Award Title: Multidimensional transcriptomic analysis of tuberculosis granulomas to define pathophysiological mechanisms
Funder: The Academy of Medical Sciences

Abstract: Tuberculosis (TB) has a huge global burden, killing 1.4 million people in 2019, and is caused by infection with Mycobacterium tuberculosis (Mtb).  Despite the long course of standard anti-tuberculous therapy, treatment is not always successful, often leading to drug-resistant TB.  The host response to Mtb plays a key role in TB immunopathology, where a balance exists between protective and pathological processes.  The granuloma is the key determinant of outcome in TB, where each granuloma consists of a macrophage-rich core and peripheral T cell / fibroblast layer.  Great heterogeneity exists simultaneously between granulomas of each individual.  The spatial organisation of these cell types with each other and surrounding extracellular matrix are emerging as critical determinants of granuloma formation and disease progression. 

My microenvironment spatial transcriptomic analysis of TB lymph node samples by laser capture microdissection has already demonstrated key pathways that differentiate TB from another granulomatous disease, sarcoidosis, and identified potential new therapeutic host targets in tuberculosis.  However, greater resolution is needed to achieve cell-level expression data.  These samples had been carefully selected, with all samples taken from patients who were naïve to antituberculous or immunosuppressing therapy.  Complete spatial profiling of the same samples would allow full transcriptomic characterisation of the different cell types in the granuloma.  Furthermore, integration of the spatial data with the cellular depth of single cell RNAseq data from human TB granulomas will provide unprecedented insights into events within TB granulomas.

Lay Abstract: Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (Mtb) infection, killing millions of people each year.  Prior to the COVID-19 pandemic, TB was the leading cause of death worldwide due to a single infection and deaths are increasing.  Standard TB therapy consists of multiple antibiotics taken for at least six months, and is often poorly tolerated due to antibiotic side effects.  Despite completing the full course of antibiotics, the treatment is not always successful.  Our immune response to Mtb plays an important role in disease outcome, where either insufficient or excessive response causes harm, yet this process is incompletely understood.  Therefore, finding medicines which alter specific immune responses are likely to benefit TB treatment. 

New technologies allow us to study disease at a cellular level and we have shown how genes influence our response at the microscopic level.  The 3-dimensional surroundings play an important role here, affecting the resulting severity of TB disease in each person.  We have carefully selected TB samples from untreated patients and have studied this genetic information to identify potential new drug targets for TB treatment.  More detailed analysis of these samples, taking into account the 3-dimensional cellular organisation, is likely to generate better understanding and more specific TB treatments.  The same approach could be used to understand and better treat other difficult human conditions such as inflammatory diseases and cancer.  Ultimately, promoting a balanced immune response in TB, together with antibiotic therapy, is likely to reduce treatment duration, reduce disease severity, and improve survival.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: INFECTION