Protective Role of Akt2 in Salmonella enterica Serovar Typhimurium-Induced Gastroenterocolitis

Abstract

The Salmonella effector protein SopB has previously been shown to induce activation of Akt and protect epithelial cells from apoptosis in vitro. To characterize the role of Akt2 in host defense against Salmonella enterica serovar Typhimurium infection, wild-type (WT) mice and mice lacking Akt2 (Akt2 knockout [KO] mice) were infected using a Salmonella acute gastroenteritis model. Infected Akt2 KO mice showed a more pronounced morbidity and mortality associated with higher bacterial loads in the intestines and elevated levels of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-␣), gamma interferon (IFN-␥), and MCP-1, in the colons at 1 day postinfection compared to those shown in WT mice. Histopathological assessment and immunohistochemical analysis of cecal sections at 1 day postinfection revealed more severe inflammation and higher levels of neutrophil infiltration in the ceca of Akt2 KO mice. Flow cytometry analysis further confirmed an increase in the recruitment of Gr-1 ؉ CD11b ؉ neutrophils and F4/80 ؉ CD11b ؉ macrophages in the intestines of infected Akt2 KO mice. Additionally, enhanced levels of annexin V ؉ and terminal transferase dUTP nick end labeling-positive (TUNEL ؉ ) apoptotic cells in the intestines of infected Akt2 KO mice were also observed, indicating that Akt2 plays an essential role in protection against apoptosis. Finally, the differences in bacterial loads and cecal inflammation in WT and Akt2 KO mice infected with WT Salmonella were abolished when these mice were infected with the sopB deletion mutant, indicating that SopB may play a role in protecting the mice from Salmonella infection through the activation of Akt2. These data demonstrate a definitive phenotypic abnormality in the innate response in mice lacking Akt2, underscoring the important protective role of Akt2 in Salmonella infection.

Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization

“…In a polymicrobial sepsis model, defective M1 response rendered Akt2 mice more susceptible to the disease whereas the robust M1 response of Akt1 −/− mice resulted in improved bacterial clearance. Our results are further supported by an earlier study showing that deletion of Akt2 renders mice more susceptible to Salmonella enterica infection (21). These findings support the role of macrophage polarization in the development of inflammatory diseases, and they show that Akt1 and Akt2 play central but opposite roles in the control of macrophage responsiveness and inflammation.…”

Salmonella enterica Induces Joint Inflammation and Expression of Interleukin-17 in Draining Lymph Nodes Early after Onset of Enterocolitis in Mice

“…Gut inflammation plays a crucial role in the development of reactive arthritis following intestinal infection (28). TNF-␣ and IL-17 are among the most prominent cytokines induced soon after Salmonella infection (17,35), and they are also linked to the generation of arthritis (39). With this in mind, we analyzed the expression of TNF-␣ and IL-17 in the large intestine by qPCR 48 h after Salmonella inoculation.…”

Impacts of Salmonella enteritidis infection on liver transcriptome in broilers

“…When regulated, the programmed death of infected cells and the degrading action of ubiquitin-specific peptidases facilitate the clearance of systemic Salmonella infection (Jiang and Zhijian, 2012;Redmond et al, 2011). Excessive inflammatory actions, however, can result in epithelial damage that enhances the ability of Salmonella to further invade the area of infection (Kum et al, 2011). Using the murine model, Parent and Eichacker (1999) reported that a disproportionate accumulation of neutrophils and monocytes results in the release of toxic levels of proteases and reactive oxygen intermediates.…”