A multi-omics investigation into the mechanisms of hyper-virulence in Mycobacterium tuberculosis
Rahim Rajwani,
Chala Galata,
Annie Wing Tung Lee,
Pui-Kin So,
Kenneth Siu Sing Leung,
Kingsley King Gee Tam,
Sheeba Shehzad,
Timothy Ting Leung Ng,
Li Zhu,
Hiu Yin Lao,
Chloe Toi-Mei Chan,
Jake Siu-Lun Leung,
Lam-Kwong Lee,
Kin Chung Wong,
Wing Cheong Yam,
Gilman Kit-Hang Siu
Affiliations
Rahim Rajwani
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, Hong Kong, China
Chala Galata
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, Hong Kong, China
Annie Wing Tung Lee
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, Hong Kong, China
Pui-Kin So
University Research Facility in Life Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, China
Kenneth Siu Sing Leung
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
Kingsley King Gee Tam
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
Sheeba Shehzad
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, Hong Kong, China
Timothy Ting Leung Ng
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, Hong Kong, China
Li Zhu
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, Hong Kong, China
Hiu Yin Lao
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, Hong Kong, China
Chloe Toi-Mei Chan
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, Hong Kong, China
Jake Siu-Lun Leung
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, Hong Kong, China
Lam-Kwong Lee
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, Hong Kong, China
Kin Chung Wong
Department of Clinical Pathology, United Christian Hospital, Hong Kong Special Administrative Region, China
Wing Cheong Yam
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
Gilman Kit-Hang Siu
Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, Hong Kong, China
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 (IS6110-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.
