Host immune mechanisms underlying the interaction of Diabetes and Tuberculosis

Bakground:

Tuberculosis (TB), caused by infection with M tuberculosis, is a major global health problem killing around 2 million individuals per year. Diabetes (DM) increases the risk of developing TB. The underlying mechanisms in the interaction between DM and TB are poorly understood despite their implications in clinical management.

T-cell immunity is critical for control of the infection with M. tuberculosis (Mtb). We hypothesize that DM alters T cell mediated responses resulting in increased susceptibility to TB. Aim:

We propose to explore immune mechanisms of bacterial control and to topologically define immune-bacterial interactions in the lung in clinical and experimental TB and TB/ DM. We will define the immune landscape of human pulmonary granulomas from TB and TB/ DM patients using spatially-resolved transcriptomics. STAT3 and HIF-1 are major T cell and macrophage regulators affecting immune and metabolic responses.

DM destabilizes HIF-1. Whether this can control TB development will be determined. The role of STAT3 and HIF-1 in during Mtb infection of TB and TB/DM patients and in diabetic mice will be investigated. Workplan: We will:

1. Simultaneously target 256 immune and mycobacterial transcripts in pulmonary sections from patients with TB and TB and DM and thereby define the distinct topography of the granuloma in these conditions using spatially resolved transcriptomics technology.

2. Compare the STAT3-mediated T cell responses in blood from pulmonary TB or latent TB individuals with DM or not, and investigate the role of STAT3 in T cells during infection with Mtb using genetically modified mice.

3. Study the role of HIF-1 during the TB infection against Mtb in diabetic mice genetically deficient or overexpressing HIF-1 or using clinically approved drugs. We will decipher the molecular mechanisms by which hyperglycemia hampers HIF-1 function and the intracellular M. tuberculosis control in macrophages.

Relevance:

We will gain novel understanding of the human granuloma immunobiology, function and structure and compare the TB granuloma in patients with DM or not. We will test if STAT3 and HIF-1 mediated responses underlie the increased susceptibility to TB of DM using genetic manipulation of different genes as well as drugs used in the clinics targeting these pathways.

Clinical studies in TB patients will be complemented by studies in experimental mouse models of DM and TB and by in vitro studies using macrophages.