Identification of App1 as a regulator of phagocytosis and virulence of Cryptococcus neoformans
Chiara Luberto, … , Edward Balish, Maurizio Del Poeta
Chiara Luberto, … , Edward Balish, Maurizio Del Poeta
Published October 1, 2003
Citation Information: J Clin Invest. 2003;112(7):1080-1094. https://doi.org/10.1172/JCI18309.
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Article Infectious disease

Identification of App1 as a regulator of phagocytosis and virulence of Cryptococcus neoformans

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 Δapp1 mutant is readily phagocytosed by AMs. Interestingly, the Δapp1 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 (Tgε26). 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.

Authors

Chiara Luberto, Beatriz Martinez-Mariño, Daniel Taraskiewicz, Benjamin Bolaños, Pasquale Chitano, Dena L. Toffaletti, Gary M. Cox, John R. Perfect, Yusuf A. Hannun, Edward Balish, Maurizio Del Poeta

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Tissue-burden cultures of C. neoformans in animal models. Number of yeas...
Tissue-burden cultures of C. neoformans in animal models. Number of yeast cells expressed as geometric mean of CFU per organ recovered from lung (left panels) and brain (right panels) of A/Jcr (top panels) and Tgε26 (bottom panels) mice during infection (in days) with C. neoformans WT, GAL7:IPC1 10, Δapp1 31, IPC1Rec, and Δapp1Rec strains. Mice were infected intranasally, organs from five animals for each group were extracted and homogenized, and serial dilutions were plated for tissue-burden cultures at selected days after inoculation. Mice infected with the GAL7:IPC1 strain showed a significant decrease of yeast cell numbers in the brains of both animal models as compared with the WT strain (P = 0.01 and P = 0.001, respectively). Brains of A/Jcr mice infected with the Δapp1 strain showed a decreased concentration of yeast cells as compared with those infected with the WT strain (P = 0.015). In contrast, the brains of Tgε26 mice infected with the Δapp1 strain showed an increased number of yeast cells as compared with the brains infected with the WT strain (P = 0.002). Both IPC1Rec and Δapp1Rec strains reconstitute the phenotype observed with the WT H99 strain in both animal models.