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PNAS 109 (21): 1360-1368

Copyright © 2012 by the National Academy of Sciences.

PNAS Plus

PNAS PLUS / BIOLOGICAL SCIENCES / IMMUNOLOGY

Janus-faced liposomes enhance antimicrobial innate immune response in Mycobacterium tuberculosis infection

Emanuela Grecoa,1, Gianluca Quintiliania,1, Marilina B. Santuccia, Annalucia Serafinob, Anna Rita Ciccaglionec, Cinzia Marcantonioc, Massimiliano Papid, Giuseppe Mauluccid, Giovanni Delogue, Angelo Martinof, Delia Golettif, Loredana Sarmatig, Massimo Andreonig, Alfonso Altierih, Mario Almah, Nadia Caccamoi, Diana Di Libertoi, Marco De Spiritod, Nigel D. Savagej, Roberto Nisinic, Francesco Dielii, Tom H. Ottenhoffj, and Maurizio Frazianoa,2

Departments of aBiology and gClinical Infectious Diseases, University of Rome "Tor Vergata," 00133 Rome, Italy; bInstitute of Translational Pharmacology, National Research Council, 00133 Rome, Italy; cDepartment of Infectious, Parasitic, and Immunomediated Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy; Institutes of dPhysics and eMicrobiology, Catholic University of Sacred Heart, 00168 Rome, Italy; fDepartment of Epidemiology and Preclinical Research, National Institute of Infectious Diseases "Lazzaro Spallanzani," 00149 Rome, Italy; hUnit of Tisiology and Bronchopneumology, S. Camillo-Forlanini Hospital, 00151 Rome, Italy; IDepartment of Biopathology and Medical and Forensics Biotechnologies, University of Palermo, 90135 Palermo, Italy; and jDepartment of Infectious Diseases, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands

2To whom correspondence should be addressed. E-mail: Fraziano{at}bio.uniroma2.it.

Abstract: We have generated unique asymmetric liposomes with phosphatidylserine (PS) distributed at the outer membrane surface to resemble apoptotic bodies and phosphatidic acid (PA) at the inner layer as a strategy to enhance innate antimycobacterial activity in phagocytes while limiting the inflammatory response. Results show that these apoptotic body-like liposomes carrying PA (ABL/PA) (i) are more efficiently internalized by human macrophages than by nonprofessional phagocytes, (ii) induce cytosolic Ca2+ influx, (iii) promote Ca2+-dependent maturation of phagolysosomes containing Mycobacterium tuberculosis (MTB), (iv) induce Ca2+-dependent reactive oxygen species (ROS) production, (v) inhibit intracellular mycobacterial growth in differentiated THP-1 cells as well as in type-1 and -2 human macrophages, and (vi) down-regulate tumor necrosis factor (TNF)-α, interleukin (IL)-12, IL-1β, IL-18, and IL-23 and up-regulate transforming growth factor (TGF)-β without altering IL-10, IL-27, and IL-6 mRNA expression. Also, ABL/PA promoted intracellular killing of M. tuberculosis in bronchoalveolar lavage cells from patients with active pulmonary tuberculosis. Furthermore, the treatment of MTB-infected mice with ABL/PA, in combination or not with isoniazid (INH), dramatically reduced lung and, to a lesser extent, liver and spleen mycobacterial loads, with a concomitant 10-fold reduction of serum TNF-α, IL-1β, and IFN-{gamma} compared with that in untreated mice. Altogether, these results suggest that apoptotic body-like liposomes may be used as a Janus-faced immunotherapeutic platform to deliver polar secondary lipid messengers, such as PA, into phagocytes to improve and recover phagolysosome biogenesis and pathogen killing while limiting the inflammatory response.

 
Conflict of interest statement: E.G., G.Q., M.D.S., and M.F. are named on a patent application for work described in this paper.

This article is a PNAS Direct Submission.

See full research article on page E1360 of www.pnas.org.

Cite this Author Summary as: PNAS 10.1073/pnas.1200484109.

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