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1.
Immunology ; 138(4): 307-21, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23186527

RESUMEN

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.


Asunto(s)
Hidrocortisona/inmunología , Interferón gamma/inmunología , Salmonelosis Animal/inmunología , Salmonella typhimurium/inmunología , Timocitos/inmunología , Timo/inmunología , Animales , Antígenos CD4/genética , Antígenos CD4/inmunología , Antígenos CD8/genética , Antígenos CD8/inmunología , Caspasa 3/genética , Caspasa 3/inmunología , Recuento de Células , Muerte Celular/efectos de los fármacos , Muerte Celular/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Antagonistas de Hormonas/farmacología , Hidrocortisona/biosíntesis , Interferón gamma/biosíntesis , Interferón gamma/genética , Ratones , Ratones Noqueados , Mifepristona/farmacología , Receptores de Glucocorticoides/antagonistas & inhibidores , Salmonelosis Animal/microbiología , Salmonelosis Animal/mortalidad , Transducción de Señal/efectos de los fármacos , Células Madre , Tasa de Supervivencia , Timocitos/microbiología , Timocitos/patología , Timo/microbiología , Timo/patología
2.
Immunobiology ; 217(3): 354-62, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21813203

RESUMEN

Pathogen encoded peptidases are known to be important during infection; however, their roles in modulating host responses in immunocompromised individuals are not well studied. The roles of S. typhimurium (WT) encoded Peptidase N (PepN), a major aminopeptidase and sole M1 family member, was studied in mice lacking Interferon-γ (IFNγ), a cytokine important for immunity. S. typhimurium lacking pepN (ΔpepN) displays enhanced colony forming units (CFU) compared to WT in peripheral organs during systemic infection in C57BL/6 mice. However, Ifnγ(-/-) mice show higher CFU compared to C57BL/6 mice, resulting in lower fold differences between WT and ΔpepN. Concomitantly, reintroduction of pepN in ΔpepN (ΔpepN/pepN) reduces CFU, demonstrating pepN-dependence. Interestingly, expression of a catalytically inactive PepN (ΔpepN/E298A) also lowers CFU, demonstrating that the decrease in CFU is independent of the catalytic activity of PepN. In addition, three distinct differences are observed between infection of C57BL/6 and Ifnγ(-/-) mice: First, serum amounts of TNFα and IL1ß post infection are significantly lower in Ifnγ(-/-) mice. Second, histological analysis of C57BL/6 mice reveals that damage in spleen and liver upon infection with WT or ΔpepN is greater compared to ΔpepN/pepN or ΔpepN/E298A. On the other hand, Ifnγ(-/-) mice are highly susceptible to organ damage by all strains of S. typhimurium used in this study. Finally, greater survival of C57BL/6, but not Ifnγ(-/-) mice, is observed upon infection with ΔpepN/pepN or ΔpepN/E298A. Overall, the roles of the host encoded IFNγ during infection with S. typhimurium strains with varying degrees of virulence are highlighted.


Asunto(s)
Aminopeptidasas/metabolismo , Interferón gamma/fisiología , Salmonelosis Animal/inmunología , Salmonelosis Animal/microbiología , Salmonella typhimurium/enzimología , Aminopeptidasas/genética , Animales , Catálisis , Línea Celular , Activación Enzimática/genética , Calor , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-1beta/sangre , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Peritonitis/inmunología , Peritonitis/metabolismo , Salmonelosis Animal/mortalidad , Salmonella typhimurium/genética , Salmonella typhimurium/crecimiento & desarrollo , Estrés Fisiológico , Análisis de Supervivencia , Factor de Necrosis Tumoral alfa/sangre
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