The Sigma factor SigE's role in mycobacterial granulomas

Abstract: Infections caused by Mycobacterium tuberculosis (Mtb) have historically been the leading cause of death from a single infectious agent and still result in 1.5 million deaths annually. One of the hallmark characteristics of the disease is an aggregate of immune cells called the granuloma, where macrophages develop epithelioid character, expressing epithelial cadherin (E-cadherin) and other canonical markers of epithelial cells. This structure restrains the bacteria within but is unable to eradicate the infection despite exposing the pathogen to pH changes, hypoxia, and antimicrobial peptides. The unique, lipid-rich cell envelope of mycobacteria protects them from these stressors while simultaneously modulating the host immune response. Thus, targeting bacterial cell envelope components that are specific to the granuloma is a potential avenue for future drugs and therapeutics. Using the zebrafish-Mycobacterium marinum (Mm) model to recapitulate key aspects of TB disease, the proposed aims will uncover novel bacterial elements with importance in mycobacterial granulomas. I will explore how specific cell envelope components impact both mycobacterial survival and host dynamics in mycobacterial granulomas. I will assess how the bacteria sigma factor SigE (σE) impacts survival within the granuloma through cell envelope-mediated interactions with the host immune response. We have identified SigE as a potential modulator of bacterial survival in the granuloma, which will help better understand the host-pathogen interactions that occur in the granuloma. In addition, the knowledge of bacterial factors that allow mycobacterial persistence in granulomas can unveil potential drug targets and therapies to treat tuberculosis.