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Tuberculosis (TB) is an ancient and complex human illness that we now know exists as a disease spectrum resulting from a dynamic interaction between the host immune system and the bacilli. Aside from COVID-19, TB is the leading cause of global morbidity and mortality from a single infectious disease agent. Mycobacterium tuberculosis (Mtb), the etiological agent of TB disease in humans, latently infects approximately one-fourth of the world’s population and kills approximately 1.5 million individuals a year.
Journal: Nature Communication
Issue: Nat Commun. 2022 Feb 15;13(1):878. doi: 10.1038/s41467-022-28509-z. PMID: 35169141
Title: Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer.
Authors: Singh AK, Praharaj M, Lombardo KA, Yoshida T, Matoso A, Baras AS, Zhao L, Srikrishna G, Huang J, Prasad P, Powell JD, Kates M, McConkey D, Pardoll DM, Bishai WR, Bivalacqua TJ.
In addition to its role as a TB vaccine, BCG has been shown to elicit heterologous protection against many other pathogens including viruses through a process termed trained immunity. Despite its potential as a broadly protective vaccine, little has been done to determine if BCG-mediated trained immunity levels can be optimized. Here we re-engineer BCG to express high levels of c-di-AMP, a PAMP recognized by stimulator of interferon genes (STING). We find that BCG overexpressing c-di-AMP elicits more potent signatures of trained immunity including higher pro-inflammatory cytokine responses, greater myeloid cell reprogramming toward inflammatory and activated states, and enhances epigenetic and metabolomic changes. In a model of bladder cancer, we also show that re-engineered BCG induces trained immunity and improved functionality. These results indicate that trained immunity levels and antitumor efficacy may be increased by modifying BCG to express higher levels of key PAMP molecules.