“It’s crucial to be able to distinguish between diseases with similar clinical manifestations like MAC disease and TB, in order to diagnose them correctly and provide relevant treatment. Winning a SPARK award would give me an opportunity to investigate this further and strengthen the potential to attract follow-on funding for this project.”
The fight against Mycobacteria
FUNDED: JANUARY 2020
FUNDED BY: the generosity of 2019-20 Various Donors
Lady Windermere is not only famous as the lead character in a play by Oscar Wilde, but also for lending her name to a syndrome, Lady Windermere syndrome, which is an infection of the lung caused by mycobacterium avium complex (MAC). MAC is closely related to mycobacterium tuberculosis, which causes TB. MAC is ubiquitous and commonly found in dust, dirt, shower-heads and faucets. The typical patient with Lady Windermere syndrome is usually a thin, lean elderly woman, who, just like the character in the play, is very well-mannered. So well-mannered that she voluntarily suppresses her cough out of politeness, which predisposes her to lung infection caused by MAC.
MAC disease, unlike its cousin tuberculosis, is not contagious, but the disease itself can be quite serious. Although symptoms can be similar to tuberculosis, the required treatment is different. Diagnosis of MAC disease often takes months and treatment usually entails three different antibiotics over the course of one to two years, often leading to many side effects and complications. Anything less and there is an increased risk of the infection coming back. Therefore, it is crucial to be able to reliably distinguish between TB and MAC disease. An improved understanding of MAC disease could enhance and facilitate diagnoses, decrease invasive interventions in clinical care, and decrease costs.
In a recent study, we have found that the immune response in MAC disease patients is different from tuberculosis-infected individuals based on classical immunological measurements. My goal for the SPARK project is to thoroughly define the immune response against MAC through the detection of MAC-specific immune signatures using next generation sequencing techniques, and compare them to uninfected healthy controls, as well as previously characterized TB-infected individuals. This will provide an increased understanding of the immune response involved against MAC infection and reveal differences between tuberculosis and MAC disease. Ultimately, this project will define targets that can be used for improved diagnosis.
Six-Month Project Update
To understand the immune response involved against infection with M. avium (MAC) and reveal differences between tuberculosis and MAC disease I have started an in-depth study of responses in individuals that were previously infected with MAC along uninfected controls. This includes determining the frequencies of major cell subsets in blood, measuring the immune response that is specific for mycobacteria and identifying the immune signatures that are triggered by the infection. Interestingly, I’ve found that MAC infected individuals have very low frequencies of a particular T cell subset as compared to uninfected controls. I’ve previously described this cell subset as being involved in immunity against mycobacteria and playing an important role in controlling the infection. The cell subset composition is also reflected in the specific gene signatures that I’ve observed when comparing the different patient cohorts. Lack of this specific T cell can help explain the differences in immune response between the cohorts. Currently, I am trying to find gene signatures that are specific for each cohort and stimulation. This will allow me to determine whether I can find immune markers and responses that further explain the differences between the cohorts and could lead to improved diagnosis.