Grant: CIHR Fellowship

It has been recently shown that memory capacity of immune response is not limited to only adaptive immunity as innate immune cells present memory-like capacity termed "trained immunity". However, many aspects of this new paradigm in immunity as well as its relevance for vaccine design remain to be determined. One of the major limitation of exploring the concept of trained immunity in vaccines was how we achieve a long lasting memory in innate immune cells, which have hours to days life span. We have recently demonstrated that Bacillus Calmette Guerin (BCG), the only available vaccine against tuberculosis is able to educate the hematopoietic stem cells (HSC) in the bone marrow (BM) to generate long-term protective innate immune memory responses. However, the key regulatory mechanisms that coordinate HSC self-renewal, proliferation and differentiation in this context as well as the mechanisms involved in durability of trained immunity have not been defined. In the current study, we aim to address these fundamental questions by comparing the impact of BCG on imprinting of HSCs to Mycobacterium tuberculosis (Mtb), which also get access into the bone marrow and reprograms HSCs. The current study is focused to dissect the mechanism acquired by BCG and Mtb in reprogramming of HSCs to generate trained immunity. However, we envision while BCG imprinting of HSCs generates a protective trained immunity, Mtb imprinting of HSCs leads to detrimental immunity. Thus identifying the cellular and molecular signatures of protective versus detrimental trained immunity will allow us to design an effective vaccines against tuberculosis and potentially many other infectious diseases.