A pioneering study by UCL scientists has discovered the presence
of a harmful inflammatory protein in patients with symptomatic
tuberculosis (TB).
Researchers say, by targeting the IL-17 cytokine, a component
produced naturally by the immune system in response to infection,
excessive and damaging lung inflammation caused by TB may be
significantly reduced to help speed up patient recovery.
TB is an infection caused by the bacterium Mycobacterium
tuberculosis and is the leading cause of death from
infections worldwide. The World Health Organisation estimates
that 1.4 million people died of TB disease worldwide in 2019.
Explaining the experimental study, lead author Dr Gabriele
Pollara (UCL Division of Infection & Immunity), said: “For
most people the body’s immune response to TB is a vital defence
strategy to contain the infection, but when disease develops it
can worsen symptoms, cause lung damage, and promote transmission
of the infection to others.
“For some time, we have thought that the body’s own immune
response to TB could in fact be causing more tissue damage and
promoting the spread of infection – but we did not know how this
happens.
“In this study, we found that in patients with active TB, the
immune system may be responding pathologically (causing harm),
and that this immune response was not present in those with
latent TB, who have controlled the infection.”
As part of the study, published in Science Translational
Medicine, medical centres in the UK, South Africa and Peru
recruited patients to take a tuberculin skin test (TST), which
involves injecting a small amount of fluid (called tuberculin)
into the skin on the lower part of the arm. Raised skin or
swelling, detected 48 hours later, denotes a positive test.
Subsequent tests confirmed 48 of the people recruited had
symptomatic TB and 191 people had asymptomatic/latent TB.
Genome-wide transcriptional profiling of biopsies of the TSTs was
then carried out to make detailed measurements of the immune
response.
Researchers discovered that samples from patients with
symptomatic TB disease showed increased activity of IL-17
cytokine, which is an immune response known to cause tissue
damage in other inflammatory conditions.
Dr Pollara, an NIHR Clinical Lecturer, added: “This new research
has identified for the first time the nature of these potentially
harmful immune pathways. We show that a specific immune pathway,
the IL-17 cytokine, is present exclusively in the immune response
of patients with TB disease, but not those who never develop
symptoms.
“This is a fascinating finding because IL-17 cytokine responses
cause disease and tissue damage in other inflammatory conditions,
such as psoriasis and ankylosing spondylitis. In both conditions,
drugs that block the IL-17 pathway are highly effective at
improving patient symptoms, and so our findings indicate these
same drugs could also be beneficial in treating patients with TB
disease.”
For over 50 years, the mainstay of treatment for tuberculosis has
been antibiotics that kill bacteria. Although effective, this
strategy carries a lot of challenges; treatment involves taking
four antibiotics and lasts for at least six months, and its
efficacy is being increasingly challenged by rising rates of
antibiotic resistance. Therefore, developing new approaches to
treating TB disease is an urgent global research priority.
Senior author, Professor Mahdad Noursadeghi (UCL Division of
Infection & Immunity) said: “Our work has the potential to
make a step change in care of TB patients, providing a rationale
for targeting specific immune components, alongside the
conventional use of antibiotics.
“We anticipate this would accelerate clinical recovery, interrupt
transmission between individuals and reduce the time antibiotic
treatment is required. More broadly, these findings open the door
to an exciting new frontier in treating infectious diseases.
“By understanding immune responses to infections that are
detrimental, it justifies the use of focused ‘host-directed’
drugs that complement the action of antibiotics. In turn this
strategy has the potential to limit disease severity, shorten
antibiotic courses, and therefore mitigate against the rise in
antibiotic resistance worldwide.”
Next steps
Researchers aim to devise a clinical trial to test whether drugs
targeting IL-17 cytokine in patients with symptomatic TB reduce
symptoms and improve patient outcomes.
This work was supported by grants from the Wellcome Trust,
Medical Research Council, Academy of Medical Sciences and NIHR
Biomedical Research Centre at University College London
Hospitals.
Notes to Editors
Research paper: Gabriele Pollara, Carolin Turner, Joshua
Rosenheim, Aneesh Chandran, Lucy Bell, Ayesha Khan, Amit Patel,
Luis Felipe Peralta, Anna Folino, Ayse Akarca, Cristina
Venturini, Tina Baker, Simone Ecker, Fabio Ricciardolo, Teresa
Marafioti, Cesar Ugarte-Gil, David Moore, Benjamin Chain, Gillian
Tomlinson and Mahdad Noursadeghi, ‘Exaggerated IL-17A activity in
human in vivo recall responses discriminates active tuberculosis
from latent infection and cured disease’, was published in
Science Translational Medicine on Thursday 5 May, 2021.
The DOI is: 10.1126/scitranslmed.abg7673.
