Type I IFN-dependent and independent contributions to the outcomes of early innate immune cell interactions during HIV/TB co-infection

PROJECT SUMMARY/ABSTRACT Granuloma formation is a feature of tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb) infection. Alveolar macrophages (alvMF) are central to this process as the first cells infected by Mtb and likely as drivers of early granuloma development. The initial events when alvMFs encounter Mtb and the cell-cell

interactions occurring in mature granulomas are extensively investigated but less is known about what happens between the initial infection event and later stages of disease. These early events have implications for the trajectory of TB and some individuals restrict Mtb at this stage and never develop disease despite multiple

exposures whereas other individuals cannot restrict Mtb replication and progress to granuloma formation. Our lack of knowledge of the molecular and cellular circuits underlying early granuloma formation and what differentiates outcomes at this stage is a fundamental gap that limits the development of therapeutic interventions

for TB. This gap is especially acute for people infected with human immunodeficiency virus (HIV), which significantly increases risks of poor outcomes from TB, and addressing it will have significant public health value. Critical unanswered questions in the acute response to Mtb infection include (1) how do interactions between

immune cells immediately after alvMF infection contribute to granuloma formation, (2) which components of these interactions can be perturbed to bias disease dynamics to improve control over Mtb replication, and (3) what interactions are altered by HIV infection that increase susceptibility to active TB? We discovered that

infected MF secrete interferons (IFNs), cytokines, and chemokines within minutes to hours after infection that drive the inflammatory responses that support granuloma formation. Moreover, we have shown that type I IFN expression and neutrophil recruitment support Mtb replication and we are investigating how these responses

contribute to infection outcomes. Recently, we showed that type I IFN drives release of neutrophil extracellular traps that promote Mtb replication instead of restricting it and are associated with the development of necrotic granulomas. Based on these data, we hypothesize that early interactions between macrophages and neutrophils

are regulated by a self-propagating cycle of type I IFN and damage-associated molecular pattern (DAMP) signaling that culminates in granuloma formation. Moreover, our work showing that I IFN-conditioned immune cells are less able to control Mtb infection leads us to hypothesize that HIV-induced type I IFN signaling amplifies

this type I IFN–DAMP circuit and promotes an environment that supports Mtb replication, tissue damage, and TB susceptibility. We predict that breaking the type I IFN–DAMP cycle therapeutically will push early responses toward protective functions. To test our hypothesis, we propose to 1) Define type 1 IFN and DAMP signaling

effects in innate immune cells following initial Mtb infection, 2) Dissect the molecular basis of the type I IFN- DAMP circuit to identify vulnerabilities where therapeutic interventions can promote control of Mtb, and 3) Determine how HIV affects the type 1 IFN-DAMP circuit propagated by Mtb infection.