WEHI Wednesday Seminar hosted by Associate Professor Chris Tonkin
 

Dr Anna Coussens

Laboratory Head, Infectious Disease & Immune Defence division – Infection, Inflammation & Immunity Theme, WEHI

Subclinical tuberculosis: redefining how we detect and prevent an ancient disease

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

Tuberculosis (TB) remains humanity’s leading single cause of global infectious mortality. However, most infected people develop natural immune protection, only 5-15% of those infected ever develop TB. Classically thought to occur following reactivation of latent infection, people present with TB years to decades after infection. The inability to eliminate TB is due to its immunological manifestations profoundly challenging our fundamental understanding of what constitutes and mediates protective immunity and disease risk. Conducting a longitudinal study of healthy people in contact with drug-resistant TB in South Africa, using 18FDG-positron emission and computerised axial tomographic scanning (PET/CT), we identified individuals with lung lesions indicative of subclinical TB at baseline were most at risk of TB diagnosis over 5 years of follow-up. Stratifying individuals according to subclinical lesion phenotypes identified distinct blood transcriptomic and DNA methylation signatures indicative of dysregulated myeloid inflammatory and programmed cell death pathways in those most at risk of future TB diagnosis, while those who had long-term protection from TB have distinct B and NK cell signalling.  Through in vitro infection of primary human macrophages and neutrophils using clinical strain variants of Mycobacterium tuberculosis utilising single cell imaging and transcriptomics we identified the molecular regulators of these pathways and the impact of therapeutic targeting on inflammatory cell death phenotypes associated with subclinical TB development.

We propose that therapeutics designed to correct immune dysfunction associated with subclinical TB development will have far greater ability, than antibiotics alone, to provide the greatest long-term cure from TB and stop onwards TB transmission.

All welcome!