Study finds a ‘balanced’ immune response in the lungs is key to protection from developing Tuberculosis

Tuberculosis (TB), a bacterial infection often thought to be a relic of the Victorian era, is on the rise in the UK and across the world.

Like many other infectious diseases, the TB bacteria are transmitted from one person to another by coughing.

An early view of the immune responses in the lungs of people that have recently been exposed to TB has provided clues to why some people keep the infection in check, while others develop disease, suggesting new ways to intervene earlier and stop it.

In a ground-breaking study, published recently in the journal Nature Immunology the NIHR BRC Leicester and Francis Crick Institute collaboration used bronchoscopy to collect fluid from the lower airways of people living in the same household as someone with TB.

Analysis of samples of the fluid suggests that the balance of inflammatory neutrophils and T cells in the airways may be a key determinant of whether an infected individual progresses to TB or remains healthy.

Dr Pranabashis Haldar, Clinical Senior Lecturer in the Department of Respiratory Sciences at the University of Leicester, Principal Investigator at the NIHR BRC Leicester and co-senior author, explains: “Most people that develop TB have had the infection in their body for quite a while. Usually, the body’s immune response is very good at controlling the infection. TB disease happens when this control is lost. 

“A quarter of the global population is estimated to have been infected with the bacteria that cause TB. That is a huge potential reservoir of future TB. We estimate that about 5% of those infected will develop TB. Although this seems like a small fraction, it is enough to keep the worldwide epidemic going. 

“For a number of years we have been working with Professor O’Garra, a world-leading immunologist with an interest in TB at the Francis Crick Institute, to investigate what distinguishes people whose immune systems control the TB infection from those whose don’t.

“Her seminal study in 2010 found a previously unexpected immune signature in the blood of people with active TB: showing that active disease was not simply marked by a weak immune response, but by a particular kind of inflammatory response.

“We know the infection takes hold in the lungs but until now little has been known of how the immune response reacts at the site of infection.”

To see what was happening in the lung itself and gain an early snapshot of the body’s response to infection, researchers at the NIHR BRC Leicester and Francis Crick Institute collaborated to analyse bronchoalveolar lavage (BAL) samples - fluid collected from the lower airways - from recent household contacts of people with pulmonary TB. 

“A critical challenge faced in studies of human TB infection is that although we have tests that can tell us whether someone has had the infection, they cannot tell us whether they still have the infection. Without knowing this, conclusions drawn from the information we were getting from the airway fluid, would have been speculative,” added Dr Haldar.

To tackle this problem, the team used PET-CT, a highly sensitive form of scanning which can detect increased activity of the immune system at sites of TB infection.

Joint first author, Dr Jee Whang Kim, Academic Clinical Lecturer in Respiratory Sciences at the University of Leicester, added: “We began using PET-CT as a clinical tool for some contacts of drug-resistant TB almost a decade ago and found clear differences that seemed to distinguish between people with and without immune activity in their lungs, after being exposed to TB. 

“These observations stimulated us to conduct research studies of TB infection using PET-CT which have consistently shown an association between immune activity and presence of the TB bacteria.”  

Dr Haldar continued: “This was an ambitious clinical study in which participants who were otherwise completely well consented to bronchoscopy and PET-CT at least twice and were followed up for two years.”

A study of this type has never previously been undertaken in the UK and is the largest study ever performed using bronchoscopy to sample the airways of people that are TB contacts. Over the course of the study, more than 200 bronchoscopy samples were collected from participants at different time points and at different stages of infection.

These samples were analysed by Postdoctoral Fellow in Lung Immunology at the Francis Crick Institute, Will Branchett, who used a variety of methods to build a detailed picture of which immune cells were present and what those cells were doing. 

What he and the team found were two very different immune responses to infection.

They observed that in people who developed active TB, the airways were dominated by immune cells called neutrophils. When they tracked which genes were active in the neutrophils, they found that a set of genes linked to type I interferon signalling were switched on and the neutrophils appeared to make high levels of CXCL8, a molecule that can bring more neutrophils into the lung, revealing potential for a vicious cycle of inflammation to develop.

The team then examined this early response to disease in more detail and found that T-cells in the lungs of patients with high numbers of neutrophils appeared to be under strain, preventing them from controlling the infection.

“We saw evidence of exhaustion and cell death in the T cells,” explains Will.

“They look like they’ve been pushed too hard.”

The balance was markedly different in people who controlled the infection.

“There, the T cells weren’t highly activated, but they weren’t exhausted either,” adds Will.

“Instead, these cells expressed genes linked to regulation and a more ‘stem-like’ state, suggesting they can persist and respond over a longer period and thus remain ready to fight the infection.”

Together, the results suggest that the balance of inflammatory neutrophils and T cells in the airways may be a key determinant of whether an infected individual progresses to TB or remains healthy.

“It’s about getting the balance right,” concluded Will.

“The immune system must control the bacterial infection without causing excessive inflammation and damage to the lungs. And that balance likely determines who stays well.”

The team’s work points towards a way to address a critical gap in TB control.  

“If we can find a way to identify these immune signatures early in people who have been infected, we might be able to predict who is at risk.” explains Dr Anne O'Garra from the Francis Crick Institute.

“More targeted interventions might look like vaccines designed to steer the immune system towards a stem-like and durable state, or therapies that dampen harmful inflammation to favour protective T cell responses and control infection.”

Dr Haldar added: “I am enormously proud of the TB research team at Leicester. Through their skill and dedication we have been able to deliver in humans the sort of study that has previously only been possible in animal models. The data gathered from all the samples we have collected and analysed will be an invaluable resource to the Scientific Community as studies like this are few and far between.”

The NIHR BRC Leicester is part of the National Institute for Health and Care Research and is hosted by the University Hospitals of Leicester NHS Trust, in partnership with the University of Leicester, Loughborough University and University Hospitals of Northamptonshire NHS Group. 

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