Microglia are not protective against cryptococcal meningitis

Sally H. Mohamed; Man Shun Fu; Sofia Hain; Alanoud Alselami; Eliane Vanhoffelen; Yanjian Li; Ebrima Bojang; Robert Lukande; Elizabeth R. Ballou; Robin C. May; Chen Ding; Greetje Vande Velde; Rebecca A. Drummond

doi:10.1038/s41467-023-43061-0

Microglia are not protective against cryptococcal meningitis

Sally H. Mohamed, Man Shun Fu, Sofia Hain, Alanoud Alselami, Eliane Vanhoffelen, Yanjian Li, Ebrima Bojang, Robert Lukande, Elizabeth R. Ballou, Robin C. May, Chen Ding, Greetje Vande Velde, Rebecca A. Drummond^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Microglia provide protection against a range of brain infections including bacteria, viruses and parasites, but how these glial cells respond to fungal brain infections is poorly understood. We investigated the role of microglia in the context of cryptococcal meningitis, the most common cause of fungal meningitis in humans. Using a series of transgenic- and chemical-based microglia depletion methods we found that, contrary to their protective role during other infections, loss of microglia did not affect control of Cryptococcus neoformans brain infection which was replicated with several fungal strains. At early time points post-infection, we found that microglia depletion lowered fungal brain burdens, which was related to intracellular residence of C. neoformans within microglia. Further examination of extracellular and intracellular fungal populations revealed that C. neoformans residing in microglia were protected from copper starvation, whereas extracellular yeast upregulated copper transporter CTR4. However, the degree of copper starvation did not equate to fungal survival or abundance of metals within different intracellular niches. Taken together, these data show how tissue-resident myeloid cells may influence fungal phenotype in the brain but do not provide protection against this infection, and instead may act as an early infection reservoir.

Original language	English
Article number	7202
Number of pages	15
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-43061-0
Publication status	Published - 8 Nov 2023

Bibliographical note

Acknowledgments:
We would like to thank the technical staff at the Biomedical Services Unit (Birmingham) for their care and help with animal husbandry. In particular, we thank Claire Lyons and Karen Boswell for their time and patience performing infections and caring for our animals. We thank Dr Guillaume Desanti and support staff at the Technology Hub and Flow Cytometry Unit at the University of Birmingham for their support with sorting, flow cytometry and microscopy experiments. This work was funded by the Academy of Medical Sciences (SBF004_1008, awarded to RAD), Medical Research Council (MR/S024611, awarded to RAD), Research Foundation Flanders (PhD studentship awarded to EV, 1SF2222N), the National Natural Science Foundation of China (31870140, awarded to CD) and the Wellcome Trust and the Royal Society (211241/Z/18/Z, awarded to ERB).

Keywords

Humans
Meningitis, Cryptococcal/prevention & control
Microglia
Copper
Cryptococcus neoformans
Neuroglia
Cryptococcosis

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10.1038/s41467-023-43061-0Licence: Creative Commons: Attribution (CC BY)

MohamedS2023MicrogliaFinal published version, 2.27 MBLicence: Creative Commons: Attribution (CC BY)

1 Finished
1 Active

Fungi on the brain: Interrogating Host-Pathogen Interactions during Fungal Meningitis
Drummond, R.
Medical Research Council
1/10/19 → 31/01/25
Project: Research Councils
Sense and respond: Investigating molecular mechanisms regulating Cryptococcus neoformans Titan cell formation in response to bacterial triggers
Ballou, L.
THE WELLCOME TRUST
1/10/18 → 20/05/21
Project: Research

Cite this

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title = "Microglia are not protective against cryptococcal meningitis",

abstract = "Microglia provide protection against a range of brain infections including bacteria, viruses and parasites, but how these glial cells respond to fungal brain infections is poorly understood. We investigated the role of microglia in the context of cryptococcal meningitis, the most common cause of fungal meningitis in humans. Using a series of transgenic- and chemical-based microglia depletion methods we found that, contrary to their protective role during other infections, loss of microglia did not affect control of Cryptococcus neoformans brain infection which was replicated with several fungal strains. At early time points post-infection, we found that microglia depletion lowered fungal brain burdens, which was related to intracellular residence of C. neoformans within microglia. Further examination of extracellular and intracellular fungal populations revealed that C. neoformans residing in microglia were protected from copper starvation, whereas extracellular yeast upregulated copper transporter CTR4. However, the degree of copper starvation did not equate to fungal survival or abundance of metals within different intracellular niches. Taken together, these data show how tissue-resident myeloid cells may influence fungal phenotype in the brain but do not provide protection against this infection, and instead may act as an early infection reservoir.",

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note = "Acknowledgments: We would like to thank the technical staff at the Biomedical Services Unit (Birmingham) for their care and help with animal husbandry. In particular, we thank Claire Lyons and Karen Boswell for their time and patience performing infections and caring for our animals. We thank Dr Guillaume Desanti and support staff at the Technology Hub and Flow Cytometry Unit at the University of Birmingham for their support with sorting, flow cytometry and microscopy experiments. This work was funded by the Academy of Medical Sciences (SBF004_1008, awarded to RAD), Medical Research Council (MR/S024611, awarded to RAD), Research Foundation Flanders (PhD studentship awarded to EV, 1SF2222N), the National Natural Science Foundation of China (31870140, awarded to CD) and the Wellcome Trust and the Royal Society (211241/Z/18/Z, awarded to ERB).",

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AU - Fu, Man Shun

AU - Hain, Sofia

AU - Alselami, Alanoud

AU - Vanhoffelen, Eliane

AU - Li, Yanjian

AU - Bojang, Ebrima

AU - Lukande, Robert

AU - Ballou, Elizabeth R.

AU - May, Robin C.

AU - Ding, Chen

AU - Velde, Greetje Vande

AU - Drummond, Rebecca A.

N1 - Acknowledgments: We would like to thank the technical staff at the Biomedical Services Unit (Birmingham) for their care and help with animal husbandry. In particular, we thank Claire Lyons and Karen Boswell for their time and patience performing infections and caring for our animals. We thank Dr Guillaume Desanti and support staff at the Technology Hub and Flow Cytometry Unit at the University of Birmingham for their support with sorting, flow cytometry and microscopy experiments. This work was funded by the Academy of Medical Sciences (SBF004_1008, awarded to RAD), Medical Research Council (MR/S024611, awarded to RAD), Research Foundation Flanders (PhD studentship awarded to EV, 1SF2222N), the National Natural Science Foundation of China (31870140, awarded to CD) and the Wellcome Trust and the Royal Society (211241/Z/18/Z, awarded to ERB).

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N2 - Microglia provide protection against a range of brain infections including bacteria, viruses and parasites, but how these glial cells respond to fungal brain infections is poorly understood. We investigated the role of microglia in the context of cryptococcal meningitis, the most common cause of fungal meningitis in humans. Using a series of transgenic- and chemical-based microglia depletion methods we found that, contrary to their protective role during other infections, loss of microglia did not affect control of Cryptococcus neoformans brain infection which was replicated with several fungal strains. At early time points post-infection, we found that microglia depletion lowered fungal brain burdens, which was related to intracellular residence of C. neoformans within microglia. Further examination of extracellular and intracellular fungal populations revealed that C. neoformans residing in microglia were protected from copper starvation, whereas extracellular yeast upregulated copper transporter CTR4. However, the degree of copper starvation did not equate to fungal survival or abundance of metals within different intracellular niches. Taken together, these data show how tissue-resident myeloid cells may influence fungal phenotype in the brain but do not provide protection against this infection, and instead may act as an early infection reservoir.

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VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7202

ER -

Microglia are not protective against cryptococcal meningitis

Abstract

Bibliographical note

Keywords

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Projects

Fungi on the brain: Interrogating Host-Pathogen Interactions during Fungal Meningitis

Sense and respond: Investigating molecular mechanisms regulating Cryptococcus neoformans Titan cell formation in response to bacterial triggers

Cite this