Cyclic di-AMP-mediated interaction between Mycobacterium tuberculosis ΔcnpB and macrophages implicates a novel strategy for improving BCG vaccination

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Abstract

Cyclic di-AMP (c-di-AMP) has been shown to play an important role in bacterial physiology and pathogen-host interactions. We previously reported that deletion of the sole c-di-AMP phosphodiesterase-encoding gene (cnpB) in Mycobacterium tuberculosis (Mtb) led to significant virulence attenuation. In this study, we found that ΔcnpB of M. bovisbacillus Calmette-Guerin (BCG) was unable to secrete c-di-AMP, which differs from Mtb ΔcnpB. We infected bone marrow-derived macrophages (BMDMs) with c-di-AMP-associated mutants generated from both Mtb and BCG. Our results showed that upon infection with Mtb ΔcnpB, BMDMs of wildtype mice secreted a large amount of interferon-β (IFN-β) post-infection similarly as we reported previously. In contrast, the response was less pronounced with BMDMs isolated from cGAS-/- mice and was nearly abolished with BMDMs prepared from STING-/- mice. Deletion of the region of difference 1 (RD1) locus in Mtb ΔcnpB did not alter the c-di-AMP secretion of ΔcnpB but eliminated the IFN-β production in the infected cells. In contrast, neither BCG ΔcnpB nor a recombinant BCG ΔcnpB with a pRD1 cosmid induced a type I interferon response. Interestingly, multiple studies have demonstrated that type I IFN enhances BCG's immunity. Thus, amending BCG based on our findings might improve BCG vaccination.

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Zhang, Y., Yang, J., & Bai, G. (2018). Cyclic di-AMP-mediated interaction between Mycobacterium tuberculosis ΔcnpB and macrophages implicates a novel strategy for improving BCG vaccination. Pathogens and Disease, 76(2). https://doi.org/10.1093/femspd/fty008

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