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Updated: Jan 9, 2026
Macrophage Cholesterol Depletion and Its Effect on the Phagocytosis of Cryptococcus neoformans
Published on: December 19, 2014
Cryptococcus exploits delayed microglial activation, and microglial osteopontin/Spp1 impairs peripheral host control
Estefany Y Reyes1, Jae Yong2, Devon T DiPalma1
1Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27705, USA.
Abstract:
Cryptococcus, a neurotropic fungus classified as a critical-priority pathogen by the World Health Organization (WHO), causes cryptococcal meningoencephalitis (CM), the second leading cause of death in HIV/AIDS patients. Despite its clinical importance, host brain responses during CM remain poorly understood. In a mouse systemic infection model, Cryptococcus infiltrates the brain within a day. However, full activation of microglia and recruitment of leukocytes takes 14 days, a delay not observed in brain infections caused by Candida albicans. Microglia exhibit limited ability to directly detect Cryptococcus, and their activation depends on interferon (IFN)-γ from Th1 cells. Therefore, adaptive immunity (Th1 responses) precedes innate immune responses (microglial activation) in the brain during CM. Moreover, microglia-derived osteopontin (OPN/Spp1) exacerbates CM by altering peripheral immunity and increasing fungal loads in peripheral organs. These findings reveal a uniquely slow host cellular response to Cryptococcus brain infiltration, allowing the fungus an extended window to establish the infection.
Insights
Cryptococcus causes deadly meningoencephalitis (CM). Host brain immune responses are surprisingly slow, allowing the fungus to establish infection before microglia fully activate.
Area of Science:
- Neuroscience
- Immunology
- Mycology
Background:
- Cryptococcus is a WHO critical-priority pathogen causing meningoencephalitis (CM).
- CM is a leading cause of death in HIV/AIDS patients.
- Host brain immune responses during CM are poorly understood.
Purpose of the Study:
- To investigate host brain immune cell responses to Cryptococcus during CM.
- To understand the kinetics of microglial activation and leukocyte recruitment in the brain.
Main Methods:
- A mouse model of systemic Cryptococcus infection was used.
- The timing of fungal brain infiltration, microglial activation, and leukocyte recruitment was analyzed.
- The role of T-helper 1 (Th1) cell-derived interferon-gamma (IFN-γ) and microglia-derived osteopontin (OPN) was examined.
Main Results:
- Cryptococcus infiltrates the brain rapidly (within 1 day).
- Microglial activation and leukocyte recruitment are significantly delayed (14 days), unlike in Candida albicans infections.
- Microglial activation depends on Th1 cell-derived IFN-γ, indicating adaptive immunity precedes innate responses.
- Microglia-derived osteopontin exacerbates CM by increasing fungal loads.
Conclusions:
- Host cellular response in the brain during Cryptococcus meningoencephalitis is uniquely slow.
- This delay provides the fungus an extended window to establish infection.
- Understanding this slow response is crucial for developing effective therapies against CM.
