Vol2-2Art2 Cryptococcus neoformans Infection in Ferret Macrophages 

Isabel A. Jimenez^1,2, Quigly Dragotakes², Arturo Casadevall^2,#

¹Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, U.S.A.; ²Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, U.S.A.

Abstract

Cryptococcus neoformans is a fungal pathogen of humans and animals. Tissue-resident alveolar macrophages (AMs) are important for pulmonary immune surveillance and act as first-responders to inhaled pathogens. AMs are the first targets during natural cryptococcal infection and play a key role in the innate immune response via pathogen recognition and antigen presentation. Prior studies suggest that alterations in AM populations impact host susceptibility to cryptococcal infection. Nonetheless, few models for cryptococcal infection of AMs exist. Here, we studied C. neoformans infection of AMs collected via post-mortem bronchoalveolar lavage from the domestic ferret (Mustela putorius furo). We selected the ferret as the donor species given its natural susceptibility to cryptococcosis, established use as a model for other respiratory pathologies, and larger body size than laboratory rodents allowing for greater AM yield. We used real-time live-cell imaging to analyze C. neoformans-AM interactions and identified events consistent with cryptococcal infection, including phagocytosis, non-lytic exocytosis (vomocytosis), cell-to-cell lateral transfer (dragotcytosis), and intracellular and extracellular replication of cryptococcal cells. Unlike murine AMs but consistent with findings in human AMs, activation of ferret AMs with interferon-gamma and lipopolysaccharide did not affect phagocytic activity upon exposure to C. neoformans. Our results indicate that ferret AMs are susceptible to experimental infection with C. neoformans, consistent with the notion that the natural susceptibility of this species reflects an inability of lung macrophages to control fungal burden.
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#Correspondence:
acasade1@jh.edu

Article info:
Received 31 July 2025
Revised 25 August 2025
Accepted 28 August 2025
Appeared online 31 August 2025
One Health Mycology 2(2): 112-122, 2025
doi.org/10.63049/OHM.25.22.2 

Cite this article:
Jimenez  IA, Dragotakes  Q, Casadevall A 2025. Experimental infection of alveolar macrophages from domestic ferrets (Mustela putorius furo) with Cryptococcus neoformans. One Health Mycology 2(2), 112-122
This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/ licenses/by-nc-nd/4.0/)

Keywords:
animal models, bronchoalveolar lavage, cryptococcosis, fungi, immunology

Article highlights:

• Alveolar macrophages from domestic ferrets (Mustela putorius furo) were exposed to Cryptococcus neoformans. Real-time live-cell imaging revealed host-pathogen interactions consistent with cryptococcal infection, including phagocytosis, non-lytic exocytosis (vomocytosis), cell-to-cell lateral transfer (dragotcytosis), and intracellular and extracellular replication of cryptococcal cells.
• Unlike murine AMs but consistent with findings in human AMs, activation of ferret AMs with interferon-gamma and lipopolysaccharide did not affect phagocytic activity upon exposure to C. neoformans.
• The domestic ferret holds potential for future development as a model for cryptococcosis.
• Ferret AMs are susceptible to experimental infection with C. neoformans, consistent with the notion that the natural susceptibility of ferrets to C. neoformans reflects an inability of lung macrophages to control fungal burden. 
• This study represents the first use of ferret macrophages to study C. neoformans in an experimental setting.