Blood vessel occlusion by Cryptococcus neoformans is a mechanism for haemorrhagic dissemination of infection
| Autor: | Robert Evans, Aleksandra Bojarczuk, Renshaw Sa, Johnston Sa, Lagendijk Ak, Gibson Jf, Kamuyango A, Ingham Pw, Hogan Bm, Richard Hotham |
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| Přispěvatelé: | Lee Kong Chian School of Medicine (LKCMedicine), Institute of Molecular and Cell Biology (A*Star) Singapore |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
medicine.medical_specialty
Cryptococcus Neoformans Immunology Biology Meningitis Cryptococcal Microbiology 03 medical and health sciences 0302 clinical medicine Text mining Virology Internal medicine Genetics medicine Animals Humans Medicine [Science] Molecular Biology Zebrafish 030304 developmental biology 0303 health sciences business.industry Mechanism (biology) Blood vessel occlusion Cryptococcosis Blood Vessel Occlusion 3. Good health Cardiology Cryptococcus neoformans Parasitology business 030217 neurology & neurosurgery |
| Popis: | 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. Agency for Science, Technology and Research (A*STAR) Nanyang Technological University Published version 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). |
| Databáze: | OpenAIRE |
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