Defining the genes required for survival of Mycobacterium bovis in the bovine host offers novel insights into the genetic basis of survival of pathogenic mycobacteria

Gibson, Amanda J; Stiens, Jennifer; Passmore, Ian J; Faulkner, Valwynne; Miculob, Josephous; Willcocks, Sam; Coad, Michael; Berg, Stefan; Werling, Dirk; Wren, Brendan W; Nobeli, Irene; Villarreal-Ramos, Bernardo; Kendall, Sharon L

Abstract

Tuberculosis has severe impacts in both humans and animals. Understanding the genetic basis of survival of both Mycobacterium tuberculosis, the human adapted species, and Mycobacterium bovis, the animal adapted species is crucial to deciphering the biology of both pathogens. There are several studies that identify the genes required for survival of M. tuberculosis in vivo using mouse models, however, there are currently no studies probing the genetic basis of survival of M. bovis in vivo. In this study we utilise transposon insertion sequencing in M. bovis to determine the genes required for survival in cattle. We identify genes encoding established mycobacterial virulence functions such as the ESX-1 secretion system, PDIM synthesis, mycobactin synthesis and cholesterol catabolism that are required in vivo. We show that, as in M. tuberculosis, phoPR is required by M. bovis in vivo despite the known defect in signalling through this system. Comparison to studies performed in glycerol adapted species such as M. bovis BCG and M. tuberculosis suggests that there are differences in the requirement for genes involved in cholesterol import (mce4 operon), oxidation (hsd) and detoxification (cyp125). We report good correlation with existing mycobacterial virulence functions, but also find several novel virulence factors, including genes involved in protein mannosylation, aspartate metabolism and glycerol-phosphate metabolism. These findings further extend our knowledge of the genetic basis of survival in vivo in bacteria that cause tuberculosis and provide insight for the development of novel diagnostics and therapeutics.

Citation

Gibson, A. J., Stiens, J., Passmore, I. J., Faulkner, V., Miculob, J., Willcocks, S., Coad, M., Berg, S., Werling, D., Wren, B. W., Nobeli, I., Villarreal-Ramos, B., & Kendall, S. L. (2022). Defining the genes required for survival of Mycobacterium bovis in the bovine host offers novel insights into the genetic basis of survival of pathogenic mycobacteria. mBio, https://doi.org/10.1128/mbio.00672-22

• Journal Article Type: Article
• Acceptance Date: Jun 22, 2022
• Publication Date: Jul 14, 2022
• Deposit Date: Apr 23, 2022
• Publicly Available Date: Jul 19, 2022
• Journal: mBio
• Electronic ISSN: 2150-7511
• Publisher: American Society for Microbiology
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1128/mbio.00672-22
• Additional Information: This is a pre-submission acceptance review. However - mistakenly I forgot to put through the worktribe system before submission. It has been put out on a preprint server https://www.biorxiv.org/content/10.1101/2022.03.15.484275v2.full