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. In the present work we have characterize the link between the ER stress response and the production of interleukin-1beta (IL-1b), a pro-inflammatory cytokine known to play a role in those conditions as well as in innate immunity to infection. Using a well-established model of ER stress induced by treatment with the drugs tunicamycin or thapsigargin, we showed in vitro that macrophages undergoing ER stress are able to potently activate pro-IL1b in response to stimulation with LPS but not other TLR agonists. Interestingly, the classical Nlrp3 inflammasome which is usually required for the generation of mature IL-1b is dispensable since maturation of pro-IL1beta does not require the critical inflammasome adaptor protein ASC or its effector caspase-1. In contrast, our results indicate that processing of pro-IL1b is dependent on caspase-8 since production of the mature cytokine is completely abrogated in macrophages lacking this non-inflammasome associated protease. Intriguingly, we found that the UPR proteins XBP1 and CHOP are not required for Caspase-8 activation, nor is the TLR4 adaptor molecule MyD88. Instead, we observed that the alternative TLR4 adaptor TRIF is fully required and thus could recruit Rip1, a signaling intermediate involved in Caspase-8 activation. This novel pathway is of interest as it could underlie the induction of IL-1-driven tissue pathology in different disease settings and could serve as a mechanism by which infections such as Mtb drive IL-1b responses. 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 by OGarra and colleagues. Such findings have raised the question of whether concomitant viral infections that trigger Type I IFN production could exacerbate active MTb infection and/or re-activate latent tuberculosis. This question is of particular relevance to influenza where much of the actual severe disease is caused by bacterial super-infection. In a collaboration with the OGarra group, we addressed this question in TB and showed that prior exposure of mice to influenza A, followed by M. tuberculosis infection, leads to enhanced mycobacterial growth and decreased host survival. In addition, we found that that following concurrent M. tuberculosis/influenza co-infection, mycobacterial growth is enhanced and this increased susceptibility is reversed in mice lacking the IFN alpha/beta receptor. Together, these findings argue that prior or concomitant viral infection can promote M. tuberculosis infection and point to the involvement of Type I IFN in this process.