A multi-omics investigation into the mechanisms of hyper-virulence in Mycobacterium tuberculosis

Abstract

Clinical manifestations of tuberculosis range from asymptomatic infection to a life-threatening disease such as tuberculous meningitis (TBM). Recent studies showed that the spectrum of disease severity could be related to genetic diversity among clinical strains of Mycobacterium tuberculosis (Mtb). Certain strains are reported to preferentially invade the central nervous system, thus earning the label “hypervirulent strains”.However, specific genetic mutations that accounted for enhanced mycobacterial virulence are still unknown. We previously identified a set of 17 mutations in a hypervirulent Mtb strain that was from TBM patient and exhibited significantly better intracellular survivability. These mutations were also commonly shared by a cluster of globally circulating hyper-virulent strains. Here, we aimed to validate the impact of these hypervirulent-specific mutations on the dysregulation of gene networks associated with virulence in Mtb via multi-omic analysis. We surveyed transcriptomic and proteomic differences between the hyper-virulent and low-virulent strains using RNA-sequencing and label-free quantitative LC-MS/MS approach, respectively. We identified 25 genes consistently differentially expressed between the strains at both transcript and protein level, regardless the strains were growing in a nutrient-rich or a physiologically relevant multi-stress condition (acidic pH, limited nutrients, nitrosative stress, and hypoxia). Based on integrated genomic-transcriptomic and proteomic comparisons, the hypervirulent-specific mutations in FadE5 (g. 295,746 C >T), Rv0178 (p. asp150glu), higB (p. asp30glu), and pip (IS 6110 -insertion) were linked to deregulated expression of the respective genes and their functionally downstream regulons. The result validated the connections between mutations, gene expression, and mycobacterial pathogenicity, and identified new possible virulence-associated pathways in Mtb .

The profile of genome-wide DNA methylation, transcriptome, and proteome in streptomycin-resistant Mycobacterium tuberculosis

“…FadE5 is an acyl-coenzyme A dehydrogenase, which introduces unsaturation to carbon chains in lipid metabolism pathways and is involved in cell wall biosynthesis [56,57]. The expression of fadE5 was altered under different antibiotic resistance and virulence [58,59]. Furthermore, fadE5 overexpression increased drug resistance to ethambutol and streptomycin in M. smegmatis [56].…”

The Defense of Shangri-La: A Thought Experiment of Periodic Community-wide Screening in the Future Pandemic

“…Smallpox (Hochman and Souza, 2022), tuberculosis (Rajwani et al, 2022), monkeypox (Bunge et al, 2022), and the sudden emergence of COVID-19(Coronavirus Disease 2019) (Mohamadian et al, 2021) in 2019 all posed great threats to the economy and life of our society because of their significant mortality and infectivity.…”

“…In 1997, the book “Guns, Germs and Steel: The Fate of Human Society” introduced the influences of pathogens in the development of human beings, and clarified that the emergence of epidemics was closely related to the development of human agriculture, domestication of animals, and population density(Diamond, 1999). Smallpox(Hochman and Souza, 2022), tuberculosis(Rajwani et al, 2022), monkeypox(Bunge et al, 2022), and the sudden emergence of COVID-19(Coronavirus Disease 2019)(Mohamadian et al, 2021) in 2019 all posed great threats to the economy and life of our society because of their significant mortality and infectivity.…”