Silence the alarm: (p)ppGpp reduces the expression of key innate immune system regulatory genes 3177

Abstract Description The GTP-derived alarmones, guanosine tetra- and pentaphosphate (collectively referred to as (p)ppGpp) are well-established mediators of the nutrient starvation response in many pathogenic bacterial genera. In most studied models, intracellular alarmone concentrations are elevated in nutrient-replete environments, resulting in changes to the bacterial transcriptional profile. Several key genes related to nutrient metabolism, pathogenicity factors, sporulation, and antibiotic resistance depend heavily on the conserved framework of (p)ppGpp signaling. Interestingly, the impact of these molecules on innate immune signaling has not been explored. Here, we evaluated the impact of ppGpp and pppGpp on general arms of innate immune signaling, specifically ISRE- and NF-ΚB-mediated gene expression, by stimulating a RAW-Dual reporter cell line with increasing concentrations of each alarmone. It was found that increasing concentrations of ppGpp or pppGpp resulted in notable reductions in the basal and induced expression of ISRE-mediated genes, while leaving NF-KB-mediated gene expression unaffected. We are also investigating the impacts of alarmone treatment on macrophage activation and polarization. These results suggest that GTP-derived alarmones may have potential as a new class of targeted non-steroidal anti-inflammatory drugs; further, these results also suggest a new mechanism of bacterial moderation of host innate immune gene expression. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)