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Multi-omics portrait of VirR protein function in cell wall remodeling and vesiculogenesis in Mycobacterium tuberculosis

J Bertol(1) V Salgueiro(2) A Palacios(3) L Lerma(2) S Alebougeh(2) L Sampedro(3) J L Lavin(4) F Elortza(3) M Azkalgorta(3) J Anguita(3) I Marchante(1) J Sanz(1) R Prados-Rosales(2)

1:University of Zaragoza; 2:Autonomous University of Madrid; 3:CIC bioGUNE; 4:Neiker - Basque Institute for agricultural research and development

VirR, a LytR_C domain containing protein, has been related to regulation of cell wall integrity and production of extracellular vesicles (EVs) in Mycobacterium tuberculosis. To test its regulatory role in vesiculogenesis, we obtained proteomic and transcriptomic profiles from a virR-KO mutant strain of M. tuberculosis, as well as from the wild-type strain H37Rv. The VirR-KO mutant presented an abnormal cell wall morphology linked to higher permeability, lower virulence and an increased production of EVs.
Transcriptomic analysis was performed on whole cell lysates from each strain revealing major differences concerning host-induced stress responses, as well as protein secretion, which partly explain the divergent secretory and virulent profiles of the wild-type and mutant strains. Furthermore, these analyses also revealed divergent expression levels for genes involved in post-transcriptional regulation, hinting at a role for VirR in these processes. To test this hypothesis, proteomic analyses were performed on whole cell lysates and isolated extracellular vesicles from each strain, revealing largely disjoint sets of differentially expressed proteins with respect to mRNAs, further pointing to a post-transcriptional regulatory role for VirR. Differential expression analysis of the proteins between the WT and the VirR mutant revealed greater differences in EVs than in whole cell lysates, indicating a primary role for VirR in the proteomic enrichment profile of EVs.

Taken together, our results highlight a relevant regulatory role for virR that leans both on transcriptional and post-transcriptional mechanisms, which significantly mediates the amount and function of EVs secreted by Mycobacterium tuberculosis.

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