Activated myeloid cells promote host resistance to infections but also drive inflammation that can damage tissue and contribute to chronic diseases. Thus, the immune system must carefully balance responses that regulate myeloid cell accumulation and activation ? ideally optimizing protective responses against infectious agents while limiting inflammatory responses. We believe an improved understanding of how myeloid cell activity is regulated will aid development of therapies that more specifically target excessive inflammation while preserving protective anti-microbial myeloid cell activities. This proposal specifically focuses on a mechanism by which type I IFNs suppress myeloid cell responses and addresses whether such suppression contributes to increased host susceptibility in a murine model for Down syndrome, the Dp16 mouse. Type I interferons (IFNs) induce an antiviral state that is protective against viruses, but these cytokines also have immune regulatory functions and are used in clinical contexts to treat inflammation-associated disease. Further, in a number of bacterial infections type I IFNs are associated with increased host susceptibility. Our lab and others have previously demonstrated that these ?pro-bacterial? effects of type I IFNs correlate with dampening of myeloid cell anti-microbial activation. Here, we investigate the impact of type I IFNs and IFNGR1 down regulation in myeloid cells on resistance/susceptibility in the context of a chromosomal triplication in mice that mimics trisomy 21 in humans. Results of these efforts could advance host-directed therapies to counter the silencing of Ifngr1 for boosting immune responses in individuals with DS and severe bacterial infections, including infections by pathogens that are resistant to conventional antibiotics.
This proposal seeks to better define the impact of altered myeloid cell IFNGR1 on susceptibility to bacterial infections in individuals with trisomy 21. Such efforts may lead to development of improved therapies to treat these and other susceptible populations.
