Post-Transcriptional Inflammatory Response to Intracellular Bacterial c-di-AMP

Abstract

Cyclic-di-AMP (c-di-AMP) is a bacterial second messenger that is produced by intracellular bacterial pathogens in mammalian host macrophages. Previous reports have shown that c-di-AMP is recognized by intracellular pattern recognition receptors of the innate immune system and stimulate type I interferon response. Here we report that the response to c-di-AMP includes a post-transcriptional component that is involved in the induction of additional inflammatory cytokines including IL-6, CXCL2, CCL3, and CCL4. Their mRNAs contain AU-rich elements (AREs) in their 3 ′ UTR that promote decay and repress translation. We show that c-di-AMP leads to the phosphorylation of p38 MAPK as well as the induction of the ARE-binding protein TTP, both of which are components of a signaling pathway that modulate the expression of ARE-containing mRNAs at the post-transcriptional level. Pharmacological inhibition of p38 reduces the c-di-AMP-dependent release of induced cytokines, while TTP knockdown increases their release and mRNA stability. C-di-AMP can specifically increase the expression of a nano-Luciferase reporter that contains AREs. We propose a non-canonical intracellular mode of activation of the p38 MAPK pathway with the subsequent enhancement in the expression of inflammatory cytokines. C-di-AMP is widely distributed in bacteria, including infectious intracellular pathogens; hence, understanding of its post-transcriptional gene regulatory effect on the host response may provide novel approaches for therapy.

Dual RNA Sequencing Reveals Key Events When Different Giardia Life Cycle Stages Interact With Human Intestinal Epithelial Cells In Vitro

“…Interestingly, Giardia infection up-regulates several downstream RIG-I signaling pathway genes during the infection ( Table S2 ), such as TRAF3, IKK, and TBK1. Furthermore, pathogenic bacteria can also manipulate TTP levels via the bacterial secondary messenger cyclic-di-AMP (c-di-AMP) ( Mahmoud et al., 2020 ). Thus, up-regulation of TTP might be a general immunosuppressive mechanism used by pathogenic microbes to suppress an initial up-regulation of inflammatory mediators and this can be studied further in the Giardia -Caco-2 system.…”

Cyclic di-AMP as endogenous adjuvant enhanced BCG-induced trained immunity and protection against Mycobacterium tuberculosis in mice

“…Trained monocytes and macrophages display functional and epigenetic reprogramming, leading to increased production of cytokines and chemokines, which are viewed as primary indicators of trained immunity ( 37 ), and improved phagocytosis and killing capacity ( 51 , 52 ). c-di-AMP has been identified to be a potent inducer of several proinflammatory cytokines and chemokines such as IL-1β, IL-6, and TNF-α in macrophages ( 27 , 31 , 32 , 53 ). These proinflammatory cytokines are also considered as mediators of trained immunity ( 8 , 9 , 54 , 55 ).…”

The role of bacterial cyclic di-adenosine monophosphate in the host immune response

“…Released type I IFN can bind to the IFN receptor, activating STATs (signal transducer and activator of transcription), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) signal pathways, regulating various physiological activities and initiating anti-pathogen responses. Mahmoud et al (2019) demonstrated that c-di-AMP could specifically enhance the expression of additional inflammatory cytokines, namely, IL-6, CXCL2, CCL3, and CCL4, the mRNAs of which contain AU-rich elements (AREs) in the 3′ UTR that promote decay and repress translation. c-di-AMP was able to promote the phosphorylation of p38 MAPK as well as the induction of the ARE-binding protein TTP, both of which are components of a signaling pathway that modulate the expression of ARE-containing mRNAs at the post-transcriptional level.…”

“…c-di-AMP was able to promote the phosphorylation of p38 MAPK as well as the induction of the ARE-binding protein TTP, both of which are components of a signaling pathway that modulate the expression of ARE-containing mRNAs at the post-transcriptional level. Pharmacological inhibition of p38 reduced the c-di-AMP-dependent release of induced cytokines, while TTP knockdown increased their release and mRNA stability ( Mahmoud et al, 2019 ). These data propose that c-di-AMP can activate the p38 MAPK pathway via a post-transcriptional regulatory effect and subsequently enhance the expression of inflammatory cytokines.…”