Mycobacterial Cell Envelope

One of the main characteristics of M. tuberculosis cell envelope is its complex, thick cell envelope. M. tuberculosis has the ability to adapt quickly its cell envelope depending on its surrounding environment. Our laboratory has special interest in understanding genomic and transcriptomic changes that M. tuberculosis experiences during the infection process, the timing and external factors that drive these changes, and if these can be used as targets to develop new treatments and diagnostic tools. With our collaborators, we are especially interested in the biosynthesis of the mannosylated-cell envelope components of M. tuberculosis, which genes are participating in their biosynthesis and transport along the cell envelope during infection, and how these specifically contribute to the latency stage of the M. tuberculosis bacterium.

Representative Papers

  • Garcia-Vilanova, Andreu, John Chan, and Jordi B Torrelles. (2019) 2019. “Underestimated Manipulative Roles of Mycobacterium Tuberculosis Cell Envelope Glycolipids During Infection”. Frontiers in Immunology 10: 2909.

    The Mycobacterium tuberculosis cell envelope has been evolving over time to make the bacterium transmissible and adaptable to the human host. In this context, the M. tuberculosis cell envelope contains a peripheral barrier full of lipids, some of them unique, which confer M. tuberculosis with a unique shield against the different host environments that the bacterium will encounter at the different stages of infection. This lipid barrier is mainly composed of glycolipids that can be characterized by three different subsets: trehalose-containing, mannose-containing, and 6-deoxy-pyranose-containing glycolipids. In this review, we explore the roles of these cell envelope glycolipids in M. tuberculosis virulence and pathogenesis, drug resistance, and further, how these glycolipids may dictate the M. tuberculosis cell envelope evolution from ancient to modern strains. Finally, we address how these M. tuberculosis cell envelope glycolipids are impacted by the host lung alveolar environment, their role in vaccination and masking host immunity, and subsequently the impact of these glycolipids in shaping how M. tuberculosis interacts with host cells, manipulating their immune response to favor the establishment of an infection.

  • Scordo, Julia M, Jesús Arcos, Holden Kelley V, Lauren Diangelo, Smitha J Sasindran, Ellie Youngmin, Mark D Wewers, Shu-Hua Wang, Joan-Miquel Balada-Llasat, and Jordi B Torrelles. (2017) 2017. “Mycobacterium Tuberculosis Cell Wall Fragments Released Upon Bacterial Contact With the Human Lung Mucosa Alter the Neutrophil Response to Infection”. Frontiers in Immunology 8: 307.

    In 2016, the World Health Organization reported that one person dies of tuberculosis (TB) every 21 s. A host environment that Mycobacterium tuberculosis (M.tb) finds during its route of infection is the lung mucosa bathing the alveolar space located in the deepest regions of the lungs. We published that human lung mucosa, or alveolar lining fluid (ALF), contains an array of hydrolytic enzymes that can significantly alter the M.tb surface during infection by cleaving off parts of its cell wall. This interaction results in two different outcomes: modifications on the M.tb cell wall surface and release of M.tb cell wall fragments into the environment. Typically, one of the first host immune cells at the site of M.tb infection is the neutrophil. Neutrophils can mount an extracellular and intracellular innate immune response to M.tb during infection. We hypothesized that exposure of neutrophils to ALF-induced M.tb released cell wall fragments would prime neutrophils to control M.tb infection better. Our results show that ALF fragments activate neutrophils leading to an increased production of inflammatory cytokines and oxidative radicals. However, neutrophil exposure to these fragments reduces production of chemoattractants (i.e., interleukin-8), and degranulation, with the subsequent reduction of myeloperoxidase release, and does not induce cytotoxicity. Unexpectedly, these ALF fragment-derived modulations in neutrophil activity do not further, either positively or negatively, contribute to the intracellular control of M.tb growth during infection. However, secreted products from neutrophils primed with ALF fragments are capable of regulating the activity of resting macrophages. These results indicate that ALF-induced M.tb fragments could further contribute to the control of M.tb growth and local killing by resident neutrophils by switching on the total oxidative response and limiting migration of neutrophils to the infection site.

  • Arcos, J, S J Sasindran, J I Moliva, J M Scordo, S Sidiki, H Guo, P Venigalla, et al. (2017) 2017. “Mycobacterium Tuberculosis Cell Wall Released Fragments by the Action of the Human Lung Mucosa Modulate Macrophages to Control Infection in an IL-10-Dependent Manner”. Mucosal Immunology 10 (5): 1248-58.

    Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis, is a major public health challenge facing the world. During infection, M.tb is deposited in the lung alveolar space where it comes in contact with the lung mucosa, known as alveolar lining fluid (ALF), an environment that M.tb encounters at different stages of the infection and disease. ALF is abundant in homeostatic and antimicrobial hydrolytic enzymes, also known as hydrolases. Here we demonstrate that ALF hydrolases, at their physiological concentrations and upon contact with M.tb, release M.tb cell envelope fragments into the milieu. These released fragments are bioactive, but non-cytotoxic, regulate the function of macrophages, and thus are capable of modulating the immune response contributing to the control of M.tb infection by human macrophages. Specifically, macrophages exposed to fragments derived from the exposure of M.tb to ALF were able to control the infection primarily by increasing phagosome-lysosome fusion and acidification events. This enhanced control was found to be dependent on fragment-induced interleukin-10 (IL-10) production but also involves the STAT3 signaling pathway in an IL-10-independent manner. Collectively our data indicate that M.tb fragments released upon contact with lung mucosa hydrolases participate in the host immune response to M.tb infection through innate immune modulation.

  • Yang, Lanhao, Tejas Sinha, Tracy K Carlson, Tracy L Keiser, Jordi B Torrelles, and Larry S Schlesinger. (2013) 2013. “Changes in the Major Cell Envelope Components of Mycobacterium Tuberculosis During in Vitro Growth”. Glycobiology 23 (8): 926-34.

    One-third of the world's population is infected with Mycobacterium tuberculosis (M.tb), which causes tuberculosis. Mycobacterium tuberculosis cell envelope components such as glycolipids, lipoglycans and polysaccharides play important roles in bacteria-host cell interactions that dictate the host immune response. However, little is known about the changes in the amounts and types of these cell envelope components as the bacillus divides during in vitro culture. To shed light on these phenomena, we examined growth-dependent changes over time in major cell envelope components of virulent M.tb by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, thin-layer chromatography, mass spectrometry, immunoblotting and flow cytometry. Our studies provide evidence that major mannosylated glycoconjugates on the M.tb cell envelope change as M.tb grows in vitro on the widely used Middlebrook 7H11 agar. In particular, our compositional analyses show that from Day 9 to 28 the amounts of mannose-containing molecules, such as mannose-capped lipoarabinomannan, lipomannan and phosphatidyl-myo-inositol mannosides, change continuously in both the cell envelope and outer cell surface. Along with these changes, mannan levels on the outer cell surface also increase significantly over time. The implications of these differences in terms of how M.tb is grown for studies performed in vitro and in vivo for assessing M.tb-host recognition and establishment of infection are discussed.