The STING controlled cytosolic-DNA activated innate immune pathway and microbial disease

The innate immune system is critically important for the primary sensing of invading pathogens. Over the past decade, the cellular sensors important for recognizing microbial entry into the host cell have been largely elucidated. These sensors, some of which are evolutionarily conserved, include the Toll-like receptor (TLR) and RIG-I-like helicase family (RLH) pathway that can recognize bacterial and viral non-self nucleic acid. In addition, a cellular sensor referred to as STING (for stimulator of interferon genes) has been shown to be critical for triggering host defense countermeasures, including stimulation of the adaptive immune response, following the detection of cytosolic DNA species. The STING pathway has now been shown to be critical for activating innate immune gene transcription in response to infection by DNA pathogens such as herpes simplex virus 1 (HSV1) as well as retroviruses. In addition, it is clear that chronic STING activation can also cause autoinflammatory disease manifested by self-DNA. Here we review recent developments in our understanding of STING function, including importance in the control of microbial disease

The interferon-related developmental regulator 1 is used by human papillomavirus to suppress NFκB activation

High-risk human papillomaviruses (hrHPVs) infect keratinocytes and successfully evade host immunity despite the fact that keratinocytes are well equipped to respond to innate and adaptive immune signals. Using non-infected and freshly established or persistent hrHPV-infected keratinocytes we show that hrHPV impairs the acetylation of NF\xce\xbaB/RelA K310 in keratinocytes. As a consequence, keratinocytes display a decreased pro-inflammatory cytokine production and immune cell attraction in response to stimuli of the innate or adaptive immune pathways. HPV accomplishes this by augmenting the expression of interferon-related developmental regulator 1 (IFRD1) in an EGFR-dependent manner. Restoration of NF\xce\xbaB/RelA acetylation by IFRD1 shRNA, cetuximab treatment or the HDAC1/3 inhibitor entinostat increases basal and induced cytokine expression. Similar observations are made in IFRD1-overexpressing HPV-induced cancer cells. Thus, our study reveals an EGFR-IFRD1-mediated viral immune evasion mechanism, which can also be exploited by cancer cells

STING: infection, inflammation and cancer

The rapid detection of microbial agents is essential for the effective initiation of host defence mechanisms against infection. Understanding how cells detect cytosolic DNA to trigger innate immune gene transcription has important implications — not only for comprehending the immune response to pathogens but also for elucidating the causes of autoinflammatory disease involving the sensing of self-DNA and the generation of effective antitumour adaptive immunity. The discovery of the STING (stimulator of interferon genes)-controlled innate immune pathway, which mediates cytosolic DNA-induced signalling events, has recently provided important insights into these processes, opening the way for the development of novel immunization regimes, as well as therapies to treat autoinflammatory disease and cancer