Interferon-γ- and glucocorticoid-mediated pathways synergize to enhance death of CD4(+) CD8(+) thymocytes during Salmonella enterica serovar Typhimurium infection
Thymic atrophy is known to occur during infections; however, there is limited understanding of its causes and of the cross-talk between different pathways. This study investigates mechanisms involved in thymic atrophy during a model of oral infection by Salmonella enterica serovar Typhimurium (S. ty...
| Main Authors: | , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2013
|
| _version_ | 1824459091545686016 |
|---|---|
| author | Deobagkar-Lele, M Chacko, SK Victor, ES Kadthur, JC Nandi, D |
| author_facet | Deobagkar-Lele, M Chacko, SK Victor, ES Kadthur, JC Nandi, D |
| author_sort | Deobagkar-Lele, M |
| collection | OXFORD |
| description | Thymic atrophy is known to occur during infections; however, there is limited understanding of its causes and of the cross-talk between different pathways. This study investigates mechanisms involved in thymic atrophy during a model of oral infection by Salmonella enterica serovar Typhimurium (S. typhimurium). Significant death of CD4(+) CD8(+) thymocytes, but not of single-positive thymocytes or peripheral lymphocytes, is observed at later stages during infection with live, but not heat-killed, bacteria. The death of CD4(+) CD8(+) thymocytes is Fas-independent as shown by infection studies with lpr mice. However, apoptosis occurs with lowering of mitochondrial potential and higher caspase-3 activity. The amounts of cortisol, a glucocorticoid, and interferon-γ (IFN-γ), an inflammatory cytokine, increase upon infection. To investigate the functional roles of these molecules, studies were performed using Ifnγ(-/-) mice together with RU486, a glucocorticoid receptor antagonist. Treatment of C57BL/6 mice with RU486 does not affect colony-forming units (CFU), amounts of IFN-γ and mouse survival; however, there is partial rescue in thymocyte death. Upon infection, Ifnγ(-/-) mice display higher CFU and lower survival but more surviving thymocytes are recovered. However, there is no difference in cortisol amounts in C57BL/6 and Ifnγ(-/-) mice. Importantly, the number of CD4(+) CD8(+) thymocytes is significantly higher in Ifnγ(-/-) mice treated with RU486 along with lower caspase-3 activity and mitochondrial damage. Hence, endogenous glucocorticoid and IFN-γ-mediated pathways are parallel but synergize in an additive manner to induce death of CD4(+) CD8(+) thymocytes during S. typhimurium infection. The implications of this study for host responses during infection are discussed. |
| first_indexed | 2025-02-19T04:36:16Z |
| format | Journal article |
| id | oxford-uuid:66d4c2a6-4edb-4e6c-987b-901060690115 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:36:16Z |
| publishDate | 2013 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:66d4c2a6-4edb-4e6c-987b-9010606901152025-02-04T13:49:00ZInterferon-γ- and glucocorticoid-mediated pathways synergize to enhance death of CD4(+) CD8(+) thymocytes during Salmonella enterica serovar Typhimurium infectionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:66d4c2a6-4edb-4e6c-987b-901060690115EnglishSymplectic ElementsWiley2013Deobagkar-Lele, MChacko, SKVictor, ESKadthur, JCNandi, DThymic atrophy is known to occur during infections; however, there is limited understanding of its causes and of the cross-talk between different pathways. This study investigates mechanisms involved in thymic atrophy during a model of oral infection by Salmonella enterica serovar Typhimurium (S. typhimurium). Significant death of CD4(+) CD8(+) thymocytes, but not of single-positive thymocytes or peripheral lymphocytes, is observed at later stages during infection with live, but not heat-killed, bacteria. The death of CD4(+) CD8(+) thymocytes is Fas-independent as shown by infection studies with lpr mice. However, apoptosis occurs with lowering of mitochondrial potential and higher caspase-3 activity. The amounts of cortisol, a glucocorticoid, and interferon-γ (IFN-γ), an inflammatory cytokine, increase upon infection. To investigate the functional roles of these molecules, studies were performed using Ifnγ(-/-) mice together with RU486, a glucocorticoid receptor antagonist. Treatment of C57BL/6 mice with RU486 does not affect colony-forming units (CFU), amounts of IFN-γ and mouse survival; however, there is partial rescue in thymocyte death. Upon infection, Ifnγ(-/-) mice display higher CFU and lower survival but more surviving thymocytes are recovered. However, there is no difference in cortisol amounts in C57BL/6 and Ifnγ(-/-) mice. Importantly, the number of CD4(+) CD8(+) thymocytes is significantly higher in Ifnγ(-/-) mice treated with RU486 along with lower caspase-3 activity and mitochondrial damage. Hence, endogenous glucocorticoid and IFN-γ-mediated pathways are parallel but synergize in an additive manner to induce death of CD4(+) CD8(+) thymocytes during S. typhimurium infection. The implications of this study for host responses during infection are discussed. |
| spellingShingle | Deobagkar-Lele, M Chacko, SK Victor, ES Kadthur, JC Nandi, D Interferon-γ- and glucocorticoid-mediated pathways synergize to enhance death of CD4(+) CD8(+) thymocytes during Salmonella enterica serovar Typhimurium infection |
| title | Interferon-γ- and glucocorticoid-mediated pathways synergize to enhance death of CD4(+) CD8(+) thymocytes during Salmonella enterica serovar Typhimurium infection |
| title_full | Interferon-γ- and glucocorticoid-mediated pathways synergize to enhance death of CD4(+) CD8(+) thymocytes during Salmonella enterica serovar Typhimurium infection |
| title_fullStr | Interferon-γ- and glucocorticoid-mediated pathways synergize to enhance death of CD4(+) CD8(+) thymocytes during Salmonella enterica serovar Typhimurium infection |
| title_full_unstemmed | Interferon-γ- and glucocorticoid-mediated pathways synergize to enhance death of CD4(+) CD8(+) thymocytes during Salmonella enterica serovar Typhimurium infection |
| title_short | Interferon-γ- and glucocorticoid-mediated pathways synergize to enhance death of CD4(+) CD8(+) thymocytes during Salmonella enterica serovar Typhimurium infection |
| title_sort | interferon γ and glucocorticoid mediated pathways synergize to enhance death of cd4 cd8 thymocytes during salmonella enterica serovar typhimurium infection |
| work_keys_str_mv | AT deobagkarlelem interferongandglucocorticoidmediatedpathwayssynergizetoenhancedeathofcd4cd8thymocytesduringsalmonellaentericaserovartyphimuriuminfection AT chackosk interferongandglucocorticoidmediatedpathwayssynergizetoenhancedeathofcd4cd8thymocytesduringsalmonellaentericaserovartyphimuriuminfection AT victores interferongandglucocorticoidmediatedpathwayssynergizetoenhancedeathofcd4cd8thymocytesduringsalmonellaentericaserovartyphimuriuminfection AT kadthurjc interferongandglucocorticoidmediatedpathwayssynergizetoenhancedeathofcd4cd8thymocytesduringsalmonellaentericaserovartyphimuriuminfection AT nandid interferongandglucocorticoidmediatedpathwayssynergizetoenhancedeathofcd4cd8thymocytesduringsalmonellaentericaserovartyphimuriuminfection |