Mechanisms of Infection by the Human Fungal Pathogen
            <i>Cryptococcus Neoformans</i>

Sabiiti, Wilber; May, Robin C.

doi:10.2217/fmb.12.102

Cited by 77 publications

(58 citation statements)

References 180 publications

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“…The encapsulated yeast Cryptococcus neoformans is an important cause of fungal meningoencephalitis worldwide and can enter the CNS by penetrating the BBB by use of transcellular, paracellular, and Trojan horse mechanisms following blood-borne dissemination from the lungs (as reviewed elsewhere [397]). Although the hematogenous route of CNS entry is well accepted for cryptococcal meningoencephalitis, some strains of C. neoformans isolated from the CSF of human patients were shown to be rhinotropic in mice (398,399), and persistent C. neoformans colonization of the nasal cavity (90 days) was reported in one study (400).…”

Section: Yeasts and Fungimentioning

confidence: 99%

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

et al. 2014

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SUMMARY The brain is well protected against microbial invasion by cellular barriers, such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). In addition, cells within the central nervous system (CNS) are capable of producing an immune response against invading pathogens. Nonetheless, a range of pathogenic microbes make their way to the CNS, and the resulting infections can cause significant morbidity and mortality. Bacteria, amoebae, fungi, and viruses are capable of CNS invasion, with the latter using axonal transport as a common route of infection. In this review, we compare the mechanisms by which bacterial pathogens reach the CNS and infect the brain. In particular, we focus on recent data regarding mechanisms of bacterial translocation from the nasal mucosa to the brain, which represents a little explored pathway of bacterial invasion but has been proposed as being particularly important in explaining how infection with Burkholderia pseudomallei can result in melioidosis encephalomyelitis.

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Section: Yeasts and Fungimentioning

confidence: 99%

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

et al. 2014

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“…In immunocompromised hosts, however, cryptococci can disseminate from the lungs to other organs, in particular the central nervous system (CNS), where the fungus causes a usually fatal meningoencephalitis (10). The variation in CM severity and outcome between individual patients may be explained by underlying deficiencies in the host immune response (11,12) and/or the virulence capacity of the infecting strain (13,14).…”

Section: Introductionmentioning

confidence: 99%

Efficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosis

Sabiiti¹,

Robertson²,

Beale³

et al. 2014

J. Clin. Invest.

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128

173

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Background. Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality globally. High fungal burden in cerebrospinal fluid (CSF) at diagnosis and poor fungal clearance during treatment are recognized adverse prognostic markers; however, the underlying pathogenic factors that drive these clinical manifestations are incompletely understood. We profiled a large set of clinical isolates for established cryptococcal virulence traits to evaluate the contribution of C. neoformans phenotypic diversity to clinical presentation and outcome in human cryptococcosis.Methods. Sixty-five C. neoformans isolates from clinical trial patients with matched clinical data were assayed in vitro to determine murine macrophage uptake, intracellular proliferation rate (IPR), capsule induction, and laccase activity. Analysis of the correlation between prognostic clinical and host immune parameters and fungal phenotypes was performed using Spearman's r, while the fungal-dependent impact on long-term survival was determined by Cox regression analysis.Results. High levels of fungal uptake by macrophages in vitro, but not the IPR, were associated with CSF fungal burden (r = 0.38, P = 0.002) and long-term patient survival (hazard ratio [HR] 2.6, 95% CI 1.2-5.5, P = 0.012). High-uptake strains were hypocapsular (r = -0.28, P = 0.05) and exhibited enhanced laccase activity (r = 0.36, P = 0.003). Fungal isolates with greater laccase activity exhibited heightened survival ex vivo in purified CSF (r = 0.49, P < 0.0001) and resistance to clearance following patient antifungal treatment (r = 0.39, P = 0.003).Conclusion. These findings underscore the contribution of cryptococcal-phagocyte interactions and laccasedependent melanin pathways to human clinical presentation and outcome. Furthermore, characterization of fungal-specific pathways that drive clinical manifestation provide potential targets for the development of therapeutics and the management of CM.

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“…In healthy individuals, C. neoformans is either cleared or causes a latent infection, but in the context of immune compromise, this facultative intracellular pathogen can multiply and disseminate throughout the body; its ability to cross the blood-brain barrier leads to a frequently fatal meningoencephalitis (6).…”

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confidence: 99%

Pbx Proteins in Cryptococcus neoformans Cell Wall Remodeling and Capsule Assembly

et al. 2014

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The cryptococcal capsule is a critical virulence factor of an important pathogen, but little is known about how it is associated with the cell or released into the environment. Two mutants lacking PBX1 and PBX2 were found to shed reduced amounts of the capsule polysaccharide glucuronoxylomannan (GXM). Nuclear magnetic resonance, composition, and physical analyses showed that the shed material was of normal mass but was slightly enriched in xylose. In contrast to previous reports, this material contained no glucose. Notably, the capsule fibers of pbx⌬ mutant cells grown under capsule-inducing conditions were present at a lower than usual density and were loosely attached to the cell wall. Mutant cell walls were also defective, as indicated by phenotypes including abnormal cell morphology, reduced mating filamentation, and altered cell integrity. All observed phenotypes were shared between the two mutants and exacerbated in a double mutant. Consistent with a role in surface glycan synthesis, the Pbx proteins localized to detergent-resistant membrane domains. These results, together with the sequence motifs in the Pbx proteins, suggest that Pbx1 and Pbx2 are redundant proteins that act in remodeling the cell wall to maintain normal cell morphology and precursor availability for other glycan synthetic processes. Their absence results in aberrant cell wall growth and metabolic imbalance, which together impact cell wall and capsule synthesis, cell morphology, and capsule association. The surface changes also lead to increased engulfment by host phagocytes, consistent with the lack of virulence of pbx mutants in animal models.

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Mechanisms of Infection by the Human Fungal Pathogen Cryptococcus Neoformans

Cited by 77 publications

References 180 publications

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

Efficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosis

Pbx Proteins in Cryptococcus neoformans Cell Wall Remodeling and Capsule Assembly

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