Michael S. Glickman: Lipid Pathogenesis Determinants of M. tuberculosis

The Mycobacterial Cell Envelope as Pathogenesis Effector

Enlarge Image The Cell Envelope of Mtb. A schematic view of the Mycobacterium tuberculosis cell envelope, depicting the chemical diversity of lipid and glycolipid molecules, including mycolic acids. (From Glickman and Jacobs. Cell. 2001;104:477-485.)

We are actively studying the relationship between M. tuberculosis pathogenesis and the chemical structure of the mycobacterial cell envelope.

The Mtb cell envelope differs substantially from the cell walls of gram-positive and gram-negative bacteria and contains many unique lipid and glycolipid molecules, including mycolic acids, Lipoarabinomannan, Trehalose Dimycolate, and Phthiocerol dimycocerosate. While the structures of many of these molecules have been defined in exquisite chemical detail, their role in pathogenesis has been unclear.

Enlarge Image Cyclopropane modification of mycolic acids Mycolic acids of virulent mycobacteria are modified with cyclopropane rings. Geneticd studies listed below the figure have determined that each ring (red) is synthesized by a distinct methyltransferases.

To understand the role of these unique chemical entities in pathogenesis, we and others have generated defined mutants of Mtb that lack specific compounds in the cell envelope. We have focused on a family of S-adenosyl Methionine dependent methyltransfersase of Mtb that modify mycolic acids with cyclopropyl groups. By studying null mutants in each methyltransferase, we have shown that site specific and stereochemically specific mycolic acid cyclopropanation has an important role in Mtb pathogenesis. In addition, we have recently demonstrated that cyclopropanation of mycolic acids on Trehalose Dimycolate acts directly to activate (cis cyclopropanation) or repress (trans-cyclopropanation) host innate immune activation. These results establish cyclopropane modification of TDM as a direct effector of pathogenesis. More generally, these result support the emerging view that the mycobacterial cell envelope is a complex array of lipid pathogenesis determinants rather than a waxy coat that serves a simple barrier function.

Enlarge Image Model of Mtb Lipids as Pathogenesis Effectors Transport of lipid effector molecules from Mtb to the host (B) is compared with the analogous system for protein effector molecules in gram-negative pathogens (A).

Future Goals:

Our immediate future experimental goals will address the following questions:

1. What is the pathogenetic importance and biochemical specificity of the full complement of cyclopropane synthases in M. tuberculosis.
2. How does M. tuberculosis regulate cyclopropane modification in response to host derived signals
3. What host cell molecules recognize cyclopropane modification of mycolic acids