Dissecting the Contribution of Neutrophils to Diabetes/Tuberculosis Comorbidity

About This Grant

Diabetes mellitus (DM) is a group of metabolic diseases that affect how the body utilizes glucose and result in elevated levels of glucose in the blood and urine. DM increases the risk of many infections and their complications, but comorbidity with tuberculosis (TB) stands out due to its tremendous global impact. DM and TB each individually rank in the top ten global causes of death. In 2020, there were approximately 537 million adults with DM and 10 million new cases of active TB. TB patients with DM are twice as likely to die from TB and 1.5 times more likely to experience TB recurrence than non-DM patients. To better protect DM patients from TB, we need to understand how DM alters immune function to favor developing active TB disease. The impact of the metabolic perturbations in DM patients on immune cell function have largely been explored in the context of lymphocytes and macrophages. However, a systems biology comparison of DM patients, TB patients, comorbid patients (DM/TB), and healthy individuals was recently performed and identified neutrophilic inflammation as a central feature of DM/TB. Dysfunctional neutrophils have been implicated in DM vascular complications and impaired wound healing, but it is unclear how they contribute to disease outcomes in Mycobacterium tuberculosis (Mtb)-infected DM patients. Neutrophils are the most abundant and predominantly-infected cell type in the airways and lung tissue of active TB patients, but are unable to control Mtb replication. In addition, we have recently demonstrated that specific neutrophil effector functions can directly promote Mtb replication and pathogenesis. It is currently unclear how neutrophils contribute to disease outcomes in DM/TB patients, particularly because neutrophils are typically discarded from blood cell isolations and must be analyzed immediately without storing. We hypothesize that altered neutrophil function during DM contributes to increased susceptibility to Mtb infection. The proposed experiments will for the first time directly dissect the neutrophil responses associated with the DM/TB comorbidity and determine how neutrophils impact the outcome of Mtb infection in the context of DM. In Aim 1 we will define the neutrophil responses in DM patients that are associated with susceptibility to developing active TB disease. In Aim 2, we will determine how DM neutrophils promote Mtb pathogenesis. The results from the proposed studies will provide the critical foundation for future translational studies aimed at modulating neutrophil responses in DM/TB comorbid human patients as new strategies to treat TB in individuals with DM. Host directed therapies will work to target drug sensitive and resistant infections. Drugs already being developed that target NET release and other neutrophil effector functions, we can exploit these.