The Interaction between Candida krusei and Murine Macrophages Results in Multiple Outcomes, Including Intracellular Survival and Escape from Killing

García-Rodas, Rocío; González-Camacho, Fernando; Rodríguez-Tudela, Juan Luis; Cuenca‐Estrella, Manuel; Zaragoza, Óscar

doi:10.1128/iai.00044-11

Cited by 47 publications

(38 citation statements)

References 33 publications

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“…Inhibition of macrophage cell division was previously reported for the fungal pathogens Cryptococcus neoformans , Candida krusei and C. albicans [21], [31], [32]. Here we found that in the presence of F. oxysporum , mitosis of macrophages was unsuccessful in approximately 25% of the cases.…”

Section: Discussionsupporting

confidence: 72%

Hyphal Growth of Phagocytosed Fusarium oxysporum Causes Cell Lysis and Death of Murine Macrophages

et al. 2014

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Fusarium oxysporum is an important plant pathogen and an opportunistic pathogen of humans. Here we investigated phagocytosis of F. oxysporum by J774.1 murine cell line macrophages using live cell video microscopy. Macrophages avidly migrated towards F. oxysporum germlings and were rapidly engulfed after cell-cell contact was established. F. oxysporum germlings continued hyphal growth after engulfment by macrophages, leading to associated macrophage lysis and escape. Macrophage killing depended on the multiplicity of infection. After engulfment, F. oxysporum inhibited macrophages from completing mitosis, resulting in large daughter cells fused together by means of a F. oxysporum hypha. These results shed new light on the initial stages of Fusarium infection and the innate immune response of the mammalian host.

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Section: Discussionsupporting

confidence: 72%

Hyphal Growth of Phagocytosed Fusarium oxysporum Causes Cell Lysis and Death of Murine Macrophages

et al. 2014

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“…Recently, similar processes have been noted in C. albicans (Bain et al 2012) and C. krusei (García-Rodas et al 2011). It is likely that nonlytic escape offers a distinct advantage by minimizing proinflammatory signaling and thus ensuring that immune activity is kept to a minimal level.…”

Section: Cryptococcus Neoformans/gattiimentioning

confidence: 60%

“…Indeed, recently, C. albicans and C. krusei yeast cells have also been shown to escape via a nonlytic process first identified in Cryptococcus neoformans, in which both fungus and macrophage are left intact postexpulsion ( Fig. 2) (García-Rodas et al 2011;Bain et al 2012). …”

Section: Candida Speciesmentioning

confidence: 98%

Fungal Pathogens: Survival and Replication within Macrophages

Gilbert¹,

Wheeler²,

May³

2014

Cold Spring Harb Perspect Med

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The innate immune system is a critical line of defense against pathogenic fungi. Macrophages act at an early stage of infection, detecting and phagocytizing infectious propagules. To avoid killing at this stage, fungal pathogens use diverse strategies ranging from evasion of uptake to intracellular parasitism. This article will discuss five of the most important human fungal pathogens (Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, Coccidiodes immitis, and Histoplasma capsulatum) and consider the strategies and virulence factors adopted by each to survive and replicate within macrophages. Macrophages are phagocytic immune cells, derived from monocyte differentiation, and are involved in the first line of defense during microbial invasion. They recognize, engulf, and destroy foreign bodies, such as pathogenic organisms before then presenting antigen to coordinate subsequent adaptive immunity (Fig. 1). Macrophages are found in almost all tissues and are particularly abundant at mucosal surfaces in which pathogen exposure is naturally higher, such as the alveoli. They are able to engulf particles ranging from 0.5 mm (such as bacteria) to .5 mm (such as yeast), although an upper size limit does exist (Chen et al. 1997;Krombach et al. 1997;Kinchen and Ravichandran 2008).Macrophages express a wide range of different receptors able to detect nonself particles. These receptors can be split into two groups: opsonic and nonopsonic. Opsonic receptors, such as the Fc receptor or complement receptor families (Flannagan et al. 2012), are able to recognize particles coated (opsonized) in antibody or complement (Johnston and May 2013). In contrast, nonopsonic receptors are pathogen recognition receptors (PRRs) that directly detect pathogen-associated molecular patterns (PAMPs) on the surface of microorganisms. Macrophages are heterogeneous in the receptors they express, and can change this repertoire when differentiating into different subtypes. For instance, the nonopsonic Dectin-1 receptor Once engulfment has been achieved, the macrophage must then digest the pathogen, now segregated into a phagosome (digesting vesicle). To complete the digestion, the phagosome must mature via the fusion of early and late stage endosomes and ultimately fuse with the lysosome, generating a phagolysosome (Kinchen and Ravichandran 2008). The phagolysosome uses vacuolar ATPases to pump H þ ions into the phagolysosome, reducing the pH. Once the pH is reduced sufficiently, acid-dependent proteases, such as cathepsin D, are activated to degrade the pathogen (Fig. 1) (Kinchen and Ravichandran 2008).Many human fungal pathogens have developed strategies to resist phagocytic attack, thus facilitating pathogenicity. The field of fungal research has exploded over the last three decades because of the increase in fungal-related illnesses that appears to correlate with the AIDS pandemic and more effective immunosuppressive medicines . Macrophages have been shown to play a role in resistance to disseminated candidiasis, although they are ...

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“…These data are particularly interesting because C. krusei is one of the few non-albicans Candida spp. that are able to form filaments of any type; C. krusei forms pseudohyphae, not true hyphae, in macrophages (33). The ability of Candida species to trigger IL-1␤ production also corre- lated with their ability to induce macrophage lysis (data not shown).…”

Section: Fig 1 C Albicans-induced Macrophage Lysis Has Characteristimentioning

confidence: 79%

Candida albicans Triggers NLRP3-Mediated Pyroptosis in Macrophages

et al. 2014

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Pyroptosis is an inflammasome-mediated programmed cell death pathway triggered in macrophages by a variety of stimuli, including intracellular bacterial pathogens. Activation of pyroptosis leads to the secretion of interleukin-1␤ (IL-1␤) and pore-mediated cell lysis. Although not considered an intracellular pathogen, Candida albicans is able to kill and, thereby, escape from macrophages. Here, we show that C. albicans-infected bone marrow-derived macrophages (BMDM) and murine J774 macrophages undergo pyroptotic cell death that is suppressed by glycine and pharmacologic inhibition of caspase-1. Infection of BMDM harvested from mice lacking components of the inflammasome revealed that pyroptosis was dependent on caspase-1, ASC, and NLRP3 and independent of NLRC4. In contrast to its role during intracellular bacterial infection, pyroptosis does not restrict C. albicans replication. Nonfilamentous Candida spp. did not trigger pyroptosis, while Candida krusei, which forms pseudohyphae in macrophages, triggered much lower levels than did C. albicans. Interestingly, a Saccharomyces cerevisiae strain from the filamentous background ⌺1278 also triggered low, but significant, levels of pyroptosis. We have found that deletion of the transcription factor UPC2 decreases pyroptosis but has little effect on filamentation in the macrophage. In addition, a gainof-function mutant of UPC2 induces higher levels of pyroptosis than does a matched control strain. Taken together, these data are most consistent with a model in which filamentation is necessary but not sufficient to trigger NLRP3 inflammasome-mediated pyroptosis. This is the first example of a fungal pathogen triggering pyroptosis and indicates that C. albicans-mediated macrophage damage is not solely due to hypha-induced physical disruption of cellular integrity.

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The Interaction between Candida krusei and Murine Macrophages Results in Multiple Outcomes, Including Intracellular Survival and Escape from Killing

Cited by 47 publications

References 33 publications

Hyphal Growth of Phagocytosed Fusarium oxysporum Causes Cell Lysis and Death of Murine Macrophages

Hyphal Growth of Phagocytosed Fusarium oxysporum Causes Cell Lysis and Death of Murine Macrophages

Fungal Pathogens: Survival and Replication within Macrophages

Candida albicans Triggers NLRP3-Mediated Pyroptosis in Macrophages

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