Editors' ChoiceImmunology

Fighting Infection with Liposomes

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Sci. Signal.  29 May 2012:
Vol. 5, Issue 226, pp. ec149
DOI: 10.1126/scisignal.2003261

In cells, specific lipids trigger specific cellular responses. The production of phosphatidic acid (PA) at the internal leaflet of the cell membrane by phospholipase D (PLD) contributes to the antimicrobial responses, such as calcium signaling, phagolysosome maturation, and reactive oxygen species (ROS) production, mounted by macrophages after ingestion of pathogens such as Mycobacterium tuberculosis (MTB). Indeed, the importance of these pathways in the antimicrobial response has led pathogenic microbes, including MTB, to inhibit PLD activity. Phosphatidylserine (PS), when exposed on the outer leaflet of the plasma membrane, serves as an “eat me” cue for macrophages and is involved in the clearance of apoptotic bodies. Greco et al. leveraged these two bioactive lipids to produce asymmetric lipososomes with PS on the outside and PA on the inside, which they called apoptotic body–like liposomes with PA (ABL/PA), and showed that ABL/PA were effectively phagocytosed by macrophages. Macrophages exposed to ABL/PA exhibited calcium signaling, the production of ROS, and a decrease in the abundance of many proinflammatory cytokine mRNAs. More important, addition of the ABL/PA to MTB-infected cell lines or cells from the lungs of infected patients resulted in a reduction in bacterial load (measured as colony-forming units). MTB-infected mice treated intranasally with ABL/PA (with or without isoniazid, a common treatment for MTB infection) exhibited a dramatic reduction in bacterial load in the lungs and a lesser effect in the liver and spleen. The treated and infected mice also showed a reduction in circulating proinflammatory mediators and markers of tissue or liver toxicity. In cultured cells, intracellular microbial killing triggered in response to ABL/PA was reduced by inhibiting phagolysosome maturation with chemicals that block lysosome acidification or by blocking the accumulation of ROS, suggesting that the exogenous PA delivered by ABL/PA overcame the inhibition of PLD in the infected cells to enable these two antimicrobial pathways to proceed. These results suggest that the ABLs may prove an effective mechanism to deliver specific therapeutics or biologically active molecules to macrophages.

E. Greco, G. Quintiliani, M. B. Santucci, A. Serafino, A. R. Ciccaglione, C. Marcantonio, M. Papi, G. Maulucci, G. Delogu, A. Martino, D. Goletti, L. Sarmati, M. Andreoni, A. Altieri, M. Alma, N. Caccamo, D. Di Liberto, M. De Spirito, N. D. Savage, R. Nisini, F. Dieli, T. H. Ottenhoff, M. Fraziano, Janus-faced liposomes enhance antimicrobial innate immune response in Mycobacterium tuberculosis infection. Proc. Natl. Acad. Sci. U.S.A. 109, E1360–E1368 (2012). [Abstract] [Full Text]

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