toxins - genetics</topic><topic>Bacterial Toxins - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Experimental bacterial diseases and models</topic><topic>Female</topic><topic>Genetic Predisposition to Disease</topic><topic>Genotype</topic><topic>Infectious diseases</topic><topic>Kinesin - genetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Congenic</topic><topic>Nitric Oxide Synthase - genetics</topic><topic>Nitric Oxide Synthase Type II</topic><topic>Quantitative Trait Loci - genetics</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Short Communication</topic><topic>Species Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McAllister, Ryan D.</creatorcontrib><creatorcontrib>Singh, Yogendra</creatorcontrib><creatorcontrib>du Bois, Wendy D.</creatorcontrib><creatorcontrib>Potter, Michael</creatorcontrib><creatorcontrib>Boehm, Thomas</creatorcontrib><creatorcontrib>Meeker, Nathan D.</creatorcontrib><creatorcontrib>Fillmore, Parley D.</creatorcontrib><creatorcontrib>Anderson, Lisa M.</creatorcontrib><creatorcontrib>Poynter, Matthew E.</creatorcontrib><creatorcontrib>Teuscher, Cory</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The American journal of pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McAllister, Ryan D.</au><au>Singh, Yogendra</au><au>du Bois, Wendy D.</au><au>Potter, Michael</au><au>Boehm, Thomas</au><au>Meeker, Nathan D.</au><au>Fillmore, Parley D.</au><au>Anderson, Lisa M.</au><au>Poynter, Matthew E.</au><au>Teuscher, Cory</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Susceptibility to Anthrax Lethal Toxin Is Controlled by Three Linked Quantitative Trait Loci</atitle><jtitle>The American journal of pathology</jtitle><addtitle>Am J Pathol</addtitle><date>2003-11-01</date><risdate>2003</risdate><volume>163</volume><issue>5</issue><spage>1735</spage><epage>1741</epage><pages>1735-1741</pages><issn>0002-9440</issn><eissn>1525-2191</eissn><coden>AJPAA4</coden><abstract>Anthrax lethal toxin (LT) is the principal virulence factor associated with lethal pathologies following infection with
Bacillus anthracis
. Macrophages are the primary effector cells mediating lethality since macrophage-depleted mice are resistant to LT challenge. Recently,
Ltxs1
, the gene controlling differential susceptibility of murine macrophages to cytolysis following
in vitro
exposure to LT, was identified as
Kif1c
. To directly assess the
in vivo
role of
Kif1c
alleles in mortality, we studied a panel of interval-specific recombinant congenic lines carrying various segments of central chromosome 11 derived from LT-resistant DBA/2 mice on the LT-susceptible BALB/c background. The results of this study reveal that mortality is controlled by three linked quantitative trait loci (QTL):
Ltxs1/Kif1c
(42–43 cM),
Ltxs2
(35–37 cM), and
Ltxs3
(45–47 cM). The
Ltxs3
interval encompasses
Nos2
, which is an attractive candidate gene for
Ltxs3
. In this regard, we demonstrate that selective, pharmacologically based inhibition of Nos2 activity
in vivo
partially overrides genetic resistance to LT and that
Nos2
expression as determined by reverse transcription-polymerase chain reaction differs significantly between DBA/2 and BALB/c macrophages. Additionally, to recapitulate dominant resistance to mortality as seen in (BALB/c × DBA/2) F
1 hybrids, DBA/2 alleles are required at all three QTL.</abstract><cop>Bethesda, MD</cop><pub>Elsevier Inc</pub><pmid>14578173</pmid><doi>10.1016/S0002-9440(10)63532-8</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antigens, Bacterial Bacterial diseases Bacterial Toxins - genetics Bacterial Toxins - pharmacology Biological and medical sciences Experimental bacterial diseases and models Female Genetic Predisposition to Disease Genotype Infectious diseases Kinesin - genetics Male Medical sciences Mice Mice, Congenic Nitric Oxide Synthase - genetics Nitric Oxide Synthase Type II Quantitative Trait Loci - genetics Reverse Transcriptase Polymerase Chain Reaction Short Communication Species Specificity |
| title | Susceptibility to Anthrax Lethal Toxin Is Controlled by Three Linked Quantitative Trait Loci |
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