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PDE4B deficiency aids macrophage differentiation and contributes to Cryptococcus neoformans brain infection.

Overview

Authors: Ying Gong1,2, Ting Wang1,2, Xin Chen1,2, Yuwei Li1,2, Shaofan Ye1,2, Shan Liu1,2, Chunan Sun1,2, Xia Zhang3, Chen Yang1,2, Yonglin Yang3, Guannan Zhang1, Mingshun Zhang1,2
ORCID iDs: Mingshun Zhang
  1. Department of Immunology, National Vaccine Innovation Platform, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
  2. NHC Key Laboratory of Antibody Technique, Jiangsu Key Laboratory of Pathogen Biology, Department of Immunology, Nanjing Medical University, Nanjing, China
  3. Department of Infectious Diseases, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Nanjing, China
Institutions: Nanjing Medical University (China); Taizhou People's Hospital (China)
Journal: PLoS pathogens, volume 22, issue 3, article e1014040
Dates: received 8 November 2025; accepted 26 February 2026; published online 10 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1371/journal.ppat.1014040 · PMID 41805786 · PMCID PMC12987588 · OpenAlex W7134928610
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: mouse (organism), other condition (population), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials
MeSH: Brain*, Cryptococcus neoformans*, Cyclic Nucleotide Phosphodiesterases, Type 4*, Macrophages*, Meningitis, Cryptococcal*, Animals, Blood-Brain Barrier, Cell Differentiation, Cryptococcosis, Female, Mice, Mice, Inbred C57BL, Mice, Knockout (* major topic)
Journal subjects: Biology and Life Sciences, Cell Biology, Cellular Types, Animal Cells, Blood Cells, White Blood Cells, Macrophages, Immune Cells, Immunology, Medicine and Health Sciences, Organisms, Eukaryota, Fungi, Cryptococcus, Medical Conditions, Infectious Diseases, Fungal Diseases, Cryptococcus Neoformans, Microbiology, Medical Microbiology, Microbial Pathogens, Fungal Pathogens, Pathology and Laboratory Medicine, Pathogens, Mycology, Cell Processes, Phagocytosis, Research and Analysis Methods, Spectrum Analysis Techniques, Spectrophotometry, Cytophotometry, Flow Cytometry, Anatomy, Nervous System, Central Nervous System
Topic: Fungal Infections and Studies (Epidemiology, Medicine), according to OpenAlex
Funding: National Natural Science Foundation of China (National Science Foundation of China) (82171738); Project of Nanjing Medical University (TZKY20230201); Taizhou Science and Technology Support Plan (Social Development) (No. TSL202503)
Citations: not cited yet (Europe PMC); 61 references in the paper

Abstract

Cryptococcal meningitis is a fatal complication. Macrophages have been proposed to function as candidate “Trojan horse” cells, transferring Cryptococcus neoformans (C. neoformans) into the brain. The mechanisms of Trojan horses in cryptococcal meningitis are largely elusive. In this study, we performed scRNA-Seq on immune cells infiltrating the brain in a murine model of cryptococcal meningitis. Bioinformatics analysis revealed that phosphodiesterase 4B (PDE4B) is a candidate regulator associated with C. neoformans infected-macrophage. C. neoformans increases the total level of PDE4B in macrophages. However, virulent strains with increased production of melanin paradoxically decreased PDE4B expression in macrophages, implying that PDE4B in macrophages may be negatively associated with C. neoformans invasion. PDE4B inhibition increased Arg1, CXCR4 and CCR7 expression in macrophages, a process regulated by the cAMP/PKA signaling pathway. As expected, PDE4B inhibitors promote the ability of C. neoformans infected-macrophages to cross the blood–brain barrier (BBB) in vitro. Similarly, PDE4B inhibitors or PDE4B knockout increase the fungal burden in the brain, which is, at least partially, rescued by macrophage depletion, and adoptive transfer experiments further support macrophage-mediated fungal delivery to the brain. In contrast, PDE4B activation reduces fungal burden in the brain, including when administered after infection onset. Overall, this study revealed that PDE4B functions as an important regulator of macrophage functional programming during infection and supports a macrophage-mediated dissemination mechanism contributing to brain invasion, and is a potential therapeutic target for cryptococcal meningitis.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data Availability

scRNA-Seq data is accessible to GEO accession GSE287392 with full open access. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE287392 All other data is provided in the manuscript and Supporting information files.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 13 MeSH terms, 3 funders, 61 references.

Cite

This paper

Gong, Y., Wang, T., Chen, X., Li, Y., Ye, S., Liu, S., Sun, C., Zhang, X., Yang, C., Yang, Y., Zhang, G., & Zhang, M. (2026). PDE4B deficiency aids macrophage differentiation and contributes to Cryptococcus neoformans brain infection. PLoS pathogens, 22(3), e1014040. https://doi.org/10.1371/journal.ppat.1014040

BibTeX

@article{gong2026pde4b,
author = {Gong, Ying and Wang, Ting and Chen, Xin and Li, Yuwei and Ye, Shaofan and Liu, Shan and Sun, Chunan and Zhang, Xia and Yang, Chen and Yang, Yonglin and Zhang, Guannan and Zhang, Mingshun},
title = {{PDE4B deficiency aids macrophage differentiation and contributes to Cryptococcus neoformans brain infection}},
journal = {PLoS pathogens},
year = {2026},
month = mar,
volume = {22},
number = {3},
pages = {e1014040},
publisher = {PLOS},
issn = {1553-7366},
doi = {10.1371/journal.ppat.1014040},
url = {https://doi.org/10.1371/journal.ppat.1014040},
pmid = {41805786},
pmcid = {PMC12987588}
}

RIS

TY - JOUR
AU - Gong, Ying
AU - Wang, Ting
AU - Chen, Xin
AU - Li, Yuwei
AU - Ye, Shaofan
AU - Liu, Shan
AU - Sun, Chunan
AU - Zhang, Xia
AU - Yang, Chen
AU - Yang, Yonglin
AU - Zhang, Guannan
AU - Zhang, Mingshun
TI - PDE4B deficiency aids macrophage differentiation and contributes to Cryptococcus neoformans brain infection
T2 - PLoS pathogens
J2 - PLoS Pathog
PY - 2026
DA - 2026/03/10
VL - 22
IS - 3
SP - e1014040
SN - 1553-7366
PB - PLOS
DO - 10.1371/journal.ppat.1014040
UR - https://doi.org/10.1371/journal.ppat.1014040
LA - en
ER -

CSL-JSON

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