Pathogen destruction versus intracellular survival: the role of lipids as phagosomal fate determinants

Abstract

Phagocytosis is a key component of the innate immune response and of the clearance of apoptotic bodies. Phagosome formation and subsequent maturation require extensive cytoskeletal rearrangement and precisely choreographed vesicular fusion and fission events. The objectives of this review are to highlight the functional importance of lipids in the phagocytic process, to discuss how pathogenic microorganisms can in some cases manipulate host lipid metabolism to either co-opt or disrupt phagosome maturation and promote their own survival, and to describe how defective phagosomal lipid metabolism can result in disease.

Figure 1. Stages of phagosome formation and maturation.

Six stages of phagocytosis are shown: i, particle engagement; i, phagocytic cup formation; iii, nascent phagosome (1–2 min after sealing); iv, early phagosome (2–10 min after sealing); v, late phagosome (10–30 min after sealing); vi, phagolysosome (>30 min after sealing). As the phagosome matures, it undergoes multiple sequential interactions with early endosomes (EE), late endosomes (LE), and lysosomes (Ly).

Figure 2. Lipids dictate domain-specific targeting of proteins during phagocytosis.

(A) Structures of the principal phospholipids within the plasma and phagosomal membranes. The phospholipids have a glycerol backbone to which fatty acyl residues are attached at the sn-1 and sn-2 positions. For simplicity, in all cases the common pairing of stearoyl and arachidonyl fatty acids are depicted in the sn-1 and sn-2 positions, respectively. The headgroups that define the lipid species attach to the glycerol backbone at the sn-3 hydroxyl group. The inositol ring of the phosphoinositides can be phosphorylated at any one of three positions (D-3, D-4, and D-5) to yield the various mono-, bis-, and tris-phosphorylated species. DAG and cholesterol (Chol) are also illustrated. PE, phosphatidylethanolamine. (B) The stages of phagocytosis from Figure 1 are shown, with the presence of specific lipids illustrated by the respective colors. Representative proteins attaching to specific lipids are shown, matched by color. Colored segments at stages with multiple lipids do not reflect subdomains or the relative abundance of the different species. Myo10, myosin X. Btk, Bruton agaggaglobulinemia tyrosine kinase.

Figure 3. Contribution of phospholipid species to membrane composition and charge.

(A) Schematic representation of the lipid composition of the plasma membrane. The color of the headgroup not only identifies the different species, but is indicative of its charge. The relative mole ratio of the lipids is shown in parentheses. (B) Anionic lipids dictate electrostatic targeting of proteins during phagocytosis. The stages of phagocytosis from Figure 1 are shown, with the relative charge of membranes or ligand proteins illustrated by color. Note that the plasmalemma is most negative, and secretory membranes are least negative. The phagosome membrane has an intermediate negativity, and polycationic proteins are shown in varying shades according to their charges.

Figure 4. Intracellular bacteria co-opt or disrupt phagosomal lipid metabolism as a survival strategy.

M. tuberculosis secretes the glycosylated PI analog lipoarabinomannan (LAM) to inhibit the production of PI(3)P by Vps34 in addition to secreting the phosphatase SapM, which dephosphorylates PI(3)P. Together, these effectors decrease vacuolar PI(3)P to arrest phagosome maturation and produce a favorable intracellular niche for M. tuberculosis survival. S. enterica injects the effector SigD into the cell. This phosphatase depletes PI(4,5)P₂ from the plasma membrane, leading to bacterial invasion into the host cell. Once inside, SigD has been suggested to dephosphorylate PI(3,4,5)P₃ to produce PI(3)P. Alternatively, SigD products might modulate Vps34 in order to increase vacuolar PI(3)P. These effects help the bacterium divert the maturation of the invasion vacuole away from the conventional antimicrobial trajectory of phagosomes.