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Updated: Dec 31, 2025
Listeria monocytogenes Infection of the Brain
Published on: October 2, 2018
Evidence of a role for monocytes in dissemination and brain invasion by Cryptococcus neoformans
Caroline Charlier1, Kirsten Nielsen, Samira Daou
1Unité de Mycologie Moléculaire, CNRS URA3012, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France.
Abstract:
The pathogenesis of cryptococcosis, including the events leading to the production of meningoencephalitis, is still largely unknown. Evidence of a transcellular passage of Cryptococcus neoformans across the blood-brain barrier (BBB) and subsequent BBB disruption exists, but the paracellular passage of free yeasts and the role of monocytes in yeast dissemination and brain invasion (Trojan horse method) remain uncertain. We used our model of disseminated cryptococcosis, in which crossing of the BBB starts 6 h after intravenous inoculation, to study paracellular passage of the BBB. We prepared bone marrow-derived monocytes (BMDM) infected in vitro with C. neoformans (BMDM yeasts) and free yeasts and measured fungal loads in tissues. (i) Spleen and lung CFU were >2-fold higher in mice treated with BMDM yeasts than in those treated with free yeasts for 1 and 24 h (P < 0.05), while brain CFU were increased (3.9 times) only at 24 h (P < 0.05). (ii) By comparing the kinetics of brain invasion in naïve mice and in mice with preestablished cryptococcosis, we found that CFU were lower in the latter case, except at 6 h, when CFU from mice inoculated with BMDM yeasts were comparable to those measured in naïve mice and 2.5-fold higher than those in mice with preestablished cryptococcosis who were inoculated with free yeasts. (iii) Late phagocyte depletion obtained by clodronate injection reduced disease severity and lowered the fungal burden by 40% in all organs studied. These results provide evidence for Trojan horse crossing of the BBB by C. neoformans, together with mechanisms involving free yeasts, and overall for a role of phagocytes in fungal dissemination.
Insights
This study reveals that Cryptococcus neoformans uses monocytes as a "Trojan horse" to invade the brain, contributing to cryptococcal meningoencephalitis. Phagocytes play a crucial role in fungal dissemination and brain invasion.
Area of Science:
- Infectious Diseases
- Neuroscience
- Immunology
Background:
- The precise mechanisms of Cryptococcus neoformans crossing the blood-brain barrier (BBB) and causing meningoencephalitis are not fully understood.
- While transcellular yeast passage across the BBB is known, paracellular routes and the role of monocytes (Trojan horse method) in dissemination remain unclear.
Purpose of the Study:
- To investigate the mechanisms of Cryptococcus neoformans dissemination and brain invasion, focusing on paracellular BBB passage and the role of monocytes.
- To elucidate the contribution of monocytes and free yeasts to fungal load in various organs and brain invasion.
Main Methods:
- Utilized a murine model of disseminated cryptococcosis with intravenous inoculation of C. neoformans.
- Compared fungal loads (CFU) in tissues after inoculation with in vitro-infected bone marrow-derived monocytes (BMDM yeasts) versus free yeasts.
- Assessed fungal burden kinetics in naïve mice versus those with pre-established cryptococcosis and evaluated the impact of late phagocyte depletion.
Main Results:
- Inoculation with BMDM yeasts led to significantly higher fungal loads in spleen and lungs compared to free yeasts.
- Brain fungal loads were significantly increased with BMDM yeasts at 24 hours post-inoculation.
- The "Trojan horse" method via monocytes facilitated BBB crossing, particularly at early time points (6 hours), and phagocyte depletion reduced fungal burden.
Conclusions:
- Provides evidence for Cryptococcus neoformans utilizing the "Trojan horse" mechanism involving monocytes for blood-brain barrier invasion.
- Demonstrates that both monocyte-mediated and free yeast dissemination contribute to cryptococcosis.
- Highlights the significant role of phagocytes in the overall dissemination and brain invasion of C. neoformans.
