Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), kills up to 1.5 million people every year. Despite sustained scientific attention, there is no effective vaccine, multidrug-resistant Mtb strains are on the rise, and impoverished people with little access to long, expensive treatments continue to bear the brunt of disease. A critical barrier to the development of an effective TB vaccine is our incomplete understanding of what constitutes a protective immune response.
Accumulating evidence suggests a role for B cells and antibodies in preventing and alleviating TB. Existing studies show that some Mtb-specific antibodies found in blood may confer protection against infection. However, whether such protective antibodies exist at the site of infection and in what quantity remains unknown. The goal of this project is to characterise antibody responses in the lung mucosa of mycobacteria-infected mice and humans, and to assess their relationship to protection versus disease. First, I will identify the antigenic targets of antibodies isolated from lung and lymphoid organs of infected mice by proteomics. Then I will use tetramer-based enrichment and single cell RNA sequencing to investigate the dynamics, transcriptional regulation and B cell receptor repertoires of lung-resident, antigen-specific B cells – the source of lung mucosal antibodies. Finally, I will translate these findings from the mouse model to humans, using bronchoalveolar lavage fluid from a clinical study of TB patients with different grades of TB susceptibility. This approach will allow me to assess the existence of these mucosal antibodies in humans and to investigate their function and protective potential. Combining the mouse infection model with this unique TB patient cohort represents a unique opportunity to address the impact of humoral immunity in the lung mucosa, thus providing a sound basis for the development of mucosal airway vaccines against TB.
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