Abstract
LytR-cpsA-Psr (LCP) domain containing proteins fulfil important functions in bacterial cell wall synthesis. In Mycobacterium tuberculosis complex (Mtbc) strains, the causative agents of tuberculosis (TB), the genes Rv3484 and Rv3267 encode for LCP proteins which are putatively involved in arabinogalactan transfer to peptidoglycan. To evaluate the significance of Rv3484 for Mtbc virulence, we generated a deletion mutant in the Mtbc strain H37Rv and studied its survival in mice upon aerosol infection. The deletion mutant failed to establish infection demonstrating that Rv3484 is essential for growth in mice. Following an initial phase of marginal replication in the lungs until day 21, the Rv3484 deletion mutant was almost eliminated by day 180 post-infectionem. Interestingly, the mutant also showed higher levels of resistance to meropenem/clavulanate and lysozyme, both targeting peptidoglycan structure. We conclude that Rv3484 is essential for Mtbc virulence in vivo where its loss of function cannot be compensated by Rv3267.
Highlights
Tuberculosis (TB) is, in conjunction with HIV infection, the leading cause of mortality and morbidity due to a single infectious agent worldwide[1]
Based on the previously defined core transcriptome of 17 Mycobacterium tuberculosis complex (Mtbc) strains responding to intracellular conditions in murine bone marrow derived macrophages[4], we selected Rv3484, which contains besides the LytR-cpsA-psr (E-value 3.49e-51) (LCP) domain conserved Csp2a (E-value 1.48e-75), PRK09379 (E-value 2.30e-16) and LytR_C (E-value 3.44e-11) domains as detected by NCBI CDD search[5]
The cell wall core of mycobacteria and corynebacteria consists of PGN, which is covalently bound to arabinogalactan (AG) and mycolic acids
Summary
Tuberculosis (TB) is, in conjunction with HIV infection, the leading cause of mortality and morbidity due to a single infectious agent worldwide[1]. Based on the previously defined core transcriptome of 17 Mtbc strains responding to intracellular conditions in murine bone marrow derived macrophages (mBMDM)[4], we selected Rv3484, which contains besides the LytR-cpsA-psr (E-value 3.49e-51) (LCP) domain conserved Csp2a (E-value 1.48e-75), PRK09379 (E-value 2.30e-16) and LytR_C (E-value 3.44e-11) domains as detected by NCBI CDD search[5] Proteins containing these domains have been associated with bacterial cell wall metabolism and regulatory functions even though the exact mechanism remained elusive[6,7,8,9,10,11,12,13]. Our findings show that inactivation of Rv3484 alone is sufficient to abolish long term growth of Mtb upon aerosol infection in C57BL/6 mice
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