Inhibition of Human Endothelial Cell Chemokine Production by the Opportunistic Fungal Pathogen<i>Cryptococcus neoformans</i>

Mozaffarian, Neelufar; Casadevall, Arturo; Berman, Joan W.

doi:10.4049/jimmunol.165.3.1541

Cited by 36 publications

(16 citation statements)

References 56 publications

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“…Research done in Cryptococcus neoformans and Blastomyces dermatitis has demonstrated that fungal pathogens can modulate host cytokines via secreted or cell surface-localized proteins (8,27). Tumor necrosis factor alpha suppression by secreted and surface-localized Bad1 is the attribute of the protein that makes it a Blastomyces virulence factor (9).…”

Section: Discussionmentioning

confidence: 99%

Surface Localization of the Yps3p Protein of Histoplasma capsulatum

Bohse

Woods

2005

Eukaryot Cell

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The YPS3 gene of Histoplasma capsulatum encodes a protein that is both resident in the cell wall and also released into the culture medium. This protein is produced only during the pathogenic yeast phase of infection and is also expressed differently in H. capsulatum strains that differ in virulence. We investigated the cellular localization of Yps3p. We demonstrated that the cell wall fraction of Yps3p was surface localized in restriction fragment length polymorphism class 2 strains. We also established that Yps3p released into the G217B culture supernatant binds to the surface of strains that do not naturally express the protein. This binding was saturable and occurred within 5 min of exposure and occurred similarly with live and heat-killed H. capsulatum. Flow cytometric analysis of H. capsulatum after enzymatic treatments was consistent with Yps3p binding to chitin, a carbohydrate polymer that is a component of fungal cell walls. Polysaccharide binding assays demonstrated that chitin but not cellulose binds to and extracts Yps3p from culture supernatants.

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Section: Discussionmentioning

confidence: 99%

Surface Localization of the Yps3p Protein of Histoplasma capsulatum

Bohse

Woods

2005

Eukaryot Cell

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“…GXM is an immunomodulator (33) and can alter cytokine and chemokine production by monocytes and PMNs in vitro (34)(35)(36)(37)(38)(39). GXM can be immunosuppressive in vivo (40), directly inhibit phagocytosis (6,41), and delay the processing of phagocytosed C. neoformans (42).…”

Section: Discussionmentioning

confidence: 99%

Phenotypic switching of Cryptococcus neoformans occurs in vivo and influences the outcome of infection

Fries¹,

Taborda²,

Serfass³

et al. 2001

J. Clin. Invest.

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103

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IntroductionCryptococcosis affects 5-30% of patients with AIDS. It is caused by Cryptococcus neoformans, an encapsulated yeast that is acquired by inhalation and ultimately results in a chronic meningoencephalitis with a high tendency to relapse despite effective antifungal therapy (1). Several virulence factors (2-5) including a polysaccharide capsule (6, 7) are described for C. neoformans. Most virulence factors are invariably present (8) in clinical strains. Genetic inactivation of their regulatory proteins, which are part of signaling pathways, renders the yeast avirulent (9, 10). It is, however, unclear whether regulation of virulence factors occurs in vivo during chronic infection in order to enhance the virulence of an infecting C. neoformans strain. Therefore, it is often assumed that failure to eradicate the fungus is a function of a diminished cellmediated immune response (CMI). Several observations, however, indicate that pathogen-specific factors contribute to the pathogenesis of cryptococcosis. First, prolonged in vitro and in vivo passage of C. neoformans isolates can result in phenotypic changes associated with differences in virulence (11)(12)(13)(14). Second, serial isolates from chronically infected patients can exhibit differences in virulence (15). Third, C. neoformans variety gattii strains cause symptomatic infections primarily in immunocompetent hosts even in areas where AIDS is endemic (16).Reversible phenotypic switching can result in microevolution, defined as rapid changing of an organism to a stable, inherited phenotype (17). Microevolution and phenotypic switching can be achieved by several mechanisms, some of which involve changes of genes and follow a mendelian inheritance pattern whereas others (e.g., silencing) are epigenetic and inherited in a nonmendelian fashion. For certain pathogens, the emergence of phenotype variants is associated with invasion of mucosal barriers and immune evasion (18). For fungi, phenotypic switching is an in vitro phenomenon defined as the spontaneous emergence of colonies with altered colony morphology at rates higher than the somatic mutation rates (19-21). Phenotypic switching was demonstrated for C. neoformans in vitro in three different clinical strains and resulted in enhanced virulence (22,23). Despite an association with virulence, phenotypic switching in vivo has been demonstrated only in pathogens with complex life cycles that require the switch for survival in the host (24). Most infections require high doses, and because of the expected in vitro switching rates (10 -2 to 10 -5 ), these inocula are likely to be contaminated with in vitro switch variants. Therefore, it is difficult to demonstrate that the emergence of new phenotypes in the infected host are the result of in vivo switching events and do not represent in vivo selection of variants from an initially heterogeneous pathogen population (25). Phenotypic switching has been linked to the virulence of many pathogens, including fungi. However, it has not been conclusively shown to occur...

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“…Prior infection could modify several parameters that could subsequently interfere with BBB crossing and fungal multiplication, including (i) disruption of the BBB and its tight junctions between endothelial cells and modification of the endothelial surface, which could increase BBB crossing (6); and (ii) alteration of local immunity, with diminished secretion of chemokines by endothelial cells, as demonstrated in vitro (40). Whatever the underlying mechanisms, prior infection modified the course of brain invasion by a second strain.…”

Section: Vol 77 2009 Role Of Monocytes During Cryptococcosis 123mentioning

confidence: 99%

Evidence of a Role for Monocytes in Dissemination and Brain Invasion byCryptococcus neoformans

et al. 2009

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The pathogenesis of cryptococcosis, including the events leading to the production of meningoencephalitis, is still largely unknown. Evidence of a transcellular passage of Cryptococcus neoformans across the blood-brain barrier (BBB) and subsequent BBB disruption exists, but the paracellular passage of free yeasts and the role of monocytes in yeast dissemination and brain invasion (Trojan horse method) remain uncertain. We used our model of disseminated cryptococcosis, in which crossing of the BBB starts 6 h after intravenous inoculation, to study paracellular passage of the BBB. We prepared bone marrow-derived monocytes (BMDM) infected in vitro with C. neoformans (BMDM yeasts) and free yeasts and measured fungal loads in tissues. (i) Spleen and lung CFU were >2-fold higher in mice treated with BMDM yeasts than in those treated with free yeasts for 1 and 24 h (P < 0.05), while brain CFU were increased (3.9 times) only at 24 h (P < 0.05). (ii) By comparing the kinetics of brain invasion in naïve mice and in mice with preestablished cryptococcosis, we found that CFU were lower in the latter case, except at 6 h, when CFU from mice inoculated with BMDM yeasts were comparable to those measured in naïve mice and 2.5-fold higher than those in mice with preestablished cryptococcosis who were inoculated with free yeasts. (iii) Late phagocyte depletion obtained by clodronate injection reduced disease severity and lowered the fungal burden by 40% in all organs studied. These results provide evidence for Trojan horse crossing of the BBB by C. neoformans, together with mechanisms involving free yeasts, and overall for a role of phagocytes in fungal dissemination.

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Inhibition of Human Endothelial Cell Chemokine Production by the Opportunistic Fungal PathogenCryptococcus neoformans

Cited by 36 publications

References 56 publications

Surface Localization of the Yps3p Protein of Histoplasma capsulatum

Surface Localization of the Yps3p Protein of Histoplasma capsulatum

Phenotypic switching of Cryptococcus neoformans occurs in vivo and influences the outcome of infection

Evidence of a Role for Monocytes in Dissemination and Brain Invasion byCryptococcus neoformans

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