Targeting Mycobacterium tuberculosis Key Genes to Potentiate BCG-Induced Trained Immunity

Mohlopheni Marakalala of the Africa Health Research Institute in South Africa and Eric Rubin of the Harvard TH Chan School of Public Health in the U.S. will use a genetic screening tool, Tn-seq, to identify the specific bacterial genes protecting Mycobacterium tuberculosis (MTB) from immune destruction that could be used to develop new therapeutic approaches to fight tuberculosis, which causes over 1.5 million deaths annually. BCG is the only approved tuberculosis vaccine, but its effect is limited, particularly in adults. This may be because BCG induces a memory-like innate immune response mediated by macrophages, so-called ‘trained immunity’, which the bacterium somehow evades. To find out how, they will use transposon-mediated mutagenesis to mutate every non-essential gene in MTB and use these mutant strains to infect BCG-trained monocytes isolated from vaccinated humans. The genes that enable MTB to survive under these conditions will then be identified by whole genome sequencing and validated using genetic and chemical approaches. This could ultimately lead to the development of targeted drugs to support BCG vaccinations.