ATF3 provides protection fromStaphylococcus aureusandListeria monocytogenesinfections

Abstract

Activating transcription factor 3 (ATF3) is a stress-induced transcriptional regulator in eukaryote. The role of ATF3 in cancer has been well defined, but how ATF3 functions in bacterial infection is not well understood. Pneumococcal infection has been shown to induce ATF3 expression, which subsequently enhances cytokine production and provides protection from lethal Streptococcus pneumoniae infection, but the role of ATF3 in other Gram-positive (G(+)) infections remains unclear. Here, we report that infection with other G(+) bacteria (Staphylococcus aureus and Listeria monocytogenes) and with G(-) bacteria (uropathogenic Escherichia coli) also significantly induced ATF3 expression. Moreover, the production of cytokines (tumor necrosis factor alpha [TNF]-α, interleukin [IL]-1β, IL-6 and interferon [IFN]-γ) was enhanced by ATF3 in S. aureus and L. monocytogenes infection, but decreased in uropathogenic E. coli (UPEC) infection. In addition, in S. aureus and L. monocytogenes infections, ATF3 WT mice cleared bacteria more efficiently and had higher survival rates than ATF3 knockout mice. However, in UPEC infection, no significant difference was found in survival rate. Taken together, these data suggest that ATF3 provides protection from S. aureus and L. monocytogenes infections; however, the role of ATF3 in UPEC infection is more complicated and should be further elucidated.

ATF3 Stimulates IL-17A by Regulating Intracellular Ca2+/ROS-Dependent IL-1β Activation During Streptococcus pneumoniae Infection

“…This phenomenon either blocks NLRP3 priming or promotes cell death (35, 36). In a previous study, we identified different reactions in cytokinesis dependent on whether infection was caused by gram-positive or -negative bacteria (9). Consistent with cytokines, ATF3 KO BMDMs exhibited increased ROS production after infection with either gram-positive or gram-negative bacteria.…”

“…Accordingly, ATF3 is believed to moderate ROS levels rather than to serve as an unconditional negative regulator in gram-negative bacteria. Thus, it was presumed that the similar ROS levels observed during infection with gram-positive bacteria in ATF3 KO mice resulted from defects in ROS inhibition and cytokine production, and thus failed to defend against E. coli through an inability to produce sufficient cytokines (9). In the case of gram-negative bacteria, inflammasome activation elicits IL-1β production via a complicated mechanism (37, 38).…”

“…Thus, the anti-inflammatory effects of ATF3 during gram-negative bacterial infection have been reported (7, 8). In addition, it has been reported that ATF3 enhances pro-inflammatory cytokine production in response to infection by gram-positive pathogens such as Streptococcus pneumoniae, Listeria monocytogenes , and Staphylococcus aureus (9). However, the functional significance of ATF3 in gram-positive infection remains poorly understood.…”

Activating transcription factor 3 modulates the macrophage immune response toMycobacterium tuberculosisinfection via reciprocal regulation of inflammatory genes and lipid body formation

“…ATF3 dampens the TLR4mediated macrophage inflammatory response to LPS (Gilchrist et al, 2006;Hoetzenecker et al, 2011), and inhibits IL-6 expression in Neisseria gonorrhoeae-infected T84 human colorectal cells (Calton, Wade, & So, 2013), or in uropathogenic Escherichia coli-infected cells (Nguyen et al, 2016). In order to develop such strategies, understanding the response of the host to the bacterium is a prerequisite.…”

“…During Streptococcus pneumoniae infection, ATF3 positively regulates the production of cytokines such as tumour necrosis factor (TNF)-α, IL-1β, and IFN-γ and ATF3-knockout mice are more susceptible to S. pneumoniae infection than their wildtype counterparts (Nguyen, Kim, Luong, Pyo, & Rhee, 2014;Nguyen et al, 2016). During Streptococcus pneumoniae infection, ATF3 positively regulates the production of cytokines such as tumour necrosis factor (TNF)-α, IL-1β, and IFN-γ and ATF3-knockout mice are more susceptible to S. pneumoniae infection than their wildtype counterparts (Nguyen, Kim, Luong, Pyo, & Rhee, 2014;Nguyen et al, 2016).…”