© 2003 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, TX, 2003

15.4.3.6.7 Inhibit Phagolysosomal Fusion

Lysosomal fusion with phagosomes containing a trapped medical nanorobot – that is, the fusion of phagocytic lysosomes (granules) with the phagosome, forming a digestive phagolysosome – is not a direct threat to diamondoid nanorobot core integrity. However, digestive substances present in phagolysosomes could possibly alter the surface characteristics of nanorobots such as their “biocompatibility coatings,” or could partially dissolve or digest semaphore display ligands, nanosensors, or exterior binding sites containing organic constituents. Thus it may sometimes be useful for nanorobots to directly modulate or control the phagolysosomal fusion process, which can occur in just 30 minutes following receptor-mediated uptake but may require hours (to complete phagolysosome formation) for other ingested particles such as latex beads [2867].

Several bacteria survive while trapped in phagosomes by preventing phagolysosome formation [3302]. The simplest chemical that inhibits phagolysomal fusion appears to be ammonia (e.g., ammonium chloride) [3537]. Mycobacterium tuberculosis [3530-3532] produces ammonia at high levels, thus interfering with phagolysosomal fusion [3533] and the saltatory movement of lysosomes [3534]. More recently, it has been found that the bacteria can recruit and retain TACO (tryptophane aspartate-containing coat protein) in the mycobacterial phagosome, preventing cargo delivery to lysosomes [3535]. It has also been proposed that the polyanionic nature of the cell wall of M. tuberculosis, containing sulfatides (anionic trehalose glycolipids [3536]) and sulfalipids [3536, 3541], could allow it to modify lysosomal membranes to inhibit phagosome-lysosome fusion in macrophages [3536-3541], although this mechanism has been disputed [3542]. The microbe also may have cytolytic pore-forming ability [3543], may inhibit complement-receptor Ca⁺⁺ signaling [3544], and may display selective inhibition of fusion only with proton-ATPase-containing lysosomal vesicles [3545]. Salmonella exhibits phagolysosomal fusion inhibition while also acquiring lysosomal membrane glycoproteins (lgp) to redirect fusion to lgp-rich compartments different from the classical mature lysosome [3546]. Cord factor [3547], the adjuvant dimethyldioctadecylammonium bromide [3548], the drug suramin [3549], and an unknown component of E. coli cytoplasmic membrane [3550] are additional phagolysosomal fusion inhibiting substances.

Legionella pneumophila [3551-3553] possesses a cytolytic activity that may allow the insertion of pores into the phagocytic membrane upon contact [3543]. This apparently facilitates delivery of bacterial-derived effector molecules to the host cell cytoplasm that are capable of inhibiting phagolysosomal fusion. Legionella-containing phagosomes may also intercept and fuse with early secretory vesicles and recruit proteins that were originally destined for the endoplasmic reticulum, setting up a privileged membrane compartment resistant to fusion with lysosomes and permitting the development of an organelle for bacterial multiplication [6029]. Afipia [3554], Bordetella [3555], Brucella [3556-3559], Chlamydia [3560], Ehrlichia (Cytoecetes) [3561], Glugea spores [3562], influenza [3563] and parainfluenza [3564] viruses, Listeria [3565], Neisseria [3566], Nocardia [3567], Pseudomonas [3568], and Toxoplasma [3569] also display total or partial inhibition of phagolysosomal fusion. Symbiont-derived lipopolysaccharides are involved in the prevention of lysosome-symbiosome fusion in amoebas harboring bacterial endosymbionts [3570]. Further identification and isolation of the mechanisms utilized by these organisms will be necessary to assess their potential usefulness in nanorobot design.

Last updated on 30 April 2004