In addition to signals delivered by pattern recognition receptors, infections can stimulate innate immunity through the host response to tissue injury (danger signals). We have been examining the possible role of one such pathway (the ER stress response) in the initiation of innate cytokine production. Maintaining normal cell physiology requires constant protein synthesis and proper folding, processes that occur in the endoplasmic reticulum (ER). Improperly folded proteins accumulate within the ER and generate perturbations known as ER stress that engage the unfolded protein response (UPR). Although not fully understood, downstream effector mechanisms of the UPR promote a wide range of inflammatory pathologies such as neurodegenerative disorders, diabetes and obesity. This year we reported that that macrophages undergoing ER stress induce the maturation of pro-IL 1 beta in response to LPS stimulation in vitro. Our findings (Shenderov et al, 2014) demonstrated a critical role for the TRIF/Caspase-8 axis in this response. During the year we have extended this project to assess the potential role of ER stress in vivo in the response to bacterial or parasite infection using mice that are deficient for the ER stress downstream transcription factor CHOP. Our preliminary data show that CHOP knockout mice display increased susceptibility to oral Toxoplasma gondii infection as assessed by survival. In contrast, CHOP deficient mice exhibit enhanced resistance to i.v. Mycobacterium avium infection as evidenced by markedly decreased CFU in spleen and lung. We are currently investigating the mechanisms underlying these divergent host resistance outcomes. As noted in previous annual reports and publications from our group we have been studying the role played by both exogenous and endogenous Type I interferons in promoting murine infection with Mycobacterium tuberculosis. A strong association between Type I interferons and their induced genes and active tuberculosis has also been documented in human Mtb infection in a number of distinct patient cohorts. We have further shown that Type I IFN can suppress the production of Interleukin (IL-1) during TB infection. The latter cytokine is required for host resistance to this pathogen. In a major study published this year (Mayer-Barber et al. 2014), we examined the mechanism by which IL-1 mediates control of infection. We demonstrated that it does so through the induction of lipid mediators known as eicosanoids that limit excessive type I interferon (IFN) production thereby promoting bacterial containment. In addition we showed in infected mice and patients, that reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Importantly, correction of this imbalance by the administration of a 5-lipoxygenase inhibitor (zileuton) and/or prostaglandin E2 in these settings prevented acute mortality of Mtb-infected mice. Together our findings reveal a cross-regulatory circuit between Type-I IFN and IL-1 that can be targetted with eicosanoids to both prevent and treat acute disease in MTb infection. Such a host-directed therapy could be of use as an adjunct to conventional antibiotic therapy to improve treatment time/efficacy or in the control of infections with drug-resistant mycobacterial strains.
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