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Role of IFN-beta in disease and characterization of the immune response following acute radiation exposure


Type I interferons (IFNs) are a group of pleiotropic of cytokines well known for their role in promoting an antiviral state through the induction of interferon stimulated genes (ISGs). Pathogen associated molecular patterns (PAMPs) expressed by bacteria such as lipid A induce type I IFNs. In macrophages we found induction by ISGs by lipid A was highly dependent on the signaling by the IFNβ subtype. Furthermore, IFNβ was required to positively regulate the feedback loop for induction of downstream ISGs. Identification of this major role led us to investigate the functional consequence of IFNβ signaling in two different bacterial infections. Both macrophages and IFNAR signaling are necessary to promote host defense against Escherchia coli peritonitis, however we found survival of Ifnb-/- mice was not drastically reduced. Next, we studied the role of IFNβ during post-influenza pneumonia since previous studies from our lab showed IFNAR signaling enhanced host susceptibility. We found IFNβ deficiency was not sufficient to protect the host from bacterial pneumonia. The results from both models led us to conclude additional subtypes of type I IFN must be cooperating with IFNβ to either promote host resistance or susceptibility.

To study the role of ISGs and IFNAR signaling in non-infectious disease we focused on three different models. In the first we examined the role of the interferon inducible protein, CXCL10 in the progression of LPS induced endotoxic shock. We found CXCL10 deficiency increased survival of female mice, not males. Moreover, CXCL10 likely mediated its pathogenic effects by signaling through the canonical receptor CXCR3. In the second model, we studied the role of poly I:C induced type I IFN on the progression of chronic experimental autoimmune encephalitis (EAE), a mouse model of human multiple sclerosis. We found poly I:C transiently attenuated symptoms of EAE by signaling through toll like receptor 3 (TLR3) to induce type I IFNs. Finally, we measured the induction and expression of type I IFNs and ISGs in the mouse model of tuberous sclerosis complex disorder. Our results demonstrate Tsc2+/- mice express elevated levels of type I IFNs and ISGs following poly I:C treatment. This result points to a possible mechanism for the increased incident of neuropsychiatric disease in TSC haploinsufficient patients.

Finally, we monitored survival of mice treated with lethal doses of whole body irradiation to characterize response during acute radiation syndrome (ARS) and delayed effects of acute radiation syndrome (DEARE). We found both PAMPs and select small molecules were able to either protect or rescue mice from ARS. Among mice that survived ARS and were monitored for one year, we noticed specific symptoms were correlated with the type of radiomitigator administered during ARS. Moreover, we observed mice that were likely to die or develop disease had higher concentrations of serum cytokines, and gut microbial dysbiosis. Immunological challenge revealed disparities between mice, but also suggested that more comprehensive studies may lead to the development of biomarkers that will be useful to predict response to future vaccination or disease.

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