Chloroquine induces human mononuclear phagocytes to inhibit and kill Cryptococcus neoformans by a mechanism independent of iron deprivation.

Abstract

Infections due to Cryptococcus neoformans are common in AIDS patients. We investigated the effect of chloroquine, which raises the pH of phagolysosomes, on the anticryptococcal activity of mononuclear phagocytes. C. neoformans multiplied within monocyte-derived macrophages (MDM) in the absence of chloroquine but were killed with the addition of chloroquine. Ammonium chloride was also beneficial, suggesting that effects were mediated by alkalinizing the phagolysosome. Chloroquine inhibits growth of other intracellular pathogens by limiting iron availability. However, chloroquine-induced augmentation of MDM anticryptococcal activity was unaffected by iron nitriloacetate, demonstrating that chloroquine worked by a mechanism independent of iron deprivation. There was an inverse correlation between growth of C. neoformans in cell-free media and pH, suggesting that some of the effect of chloroquine on the anticryptococcal activity of MDM could be explained by relatively poor growth at higher pH. Chloroquine enhanced MDM anticryptococcal activity against all tested cryptococcal strains except for one large-capsule strain which was not phagocytosed. Positive effects of chloroquine were also seen in monocytes from both HIV-infected and -uninfected donors. Finally, chloroquine was therapeutic in experimental cryptococcosis in outbred and severe combined immunodeficient mice. Thus, chloroquine enhances the activity of mononuclear phagocytes against C. neoformans by ironindependent, pH-dependent mechanisms and is therapeutic in murine models of cryptococcosis. Chloroquine might have clinical utility for the prophylaxis and treatment of human cryptococcosis. (

Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury

“…The degree of protection is similar to that seen with ethyl pyruvate (34,41) or simvastatin (49). Chloroquine has also been shown to improve survival after CpG/LPS administration (18), in a 2-hit model of hemorrhage followed by CLP (13), and in a mouse cryptococcosis infection model (31). Hence, chloroquine might be useful for treating newly diagnosed sepsis, rather than just as a preventative agent.…”

“…When trafficking and/or acidification is disrupted by chloroquine or bafilomycin A1, TLR signaling is inhibited (1,14,30,32,37). In addition to these studies in vitro, a few reports suggest that chloroquine can inhibit innate immune responses in vivo: in a two-hit model of hemorrhage then CLP (13), after CpG/LPS administration (18), and in a mouse cryptococcosis infection model (31).…”

Cryptococcus neoformansEnters the Endolysosomal Pathway of Dendritic Cells and Is Killed by Lysosomal Components

“…C. neoformans killing assays were performed as previously described (28,33,42). Briefly, following culture of encapsulated C. neoformans yeast cells, the organisms were washed three times with sterile PBS and resuspended in 10 mM phosphate buffer with 2% RPMI 1640, pH 5.5 (lysosomal buffer).…”

“…While C. neoformans can be killed by DCs (22) and by macrophages (5,27,28), under some conditions, C. neoformans has also been shown to survive the phagolysosome of macrophages (29). Several mechanisms have on May 11, 2018 by guest http://iai.asm.org/ been described for macrophages by which C. neoformans can escape the phagosome and even the phagocyte.…”

Effect of Tenofovir/Emtricitabine/Efavirenz with and without Chloroquine in Patients with HIV/AIDS C3: Double Blinded Randomized Clinical Trial

“…These results are of considerable importance despite of such a small sample. Not all the involved mechanisms in immune recovery are clear, although a part of this could be that chloroquine shows not only antiviral properties, but also antifungal and antiparasitic and over other microorganisms which could be part of the opportunistic coinfections present at advanced stages of AIDS and are not always identified [20,21].…”