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Updated: Aug 19, 2025
Macrophage Cholesterol Depletion and Its Effect on the Phagocytosis of Cryptococcus neoformans
Published on: December 19, 2014
Protective interaction of human phagocytic APC subsets with Cryptococcus neoformans induces genes associated with
Benjamin N Nelson1, Cheyenne S Daugherty1, Rachel R Sharp2
1Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, OK, United States.
Abstract:
Cryptococcal meningitis is the most common cause of meningitis among HIV/AIDS patients in sub-Saharan Africa, and worldwide causes over 223,000 cases leading to more than 181,000 annual deaths. Usually, the fungus gets inhaled into the lungs where the initial interactions occur with pulmonary phagocytes such as dendritic cells and macrophages. Following phagocytosis, the pathogen can be killed or can replicate intracellularly. Previous studies in mice showed that different subsets of these innate immune cells can either be antifungal or permissive for intracellular fungal growth. Our studies tested phagocytic antigen-presenting cell (APC) subsets from the human lung against C. neoformans. Human bronchoalveolar lavage was processed for phagocytic APCs and incubated with C. neoformans for two hours to analyze the initial interactions and fate of the fungus, living or killed. Results showed all subsets (3 macrophage and 3 dendritic cell subsets) interacted with the fungus, and both living and killed morphologies were discernable within the subsets using imaging flow cytometry. Single cell RNA-seq identified several different clusters of cells which more closely related to interactions with C. neoformans and its protective capacity against the pathogen rather than discrete cellular subsets. Differential gene expression analyses identified several changes in the innate immune cell's transcriptome as it kills the fungus including increases of TNF-α (TNF) and the switch to using fatty acid metabolism by upregulation of the gene FABP4. Also, increases of TNF-α correlated to cryptococcal interactions and uptake. Together, these analyses implicated signaling networks that regulate expression of many different genes - both metabolic and immune - as certain clusters of cells mount a protective response and kill the pathogen. Future studies will examine these genes and networks to understand the exact mechanism(s) these phagocytic APC subsets use to kill C. neoformans in order to develop immunotherapeutic strategies to combat this deadly disease.
Insights
Researchers studied how human lung immune cells fight Cryptococcus neoformans, the cause of cryptococcal meningitis. They found specific immune cell responses and gene changes that help kill the fungus, paving the way for new treatments.
Area of Science:
- Immunology
- Infectious Diseases
- Mycology
Background:
- Cryptococcal meningitis is a major cause of death in HIV/AIDS patients, particularly in sub-Saharan Africa.
- The fungus Cryptococcus neoformans is inhaled and interacts with lung phagocytes, which can either kill or support fungal growth.
- Previous mouse studies indicated varied responses among innate immune cell subsets to C. neoformans.
Purpose of the Study:
- To investigate the initial interactions between human lung phagocytic antigen-presenting cell (APC) subsets and C. neoformans.
- To analyze the fate of C. neoformans (living or killed) after interaction with human APCs.
- To identify molecular mechanisms underlying the protective immune response against C. neoformans in human lung phagocytes.
Main Methods:
- Human bronchoalveolar lavage was processed to isolate phagocytic APC subsets.
- APCs were incubated with C. neoformans and analyzed using imaging flow cytometry.
- Single-cell RNA sequencing (scRNA-seq) and differential gene expression analysis were performed to study cellular responses.
Main Results:
- All tested macrophage and dendritic cell subsets interacted with C. neoformans, with both viable and non-viable fungi observed.
- scRNA-seq revealed cell clusters associated with C. neoformans interaction and protective capacity, rather than distinct cellular subsets.
- Gene expression changes included increased TNF-α and upregulation of FABP4 (fatty acid metabolism) in cells killing the fungus.
Conclusions:
- Immune cell responses to C. neoformans involve complex signaling networks regulating metabolic and immune genes.
- Increased TNF-α correlates with C. neoformans interaction and uptake by phagocytes.
- Understanding these protective mechanisms can inform the development of immunotherapeutic strategies against cryptococcal meningitis.
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