Identifying a protective role for interferon lambda in tuberculosis - PROJECT SUMMARY Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and causes more than 1.5 million deaths annually. The current therapeutic regimen requires prolonged administration of antibiotics (3-6 months), which limits compliance. Further, the emergence of multidrug-resistant (MDR) Mtb strains including extensive MDR strains that are resistant to most antibiotics, poses an unprecedented threat to human health. Development of novel antibiotics has been challenging and the risk of developing antibiotic resistance against new antibiotics remains. Considering this, host-directed therapies (HDTs) targeting the immune response to shorten therapeutic regimens and can be used against MDR TB and nontuberculous mycobacterial infection, are urgently needed. Interferons (IFN) including IFNg and the type 1 IFNs are important components of anti-Mtb immune responses. IFNg is well-described as a protective factor in TB and type 1 IFNs are known to be detrimental to anti-TB immunity, but very little is known about type 3 IFNs (IFN lambda; IFNL) in TB. IFNLs share some signaling pathways with the other IFNs but have different receptor usage that leads to them having a blend of pro-and anti-inflammatory properties. We found that IFNLs are expressed in TB granulomas and can induce a unique anti-mycobacterial activation program in macrophages that improves lysosomal acidification, overcoming an Mtb immune evasion mechanism that allows the bacilli to survive and replicate within these cells. An antimicrobial role for IFNL during TB was further supported by our data showing an inverse correlation between Mtb burden and IFNL concentration in NHP granulomas. Based on these findings, we hypothesized that IFNL has protective functions in TB and propose that IFNL may have application as a HDT in TB. We will test our hypothesis by investigating the following two specific aims: Aim 1. Define IFNL’s relationship to lung inflammation and granuloma formation over the course of TB. Aim 2. Identify how IFNL, IFN1 and IFNg differentially regulate macrophage anti-mycobacterial activity. To complete these aims, we will use longitudinal sampling of NHPs with TB, analysis of PET-CT data from these animals, and analysis of IFNLs in granulomas with defined Mtb loads to measure the kinetics and effect of IFNL expression over the course of TB. We will augment these data with sophisticated in vitro granuloma models using NHP cells and healthy human PBMCs. We will comprehensively examine macrophage transcriptional and proteomic responses to Mtb infection and IFNL stimulation to fully describe the interaction of these cytokines and macrophages. These projects are highly significant to the 2024 NIAID Strategic Plan for TB Research and will lead to novel insights into regulation and stage specific roles of IFNLs during TB in a highly translational model and the mechanisms underlying its activity. This grant will generate feasibility data for future studies including an NIH R01 application where we will test therapeutic use of IFNL in murine and NHP-models to test this HDT’s application to a current therapeutic TB regimen.
