Blood vessel occlusion by Cryptococcus neoformans is a mechanism for haemorrhagic dissemination of infection

Josie F Gibson, Aleksandra Bojarczuk, Robert J Evans, Alfred Alinafe Kamuyango, Richard Hotham, Anne K Lagendijk, Benjamin M Hogan, Philip W Ingham, Stephen A Renshaw, Simon A Johnston

Research output: Contribution to journalArticlepeer-review

9 Citations (SciVal)

Abstract

Meningitis caused by infectious pathogens is associated with vessel damage and infarct formation, however the physiological cause is often unknown. Cryptococcus neoformans is a human fungal pathogen and causative agent of cryptococcal meningitis, where vascular events are observed in up to 30% of patients, predominantly in severe infection. Therefore, we aimed to investigate how infection may lead to vessel damage and associated pathogen dissemination using a zebrafish model that permitted noninvasive in vivo imaging. We find that cryptococcal cells become trapped within the vasculature (dependent on their size) and proliferate there resulting in vasodilation. Localised cryptococcal growth, originating from a small number of cryptococcal cells in the vasculature was associated with sites of dissemination and simultaneously with loss of blood vessel integrity. Using a cell-cell junction tension reporter we identified dissemination from intact blood vessels and where vessel rupture occurred. Finally, we manipulated blood vessel tension via cell junctions and found increased tension resulted in increased dissemination. Our data suggest that global vascular vasodilation occurs following infection, resulting in increased vessel tension which subsequently increases dissemination events, representing a positive feedback loop. Thus, we identify a mechanism for blood vessel damage during cryptococcal infection that may represent a cause of vascular damage and cortical infarction during cryptococcal meningitis.

Original languageEnglish
Article numbere1010389
Number of pages21
JournalPLoS Pathogens
Volume18
Issue number4
DOIs
Publication statusPublished - 21 Apr 2022

Bibliographical note

Funding: JFG was supported by an award from the Singapore A STAR Research Attachment Programme (ARAP) in partnership with the University of Sheffield. Work in the PWI lab was funded by the A STAR Institute of Molecular and
Cell Biology (IMCB) and the Lee Kong Chian School of Medicine. RJE was supported by a British Infection Association postdoctoral fellowship (https://www.britishinfection.org/). AKL was supported by a University of Queensland Postdoctoral Fellowship. BMH by an NHMRC/ National Heart Foundation Career Development Fellowship (1083811). SAJ, AB, RJE, AK and RH,
were supported by Medical Research Council and Department for International Development Career Development Award Fellowship MR/J009156/1
(http://www.mrc.ac.uk/). SAJ was additionally supported by a Krebs Institute Fellowship (http://krebsinstitute.group.shef.ac.uk/), and Medical
Research Council Centre grant (G0700091). AK was supported by a Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377/Z/11/Z). SAR was supported by a Medical Research Council Programme Grant (MR/M004864/1). Light sheet microscopy was carried out in the Wolfson Light Microscopy Facility, supported by a BBSRC ALERT14 award for
light-sheet microscopy (BB/M012522/1). Funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the
manuscript.

Data Availability Statement: All relevant data are within the manuscript and its supporting Information file

Keywords

  • Animals
  • Cryptococcosis/microbiology
  • Cryptococcus neoformans
  • Humans
  • Meningitis, Cryptococcal
  • Zebrafish

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