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Research sheds new light on the process of tuberculosis disease

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Two new studies have identified important genetic changes that shed unprecedented light on the process of tuberculosis disease, causing lung damage, and medications that may accelerate recovery.

Tuberculosis (TB) is a lung infection that kills more people than anyone else and was the most infectious murderer in the world until last year. Worldwide, an estimated 10 million people develop the disease each year.

The findings are reported in two papers. Clinical Research Journal..

The first study used a new 3D culture system developed by a team at the University of Southampton to observe the changes that occur in tuberculosis-infected cells. Unlike laboratory standard 2D culture systems, where cells are placed on a flat plastic dish, the 3D system uses engineering techniques to suspend the cells in droplets, much like a frog spawn. The team found that tuberculosis-infected cells in the droplets responded very closely to the cells in the lungs of patients with the disease.

This observation has broadly influenced further studies of infectious diseases, including COVID-19.

Next, a second team at the University of Southampton performed a complex sequencing technique on the cells to identify the events in which tuberculosis causes excessive inflammation and lung damage.

Human genome sequencing produces information about tens of thousands of genetic changes from each sample, making it difficult to determine which changes are important and which are accidental. The Southampton Systems Immunology Group has combined various mathematical approaches, such as clustering algorithms, to narrow this down to seven genes that appear to support lung destruction that occurs in tuberculosis.

The integration of state-of-the-art sequencing technology and clinical samples enables unprecedented insights into disease mechanisms, and a 3D cell culture system that allows patients to recreate their condition and identify new therapeutic approaches... “

Dr. Michaela Reichmann, University of Southampton

In a second study, a clinical trial led by Dr. Catherine Ong of the National University of Singapore examined the use of the common antibiotic doxycycline to reverse these changes. Phase 2 Double-blind study In 30 patients, doxycycline has been shown to reduce lung cavity size and accelerate markers of lung recovery to health in combination with tuberculosis medication. These bioinformatics analyzes were performed by the Southampton Systems Immunology Group.

The treatment proved to be safe and had side effects similar to those experienced by patients taking placebopills. This study shows that it is promising to provide new standard therapies that may prevent long-term complications.

“Patients with pulmonary tuberculosis tend to suffer from lung damage after tuberculosis, which is associated with reduced mortality and quality of life. Doxycycline reduces lung damage and reduces these quality of life. A cheap and widely available antibiotic that has the potential to improve. Patients. “

The team is currently seeking funding for a full-power, large-scale Phase 3 trial to validate these findings.

The international team also aims to translate these new insights into approaches that could shorten treatment from the current minimum of 6 months and improve treatment of the gradual increase in drug-resistant diseases. ..

The clinical trials were based on a joint network involving the National University of Singapore, the University of Southampton, and St. George’s London, and basic scientific research also involved the African Institute of Health, Durban, Yale University, and Columbia University in the United States.

Source:

Journal reference:

Reichmann, MT, et al.. (2021) Integrated transcriptomics analysis and biomimetic models of human tuberculosis granulomas identify therapeutic targets. Clinical Research Journal.. doi.org/10.1172/JCI148136..

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