The Intracellular Life of<i>Cryptococcus neoformans</i>

Coelho, Carolina; Bocca, Anamélia Lorenzetti; Casadevall, Arturo

doi:10.1146/annurev-pathol-012513-104653

Cited by 115 publications

(112 citation statements)

References 130 publications

(143 reference statements)

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“…Additionally, deficiency in NO production, due to either STAT1 or iNOS deletion, resulted in increased intramacrophage fungal burden even in the presence of intact ROS production. These findings draw a parallel with previous studies indicating an important role for macrophage NO in killing and control of cryptococcal infections (23,25,37,41,59,71). Here, we definitively show that NO production by STAT1-mediated classically activated macrophages is essential for protection against C. neoformans.…”

Section: Discussionsupporting

confidence: 91%

STAT1 Signaling within Macrophages Is Required for Antifungal Activity against Cryptococcus neoformans

et al. 2015

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Cryptococcus neoformans, the predominant etiological agent of cryptococcosis, is an opportunistic fungal pathogen that primarily affects AIDS patients and patients undergoing immunosuppressive therapy. In immunocompromised individuals, C. neoformans can lead to life-threatening meningoencephalitis. Studies using a virulent strain of C. neoformans engineered to produce gamma interferon (IFN-␥), denoted H99␥, demonstrated that protection against pulmonary C. neoformans infection is associated with the generation of a T helper 1 (Th1)-type immune response and signal transducer and activator of transcription 1 (STAT1)-mediated classical (M1) macrophage activation. However, the critical mechanism by which M1 macrophages mediate their anti-C. neoformans activity remains unknown. The current studies demonstrate that infection with C. neoformans strain H99␥ in mice with macrophage-specific STAT1 ablation resulted in severely increased inflammation of the pulmonary tissue, a dysregulated Th1/Th2-type immune response, increased fungal burden, deficient M1 macrophage activation, and loss of protection. STAT1-deficient macrophages produced significantly less nitric oxide (NO) than STAT1-sufficient macrophages, correlating with an inability to control intracellular cryptococcal proliferation, even in the presence of reactive oxygen species (ROS). Furthermore, macrophages from inducible nitric oxide synthase knockout mice, which had intact ROS production, were deficient in anticryptococcal activity. These data indicate that STAT1 activation within macrophages is required for M1 macrophage activation and anti-C. neoformans activity via the production of NO.

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Section: Discussionsupporting

confidence: 91%

STAT1 Signaling within Macrophages Is Required for Antifungal Activity against Cryptococcus neoformans

et al. 2015

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“…For example, C. neoformans is able to survive and replicate within macrophages in a similar way to which it exists as an intracellular parasite of amoebae in the environment. 19,20 Furthermore, its polysaccharide capsule which protects it from harsh conditions, including UV light and extremes of temperature in the environment, exhibits antiphagocytic mechanisms, causing macrophage dysfunction and lysis, and allowing resistance to phagosomal digestion. 21 These, along with many other 'ready-made' virulence factors (production of melanin, degradative enzymes and an ability to grow at physiological temperatures), 22 allow Cryptococcus to remain in dormant until host immune-compromise allows dissemination and disease, most commonly meningoencephalitis in HIV-infected individuals.…”

Section: Pathophysiologymentioning

confidence: 99%

Cryptococcosis in apparently immune-competent patients: taxonomy, epidemiology, pathophysiology and treatment

Wake

Govender

2016

Southern African Journal of Infectious Diseases

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“…While acute new infection can cause its share of disease, it is generally thought that a large percentage of clinical cases represent remote reactivation rather than new infection (8,9). Depending on the location, a large percentage of children already produce anticryptococcal antibody by the age of 10 (10, 11), and there is direct evidence of reactivated disease occurring years after exposure to the responsible cryptococcal strains (12).…”

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confidence: 99%

A Zebrafish Model of Cryptococcal Infection Reveals Roles for Macrophages, Endothelial Cells, and Neutrophils in the Establishment and Control of Sustained Fungemia

et al. 2016

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Cryptococcal meningoencephalitis is a fungal infection that predominantly affects immunocompromised patients and is uniformly fatal if left untreated. Timely diagnosis is difficult, and screening or prophylactic measures have generally not been successful. Thus, we need a better understanding of early, asymptomatic pathogenesis. Inhaled cryptococci must survive the host immune response, escape the lung, and persist within the bloodstream in order to reach and invade the brain. Here we took advantage of the zebrafish larval infection model to assess the process of cryptococcal infection and disease development sequentially in a single host. Using yeast or spores as infecting particles, we discovered that both cell types survived and replicated intracellularly and that both ultimately established a sustained, low-level fungemia. We propose that the establishment and maintenance of this sustained fungemia is an important stage of disease progression that has been difficult to study in other model systems. Our data suggest that sustained fungemia resulted from a pattern of repeated escape from, and reuptake by, macrophages, but endothelial cells were also seen to play a role as a niche for cryptococcal survival. Circulating yeast collected preferentially in the brain vasculature and eventually invaded the central nervous system (CNS). As suggested previously in a mouse model, we show here that neutrophils can play a valuable role in limiting the sustained fungemia, which can lead to meningoencephalitis. This early stage of pathogenesis-a balanced interaction between cryptococcal cells, macrophages, endothelial cells, and neutrophils-could represent a window for timely detection and intervention strategies for cryptococcal meningoencephalitis. R ecent data from Uganda and Tanzania indicate that there are over 10,000 cases of HIV-related cryptococcosis per year in these countries alone (1, 2). Of those, roughly 5,000 to 8,000 (54 to 79%) are fatal. At a global scale, the survival rate is similarly poor, and over 600,000 deaths are attributed to Cryptococcus neoformans every year (3). The high mortality rate is in part due to difficulties in timely diagnosis; even in susceptible hosts, clinical signs of the initial pulmonary infection can be subtle or essentially absent (4). Studies in this population using serum cryptococcal antigen testing suggest that antigenemia (which may or may not represent actual fungemia) is a harbinger of meningoencephalitis but can precede it by weeks or more (5, 6). Once the infection has progressed to clinical meningoencephalitis, the prognosis is grim even with aggressive treatment. Beyond the HIV-infected population, a growing transplant and otherwise immunosuppressed population is also vulnerable, and even an immunocompetent host may be susceptible to infection and disease caused by the closely related species Cryptococcus gattii (7). An understanding of the events prior to fulminant disease is critical to better management of patients at risk for cryptococcal meningoencephalitis.While ...

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The Intracellular Life ofCryptococcus neoformans

Cited by 115 publications

References 130 publications

STAT1 Signaling within Macrophages Is Required for Antifungal Activity against Cryptococcus neoformans

STAT1 Signaling within Macrophages Is Required for Antifungal Activity against Cryptococcus neoformans

Cryptococcosis in apparently immune-competent patients: taxonomy, epidemiology, pathophysiology and treatment

A Zebrafish Model of Cryptococcal Infection Reveals Roles for Macrophages, Endothelial Cells, and Neutrophils in the Establishment and Control of Sustained Fungemia

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