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Live-cell Video Microscopy of Fungal Pathogen Phagocytosis
Published on: January 9, 2013
Identification of App1 as a regulator of phagocytosis and virulence of Cryptococcus neoformans
Chiara Luberto1, Beatriz Martinez-Mariño, Daniel Taraskiewicz
1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
Abstract:
Cryptococcus neoformans is a fungal pathogen that, after inhalation, can disseminate to the brain. Host alveolar macrophages (AMs) represent the first defense against the fungus. Once phagocytosed by AMs, fungal cells are killed by a concerted mechanism, involving the host-cellular response. If the cellular response is impaired, phagocytosis of the fungus may be detrimental for the host, since C. neoformans can grow within macrophages. Here, we identified a novel cryptococcal gene encoding antiphagocytic protein 1 (App1). App1 is a cryptococcal cytoplasmic protein that is secreted extracellularly and found in the serum of infected patients. App1 does not affect melanin production, capsule formation, or growth of C. neoformans. Treatment with recombinant App1 inhibited phagocytosis of fungal cells through a complement-mediated mechanism, and Deltaapp1 mutant is readily phagocytosed by AMs. Interestingly, the Deltaapp1 mutant strain showed a decreased virulence in mice deficient for complement C5 (A/Jcr), but it was hypervirulent in mice deficient for T and NK cells (Tgepsilon26). This study identifies App1 as a novel regulator of virulence for C. neoformans, and it highlights that internalization of fungal cells by AMs increases the dissemination of C. neoformans when the host cellular response is impaired.
Insights
A novel fungal protein, antiphagocytic protein 1 (App1), helps Cryptococcus neoformans evade host macrophages. Disrupting App1 impacts fungal virulence, highlighting its role in cryptococcal infections.
Area of Science:
- Mycology
- Immunology
- Pathogenesis
Background:
- Cryptococcus neoformans (C. neoformans) is a fungal pathogen that can spread to the brain after inhalation.
- Alveolar macrophages (AMs) are the primary host defense against inhaled C. neoformans.
- Impaired host cellular response can lead to C. neoformans growth within macrophages, increasing dissemination risk.
Purpose of the Study:
- Identify novel C. neoformans virulence factors.
- Investigate the role of antiphagocytic protein 1 (App1) in fungal pathogenesis.
- Elucidate the mechanism by which App1 influences host-fungal interactions.
Main Methods:
- Gene identification and characterization of App1 in C. neoformans.
- In vitro assays using recombinant App1 to assess phagocytosis inhibition via complement.
- Virulence studies using C. neoformans strains with and without App1 in immunocompromised mouse models.
Main Results:
- App1 is a secreted protein found in infected patient serum, not affecting fungal growth, melanin, or capsule.
- Recombinant App1 inhibits fungal phagocytosis through a complement-mediated mechanism.
- A Deltaapp1 mutant showed reduced virulence in complement-deficient mice but increased virulence in T and NK cell-deficient mice.
Conclusions:
- App1 is a novel regulator of C. neoformans virulence.
- App1 facilitates fungal evasion of phagocytosis, impacting dissemination.
- Host cellular response impairment exacerbates C. neoformans dissemination when phagocytosis is hindered.
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