Genetic Targets for New Tuberculosis Lung Treatments Identified

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Secondary tuberculosis infection, illustration

Key genetic changes that are behind the lung damage seen in tuberculosis patients as well as a potential candidate treatment to exploit these genetic targets have been identified by researchers.

The two new studies cast light on disease processes in tuberculosis (TB)and are reported in two papers in the Journal of Clinical Investigation.

In the first study (“Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets”), a team from the University of Southampton used a new 3D culture system they have developed to observe the changes that occur in cells infected with TB. Unlike the laboratory-standard 2D culture system, where cells are placed in a flat plastic dish, the 3D system uses an engineering technique to suspend them in droplets. The team found that the TB-infected cells in droplets responded very closely to cells in the lungs of patients with the disease.

A second university team then carried out complex sequencing techniques on the cells to identify the events through which TB causes excessive inflammation and damage to the lung.

Human genome sequencing methods generate information on tens of thousands of changes in genes from each sample, making it difficult to work out which changes are important and which are from chance. The Southampton Systems Immunology Group combined different mathematical approaches, such as clustering algorithms, to whittle this down to seven genes which seem to underpin the lung destruction that occurs in TB.

“Tuberculosis (TB) is a persistent global pandemic and standard treatment has not changed for thirty years. Mycobacterium tuberculosis (Mtb) has undergone prolonged co-evolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas,” write the investigators.

“We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a non-infectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response.

“To translate these insights, we compared three primary human cell culture models at the whole transcriptome level, and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified twelve intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion.

“Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.”

Further studies into infectious diseases

This observation has widespread implications for further studies into infectious diseases, including COVID-19, according to the researchers.

“The integration of modern sequencing techniques with clinical samples is permitting unprecedented insight into disease mechanisms, while our 3D cell culture system then lets us replicate conditions in patients and identify new treatment approaches,” says Michaela Reichmann, of the University of Southampton, and who conducted the study.

In the second study (“Doxycycline host-directed therapy in human pulmonary tuberculosis”), a clinical trial led Catherine Ong, PhD, of the National University of Singapore, explored the use of a common antibiotic, doxycycline, to reverse these changes. The Phase II double blind trial in 30 patients showed that doxycycline, in combination with TB drug treatment, reduces the size of lung cavities and accelerates markers of lung recovery towards health. These bioinformatics analyses were performed by the Systems Immunology Group in Southampton.

The treatment was found to be safe, with similar side effects to those experience by patients on placebo pills. The study shows promise in delivering a new standard-of-care which can potentially prevent long term complications, notes Ong.

“Pulmonary TB patients tend to suffer from lung damage after TB, which is associated with mortality, and poorer quality of life,” she continues. “Doxycycline is a cheap and widely available antibiotic that can decrease lung damage, and potentially improve quality of life for these patients.”

 

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