Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner

Abstract

Defects in nucleic acid metabolizing enzymes can lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing type I interferon–driven inflammatory diseases. In these pathophysiological conditions, activation of the DNA sensor cGAS and IFN production are linked to spontaneous DNA damage. Physiological, or tonic, IFN signaling on the other hand is essential to functionally prime nucleic acid sensing pathways. Here, we show that low-level chronic DNA damage in mice lacking the Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed to a p53-deficient, but not to a DNA mismatch repair-deficient background. Increased DNA damage did not result in higher levels of type I interferon. Instead, we found that the chronic interferon response in SAMHD1-deficient mice was driven by the MDA5/MAVS pathway but required functional priming through the cGAS/STING pathway. Our work positions cGAS/STING upstream of tonic IFN signaling in Samhd1-deficient mice and highlights an important role of the pathway in physiological and pathophysiological innate immune priming.

SAMHD1 expression modulates innate immune activation and correlates with ovarian cancer prognosis

“…Indeed, in agreement with our data, SAMHD1-deficiency and subsequent accumulation of endogenous RNA substrates is a cause of type I interferonopathies, characterized by an upregulation of distinct IFN-stimulated genes (ISGs) ( 20 , 24 ). Moreover, it has also been shown that chronic interferon response in SAMHD1-KO mice was driven by the MDA5 pathway in close concordance with our data in ovarian cancer cells ( 25 ) and further supporting the idea that SAMHD1 depletion is able to enhance innate immune activation and inflammation in cancer cells, a process that might have an important impact on ovarian cancer clinical outcome. In view of the promising pre-clinical data, we evaluated the role of SAMHD1 in 22 ovarian cancer patients.…”

p16Highimmune cell - controlled disease tolerance as a broad defense and healthspan extending strategy

“…For example, in long-lived bats, continuous presence of multiple viruses could trigger a TLR7/STING-induced activation of a p16 program in immune cells and tissue protection against both infection and tissue damage 66 . At the same time, significantly reduced DNA-sensing in bats could keep STING activation in its low and physiological or, as also referred to, "tonic" state 67 while preventing a strong pro-inflammatory response that could be detrimental for disease tolerance (Figures 4F&G). In another long-lived animal, the naked mole-rat, a lack of response to Poly (I:C) reported in hematopoietic stem cells may suggest a strong attenuation of MDA5-dependent sensing 68 .…”

“…From a clinical standpoint, we found that p16-expressing immune subsets were significantly reduced in the blood of severe COVID-19 patients further supporting their critical role in preventing lethal inflammation. The clinical efficacy of the BNT162b2 mRNA vaccine in reducing the risk of hospitalization was demonstrated as early as 10 days after the first dose when the specific immune response has not yet been established 66 in terms of development of specific antibodies 67 and the cellular responses 68 . Our results could explain these early benefits of vaccination on the risk of hospitalization by temporarily inducing p16 high immune cell-dependent disease tolerance that would eventually limit the evolution towards an inflammatory form of COVID-19 thus reducing the risk of hospitalization for severe cases.…”

Juvenile Dermatomyositis and Infantile Cerebral Palsy: Aicardi-Gouteres Syndrome, Type 5, with a Novel Mutation in SAMHD1—A Case Report

“…A recent study of SAMHD1-deficient mice has demonstrated that increased DNA damage does not result in higher levels of type I interferon. Instead, the chronic interferon response is driven by the MDA5/MAVS pathway [ 13 ].…”