In the paper titled “The conical shape of DIM lipids promotes Mycobacterium tuberculosis infection of macrophages” in PNAS, Augenstreich et al. (1) report on molecular mechanisms underlying the virulence of Mycobacterium tuberculosis bacteria (Mtb) expressing phthiocerol dimycocerosate (DIM), a well-known constituent in the cell wall of Mtb (2⇓–4).

A critical step of tuberculosis (TB) infection is uptake of the foreign Mtb into macrophages, in particular, the macrophages of lung tissue where Mtb may survive for extended periods of time (5⇓–7). Macrophages recognize bacteria by their surface proteins and glycolipids. Attachment of Mtb to the surface is followed by entry via endocytosis and formation of a phagosome, a liposome inside the macrophage containing the extrinsic bacterium (8). Rates of uptake by endocytosis are limited by rates of fusion events at the plasma membrane of macrophages. Augenstreich et al. (1) report how DIM facilitates membrane fusion, thereby easing uptake of Mtb into phagosomes where the bacteria are protected.

Membrane fusion is directed by proteins but enabled by properties of the lipid matrix into which proteins are imbedded. It is well established that 2 properties of lipid monolayers are critical for high rates of membrane fusion: 1) a high content of lipids with a relatively small headgroup compared to the volume of hydrocarbon chains (conical shape) that lower packing strain in highly curved membrane regions and 2) lower strain from hydrophobic interstices in hemifusion structures that form during fusion events (9⇓–11) (Fig. 1).

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Fig. 1.

Schematic presentation of endocytotic uptake of Mtb into a macrophage. Insert shows a hemifusion structure of the macrophage plasma membrane shortly before release of the phagosome containing Mtb into the lumen of the macrophage. Packing stress from high curvature of lipid monolayers and lipid packing interstices during hemifusion is reduced by lipids with conical shape like DIM.

DIM is a cell wall-associated class of lipids found only in pathogenic mycobacteria (3, 12). It is a rather hydrophobic molecule composed of long-chain β-diols esterified by multimethyl-branched mycocerosic acids (2). The laboratories of Astarie-Dequeker and Milon (1) report that DIM is transferred from the cell wall of Mtb to the plasma membrane of macrophages. Using molecular simulations, they determined that the highly flexible DIM locates in the hydrophobic core of membranes with a tendency of DIM ester bonds to approach the lipid−water interface. This gives DIM an effective conical shape that spreads hydrocarbon chains near their terminal methyl ends while leaving the lipid−water interface of membranes mostly unaltered. It is the classical recipe for generating elastic curvature stress in the monolayers of a lipid bilayer, an asymmetric lateral pressure which is released in highly curved membrane regions (Fig. 1). Such release is taking place during fusion events inherent to endocytosis (9⇓–11), but also upon formation of nonlamellar lipid phases such as the inverse hexagonal phase H_II (9). Formation of the H_II phase is a well-established litmus test for presence of curvature stress in membranes. Indeed, relatively low concentrations of DIM in membranes lower the temperature of the lamellar (L_α)–H_II phase transition, indicating that DIM has a conical shape and is very powerful in reducing packing stress (1).

The effective conical shape of DIM eases Mtb entry into macrophages by endocytosis. It results in formation of a phagosome, a particle inside macrophages that encloses Mtb with a membrane composed of lipids from the macrophage as well as components from the cell wall of Mtb. There is evidence that Mtb survives for extended periods of time inside phagosomes and may travel with the macrophages to other tissues, manifesting the TB infection in various locations throughout the body (6, 8). While enhancement of Mtb entry into macrophages might not be the sole mechanism of DIM action, it is certainly a critical step in the sequence of events during infection with Mtb. Development of drugs that target expression of DIM and its transport to the cell wall of Mtb could be an important strategy to fight drug-resistant TB.