Binding of Cryptococcus neoformans by human cultured macrophages. Requirements for multiple complement receptors and actin.

Levitz, Stuart M.; Tabuni, Abdulmoneim

doi:10.1172/jci115027

Cited by 110 publications

(86 citation statements)

References 43 publications

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“…neoformans activates the alternative complement pathway (14,16), which results in the deposition of C3 fragments on the surface of the microorganism, mostly in the form of iC3b (15,16). iC3b acts as the major opsonic component for phagocytosis of this microorganism by phagocytic leukocytes through binding to CR3 (Mac-1) (2,17,18). In the present study, the mAb that recognizes the α chain (CD11b) of CR3 significantly suppressed the dissemination of C. neoformans from the lung to the brain.…”

Section: Resultssupporting

confidence: 48%

Anti‐CD11b Monoclonal Antibody Suppresses Brain Dissemination of Cryptococcus neoformans in Mice

Kawakami

Koguchi

Qureshi

et al. 2002

Microbiology and Immunology

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To elucidate the role of the β2 integrin family of adhesion molecules in the disseminated infection of Cryptococcus neoformans from the lung to the central nervous system, we examined the effects of monoclonal antibodies (mAbs) against CD11a, CD11b, CD11c and CD18 on the number of live microorganisms in both the lung and brain of mice three weeks after intratracheal infection. Administration of anti‐CD11b mAb partially, but reproducibly, reduced the fungal loads in the brain in three independent experiments, while the lung loads were not affected. In addition, the same treatment significantly decreased the number of live microorganisms in the blood. In sharp contrast, the brain loads one week after intravenous injection with C. neoformans were not affected by treatment with anti‐CD11b mAb. Finally, administration of mAb against other adhesion molecules (CD11a, CD11c or CD18) failed to affect the fungal loads in the brain as well as in the lung three weeks after intratracheal instillation, except for anti‐CD18 mAb which rather increased the brain loads. Our results suggested that CD11b might be involved at least in part in the process of fungal dissemination from lung to brain, although the significance of other β2 integrin family adhesion molecules remains to be substantiated.

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Section: Resultssupporting

confidence: 48%

Anti‐CD11b Monoclonal Antibody Suppresses Brain Dissemination of Cryptococcus neoformans in Mice

Kawakami

Koguchi

Qureshi

et al. 2002

Microbiology and Immunology

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“…Importantly, the outer capsule of Cryptococcus sp. has been shown to bind with C3, a component of the alternate complement system and activates the respective pathway in vitro [40][41][42]. However, binding of C3, and thus the alternating complement activation cascade, is largely dependent on the nature and density of the capsule.…”

Section: Discussionmentioning

confidence: 99%

Cryptococcus inositol utilization modulates the host protective immune response during brain infection

Liu

Subbian

Pan

et al. 2014

Cell Communication and Signaling

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Background: Cryptococcus neoformans is the most common cause of fungal meningitis among individuals with HIV/AIDS, which is uniformly fatal without proper treatment. The underlying mechanism of disease development in the brain that leads to cryptococcal meningoencephalitis remains incompletely understood. We have previously demonstrated that inositol transporters (ITR) are required for Cryptococcus virulence. The itr1aΔ itr3cΔ double mutant of C. neoformans was attenuated for virulence in a murine model of intra-cerebral infection; demonstrating that Itr1a and Itr3c are required for full virulence during brain infection, despite a similar growth rate between the mutant and wild type strains in the infected brain.

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“…Binding of C. neoformans to MDM was determined using a modification of our previously described assay (19). MDM were incubated with C. neoformans in the presence or absence of chloroquine, using the exact same conditions as for the above antifungal activity except that the C. neoformans were labeled with rhodamine isothiocyanate (RITC) to facilitate their identification.…”

Section: Methodsmentioning

confidence: 99%

“…Our previously described Uvitex assay was used to determine the percentage of cell-associated fungi that were internalized (phagocytosed) by the MDM (19,20). Briefly, MDM and RITC-labeled C. neoformans were coincubated for 4 h as described for the binding assay.…”

Section: Methodsmentioning

confidence: 99%

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

Levitz¹,

Harrison²,

Tabuni³

et al. 1997

J. Clin. Invest.

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119

123

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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. (

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Binding of Cryptococcus neoformans by human cultured macrophages. Requirements for multiple complement receptors and actin.

Abstract: We studied the receptors on human cultured macrophages (MO-MO)

Cited by 110 publications

References 43 publications

Anti‐CD11b Monoclonal Antibody Suppresses Brain Dissemination of Cryptococcus neoformans in Mice

Anti‐CD11b Monoclonal Antibody Suppresses Brain Dissemination of Cryptococcus neoformans in Mice

Cryptococcus inositol utilization modulates the host protective immune response during brain infection

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

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