Elucidating the Immunological Function of the
            <i>Cryptococcus Neoformans</i>
            Capsule

Vecchiarelli, Anna; Pericolini, Eva; Gabrielli, Elena; Kenno, Samyr; Perito, Stefano; Cenci, Elio; Monari, Claudia

doi:10.2217/fmb.13.84

Cited by 82 publications

(74 citation statements)

References 85 publications

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“…Furthermore, GXM shed from cells during infection interferes with immune cell function. 14,15 Similar to what is seen in mammals, capsule size increases during G. mellonella infection and increased capsule size in correlated with reduced phagocytosis by hemocytes. 16 In the present study, the authors find that capsule and GXM have an effect on lytic activity of the larval hemolymph, a humoral immune response of G. mellonella.…”

supporting

confidence: 53%

Metamorphosis of Galleria mellonella research

Eisenman

2015

Virulence

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supporting

confidence: 53%

Metamorphosis of Galleria mellonella research

Eisenman

2015

Virulence

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“…Subsequent studies showed that GXM activates SHIP via surface Fc␥RIIb receptors. Active SHIP then blocks the recruitment of MyD88 (myeloid differentiation primary response gene 88) and Akt, thereby impeding IB␣ phosphorylation and degradation (11,12). These data imply that GXM would block LPS-induced nuclear accumulation of p65-containing NF-B dimers, thereby preventing the NF-B-dependent production of pro-inflammatory cytokines.…”

Section: Gxm Attenuates Lps-induced Nuclear Translocation Of Nf-b-mentioning

confidence: 95%

“…These effects can be explained, at least in part, by the ability of GXM to subvert the activity of the NF-B signaling pathway (reviewed in Ref. 12).…”

mentioning

confidence: 99%

Modulation of Macrophage Inflammatory Nuclear Factor κB (NF-κB) Signaling by Intracellular Cryptococcus neoformans

Hayes

Sircy

Heusinkveld

et al. 2016

Journal of Biological Chemistry

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Cryptococcus neoformans (Cn) is a common facultative intracellular pathogen that can cause life-threatening fungal meningitis in immunocompromised individuals. Shortly after infection, Cn is detectable as both extra-and intracellular yeast particles, with Cn being capable of establishing long-lasting latent infections within host macrophages. Although recent studies have shown that shed capsular polysaccharides and intact extracellular Cn can compromise macrophage function through modulation of NF-B signaling, it is currently unclear whether intracellular Cn also affects NF-B signaling. Utilizing live cell imaging and computational modeling, we find that extra-and intracellular Cn support distinct modes of NF-B signaling in cultured murine macrophages. Specifically, in RAW 264.7 murine macrophages treated with extracellular glucuronoxylomannan (GXM), the major Cn capsular polysaccharide, LPS-induced nuclear translocation of p65 is inhibited, whereas in cells with intracellular Cn, LPS-induced nuclear translocation of p65 is both amplified and sustained. Mathematical simulations and quantification of nascent protein expression indicate that this is a possible consequence of Cn-induced "translational interference," impeding IB␣ resynthesis. We also show that long term Cn infection induces stable nuclear localization of p65 and IB␣ proteins in the absence of additional proinflammatory stimuli. In this case, nuclear localization of p65 is not accompanied by TNF␣ or inducible NOS (iNOS) expression. These results demonstrate that capsular polysaccharides and intact intracellular yeast manipulate NF-B via multiple distinct mechanisms and provide new insights into how Cn might modulate cellular signaling at different stages of an infection.Cryptococcus neoformans (Cn) 3 is a spore-forming, intracellular pathogenic yeast found in soil and other niches worldwide (1). Inhalation of spores is thus extremely common, allowing Cn to infect ϳ70% of children in urban environments (2). In most cases Cn infections do not present immediate clinical symptoms; rather, Cn is able to enter a chronic latent state that may last for many years by residing within host macrophages. However, in immune compromised individuals, an acute Cn infection or re-emergence of an existing infection can result in life-threatening conditions such as pneumonia or fungal meningitis. A recent estimate suggests these and other Cn-related illnesses cause ϳ600,000 deaths per year (3).A key regulator of this host-pathogen interaction is the Cn polysaccharide capsule. The capsule, primarily composed of glucuronoxylomannan (GXM, ϳ80% by mass (4)), is produced and shed during growth and is essential for virulence (5, 6). It promotes Cn survival during the initial stage of infection by acting as an anti-phagocytic coating, thereby preventing ingestion of yeast in a naïve host during the short-lived acute stage of infection (ϳ7 days after exposure (7)). An escalating humoral response then leads to the phagocytosis of Cn. Unfortunately, the macrophage phagolysosome...

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“…This complex structure is composed mainly of polysaccharides that are linked to the cell wall (102). Mutant strains unable to synthesize a capsule are avirulent, and the capsular polysaccharides exert profound depressive effects on both innate and adaptive immune responses (103,104). Different factors, including pH, have been shown to influence the capsule size and structure (105).…”

Section: Ph Signaling and Cryptococcus Neoformans Virulencementioning

confidence: 99%

pH Signaling in Human Fungal Pathogens: a New Target for Antifungal Strategies

Cornet

Gaillardin

2014

Eukaryot Cell

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dFungi are exposed to broadly fluctuating environmental conditions, to which adaptation is crucial for their survival. An ability to respond to a wide pH range, in particular, allows them to cope with rapid changes in their extracellular settings. PacC/Rim signaling elicits the primary pH response in both model and pathogenic fungi and has been studied in multiple fungal species. In the predominant human pathogenic fungi, namely, Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans, this pathway is required for many functions associated with pathogenesis and virulence. Aspects of this pathway are fungus specific and do not exist in mammalian cells. In this review, we highlight recent advances in our understanding of PacC/Rim-mediated functions and discuss the growing interest in this cascade and its factors as potential drug targets for antifungal strategies. We focus on both conserved and distinctive features in model and pathogenic fungi, highlighting the specificities of PacC/Rim signaling in C. albicans, A. fumigatus, and C. neoformans. We consider the role of this pathway in fungal virulence, including modulation of the host immune response. Finally, as now recognized for other signaling cascades, we highlight the role of pH in adaptation to antifungal drug pressure. By acting on the PacC/Rim pathway, it may therefore be possible (i) to ensure fungal specificity and to limit the side effects of drugs, (ii) to ensure broad-spectrum efficacy, (iii) to attenuate fungal virulence, (iv) to obtain additive or synergistic effects with existing antifungal drugs through tolerance inhibition, and (v) to slow the emergence of resistant mutants.

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Elucidating the Immunological Function of the Cryptococcus Neoformans Capsule

Cited by 82 publications

References 85 publications

Metamorphosis of Galleria mellonella research

Metamorphosis of Galleria mellonella research

Modulation of Macrophage Inflammatory Nuclear Factor κB (NF-κB) Signaling by Intracellular Cryptococcus neoformans

pH Signaling in Human Fungal Pathogens: a New Target for Antifungal Strategies

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