Abstract
Virulent intracellular pathogens, such as the Salmonella species, engage numerous virulence factors to subvert host defence mechanisms to induce a chronic infection that leads to typhoid or exacerbation of other chronic inflammatory conditions. Here we show the role of the forkhead transcription factor FoxO3a during infection of mice with Salmonella typhimurium (ST). Although FoxO3a signalling does not affect the development of CD8+ T cell responses to ST, FoxO3a has an important protective role, particularly during the chronic stage of infection, by limiting the persistence of oxidative stress. Furthermore, FoxO3a signalling regulates ERK signalling in macrophages, which results in the maintenance of a proinflammatory state. FoxO3a signalling does not affect cell proliferation or cell death. Thus, these results reveal mechanisms by which FoxO3a promotes host survival during infection with chronic, virulent intracellular bacteria.
Highlights
Virulent intracellular pathogens, such as the Salmonella species, engage numerous virulence factors to subvert host defence mechanisms to induce a chronic infection that leads to typhoid or exacerbation of other chronic inflammatory conditions
Results are pooled from 5 to 7 biological replicates with each being an average of 2–3 experimental replicates. (c) Cytokine levels in supernatants of wild type (WT) and FoxO3a À / À monocytes infected with Salmonella typhimurium (ST)-OVA (10 MOI) at 18–24 h post-infection
Pathogens express numerous virulence mechanisms to subvert the army of various types of immune cells; the immune system efficiently controls a myriad of pathogens[46,47]
Summary
Virulent intracellular pathogens, such as the Salmonella species, engage numerous virulence factors to subvert host defence mechanisms to induce a chronic infection that leads to typhoid or exacerbation of other chronic inflammatory conditions. FoxO3a signalling does not affect the development of CD8 þ T cell responses to ST, FoxO3a has an important protective role, during the chronic stage of infection, by limiting the persistence of oxidative stress. FoxO3a signalling does not affect cell proliferation or cell death These results reveal mechanisms by which FoxO3a promotes host survival during infection with chronic, virulent intracellular bacteria. We previously reported that FoxO3a does not promote host survival against the intracellular bacterium, Listeria monocytogenes that induces an acute infection, FoxO3a signalling reduces the CD8 þ T cell responses to Listeria monocytogenes[25]. FoxO3a signalling, in addition, promotes the termination of extracellular signal-regulated kinase (ERK) signalling to induce inflammatory immune responses that are necessary to control infection with virulent intracellular pathogens such as ST
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