Molecular mechanisms of cryptococcal meningitis

Liu, Tong‐Bao; Perlin, David S.; Xue, Chaoyang

doi:10.4161/viru.18685

Cited by 117 publications

(99 citation statements)

References 109 publications

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“…The molecular basis of cryptococcal infection of the CNS is an area of intensive investigation. Multiple fungal and host factors have been identified to play a role in the fungal penetration of the blood brain barrier (BBB) and to cause CNS infection [2][3][4][5]. The polysaccharide capsule of C. neoformans is a major virulence factor that is associated with the outcome following initial pathogen-host interaction, including BBB crossing and establishing CNS infection [6][7][8].…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…ryptococcus neoformans, an invasive opportunistic pathogen of the central nervous system, is the most frequent cause of fungal meningitis, resulting in more than 625,000 deaths per year worldwide (1,2). Exposure to C. neoformans is common, as it is an environmental fungus found in the soil and can enter the lungs through inhalation, leading to pulmonary infection.…”

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confidence: 99%

Biochemical and Kinetic Characterization of Xylulose 5-Phosphate/Fructose 6-Phosphate Phosphoketolase 2 (Xfp2) from Cryptococcus neoformans

2014

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Xylulose 5-phosphate/fructose 6-phosphate phosphoketolase (Xfp), previously thought to be present only in bacteria but recently found in fungi, catalyzes the formation of acetyl phosphate from xylulose 5-phosphate or fructose 6-phosphate. Here, we describe the first biochemical and kinetic characterization of a eukaryotic Xfp, from the opportunistic fungal pathogen Cryptococcus neoformans, which has two XFP genes (designated XFP1 and XFP2). Our kinetic characterization of C. neoformans Xfp2 indicated the existence of both substrate cooperativity for all three substrates and allosteric regulation through the binding of effector molecules at sites separate from the active site. Prior to this study, Xfp enzymes from two bacterial genera had been characterized and were determined to follow Michaelis-Menten kinetics. C. neoformans Xfp2 is inhibited by ATP, phosphoenolpyruvate (PEP), and oxaloacetic acid (OAA) and activated by AMP. ATP is the strongest inhibitor, with a half-maximal inhibitory concentration (IC 50 ) of 0.6 mM. PEP and OAA were found to share the same or have overlapping allosteric binding sites, while ATP binds at a separate site. AMP acts as a very potent activator; as little as 20 M AMP is capable of increasing Xfp2 activity by 24.8% ؎ 1.0% (mean ؎ standard error of the mean), while 50 M prevented inhibition caused by 0.6 mM ATP. AMP and PEP/OAA operated independently, with AMP activating Xfp2 and PEP/OAA inhibiting the activated enzyme. This study provides valuable insight into the metabolic role of Xfp within fungi, specifically the fungal pathogen Cryptococcus neoformans, and suggests that at least some Xfps display substrate cooperative binding and allosteric regulation.

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“…Clinical observations and experimental data have shown that uncontrolled infection of the respiratory tract precedes the development of disseminated infection and/or meningitis. The mechanisms by which C. neoformans reaches and actually enters the brain following its escape from the lung are complex and not fully understood; these include intravascular trapping followed by paracellular or transcellular migration or transmigration within circulating phagocytes (56). The data presented here suggest that Cnes2 restricts progressive infection by enhancing the pulmonary The expression of classical (Nos2) and alternative (Arg1 and Fizz1) activation markers by total adherent pulmonary macrophages was evaluated by qRT-PCR at 14 dpi.…”

Section: Discussionmentioning

confidence: 99%

TheCnes2Locus on Mouse Chromosome 17 Regulates Host Defense against Cryptococcal Infection through Pleiotropic Effects on Host Immunity

et al. 2015

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The genetic basis of natural susceptibility to progressive Cryptococcus neoformans infection is not well understood. Using C57BL/6 and CBA/J inbred mice, we previously identified three chromosomal regions associated with C. neoformans susceptibility (Cnes1, Cnes2, and Cnes3). To validate and characterize the role of Cnes2 during the host response, we constructed a congenic strain on the C57BL/6 background (B6.CBA-Cnes2). Phenotypic analysis of B6.CBA-Cnes2 mice 35 days after C. neoformans infection showed a significant reduction of fungal burden in the lungs and spleen with higher pulmonary expression of gamma interferon (IFN-␥) and interleukin-12 (IL-12), lower expression of IL-4, IL-5, and IL-13, and an absence of airway epithelial mucus production compared to that in C57BL/6 mice. Multiparameter flow cytometry of infected lungs also showed a significantly higher number of neutrophils, exudate macrophages, CD11b؉ dendritic cells, and CD4 ؉ cells in B6.CBA-Cnes2 than in C57BL/6 mice. The activation state of recruited macrophages and dendritic cells was also significantly increased in B6.CBA-Cnes2 mice. Taken together, these findings demonstrate that the Cnes2 interval is a potent regulator of host defense, immune responsiveness, and differential Th1/Th2 polarization following C. neoformans infection.

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Molecular mechanisms of cryptococcal meningitis

Cited by 117 publications

References 109 publications

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

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

Biochemical and Kinetic Characterization of Xylulose 5-Phosphate/Fructose 6-Phosphate Phosphoketolase 2 (Xfp2) from Cryptococcus neoformans

TheCnes2Locus on Mouse Chromosome 17 Regulates Host Defense against Cryptococcal Infection through Pleiotropic Effects on Host Immunity

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