Active tuberculosis (TB) is characterized by the failure of the host to control bacterial replication and pathological inflammation in lungs and other organs. Although antibiotics achieve microbiological cure of this disease, inflammation persists even after chemotherapy and is associated with impaired lung functions. Recent studies in humans have shown that genetic polymorphisms in interleukin-1b (a prototypical IL-1 cytokine) promoter increases the risk of hyperinflammation, and long-term respiratory failure during pulmonary TB. Our preliminary data in mice reaffirmed this association as interleukin-1 (IL-1) blockade ameliorates exacerbating inflammation in mouse strains susceptible to TB. IL-1 inhibition therapy is routinely used in the clinic to treat a number of human diseases where this cytokine acts as a pathogenic mediator. But, the role of IL-1 in TB is very complex, as expression of this cytokine is pivotal for host defense early during infection. Mice deficient in this cytokine signaling rapidly succumb to inflammatory TB disease and loss of function genetic polymorphisms in human IL-1R1 were associated with increased risk for active TB. Given these protective functions of IL-1 in TB, drugs that act by antagonizing IL-1 signaling may not be very safe for patients dwelling in TB endemic areas as they elevate the risk for reactivating latent TB. This dichotomous function of IL-1 has not received due attention partly because the pathological functions of this cytokine during TB was perceived as a consequence of failed antimicrobial function in conditions where the host makes sub-optimal level of IL-1. Despite being a well-studied cytokine in terms of its regulation and signaling pathways, the role of different cells in IL-1- mediated protective immunity and pathological inflammation is not explored in details, especially in the context of chronic TB. To bridge this knowledge gap, and with the long-term goal to understand the cell-specific role of IL-1 in TB immunity, we generated conditional deletion and gain-in function mutant mouse strains and discovered that IL-1 provides protection against TB by acting on non-hematopoietic cells, e.g. airway epithelial cells (AECs) and endothelial cells (ECs) that control neutrophil influx, tissue damage and bacterial growth in the lungs. We hypothesize that IL-1 activation on ECs and AECs are integral to protection against chronic TB as it restrains tissue-damaging inflammation caused by uncontrolled neutrophil influx, and boosts anti-microbial immunity. We will test this hypothesis by two specific aims.
In aim. 1, we will investigate the mechanisms by which AECs and ECs regulate inflammation and microbicidal functions of phagocytes. We will specifically test the contribution of prostaglandin E2/EP4 signaling pathway in mice that express or lack IL-1 receptor on these cells.
In aim. 2, we will investigate the mechanisms by which neutrophils cause tissue damage in the absence of regulatory signals from AECs and ECs. We will test the hypothesis that neutrophils produce 5- and 12/15- lipoxygenases to generate potent chemo attractants of these cells and amplify inflammation by a feed-forward mechanism. Collectively, these studies will provide an in-depth understanding of the IL-1-mediated immune response involved in protection and pathology, and will lay the groundwork for the future development of cell- specific modulation of IL-1R1-signaling as host-directed therapeutics. Successful completion of the studies proposed here, in our opinion, will provide rationale targeting of various downstream pathways, for which clinically relevant pharmacological inhibitors are available.
Tuberculosis (TB), kills a human being every 24 seconds, making this disease the top cause of mortality and morbidity from infectious diseases. Increasing prevalence of multi-drug resistant Mycobacterium tuberculosis strains, has spurred the search for alternative therapeutics. The proposed research is relevant to public health because the findings of this work is ultimately expected to increase our understanding of TB pathogenesis, and provide mechanistic insights into the pathogenic inflammation which persists even after antibiotic treatment and compromises lung functions in Tuberculosis patients. In addition, successful completion of this project will generate new knowledge regarding the cell-specific functions of interleukin-1 signaling in TB immunity that can be harnessed for designing novel host-directed treatments for tuberculosis.