Blood vessel occlusion byCryptococcus neoformansis a mechanism for haemorrhagic dissemination of infection

Abstract

24Meningitis caused by infectious pathogens are associated with vessel damage and infarct 25 formation, however the physiological cause is unknown. Cryptococcus neoformans, is a 26 human fungal pathogen and causative agent of cryptococcal meningitis, where vascular 27 events are observed in up to 30% of cases, predominantly in severe infection. Therefore, we 28 aimed to investigate how infection may lead to vessel damage and associated pathogen 29 dissemination using a zebrafish model for in vivo live imaging. We find that cryptococcal 30 cells become trapped within the vasculature (dependent on there size) and proliferate there 31 resulting in vasodilation. Localised cryptococcal growth, originating from a single or small 32 number of cryptococcal cells in the vasculature was associated with sites of dissemination 33 and simultaneously with loss of blood vessel integrity. Using a cell-cell junction tension 34 reporter we identified dissemination from intact blood vessels and where vessel rupture 35 occurred. Finally, we manipulated blood vessel stifness via cell junctions and found 36 increased stiffness resulted in increased dissemination. Therefore, global vascular 37 vasodilation occurs following infection, resulting in increased vessel tension which 38 subsequently increases dissemination events, representing a positive feedback loop. Thus, 39 we identify a mechanism for blood vessel damage during cryptococcal infection that may 40 represent a cause of vascular damage and cortical infarction more generally in infective 41 meningitis. 42 43 44 45 46 47 48 Introduction 49 Life threatening systemic infection commonly results from tissue invasion requiring 50 dissemination of microbes, usually via the blood stream. Blood vessel damage and blockage 51 are commonly associated with blood infection, as exemplified by mycotic (infective) 52 aneurisms or sub-arachnoid haemorrhage (1). Indeed, both bacterial and fungal meningitis 53 are associated with vascular events including vasculitis, aneurisms and infarcts (1-5). 54The mechanisms of dissemination to the brain in meningitis have been extensively studied in 55 vitro and in vivo. Experimental studies suggest three potential mechanisms: passage of the 56 pathogen between cells of the blood brain barrier, polarised endocytosis and exocytosis of 57 the pathogen by brain vascular endothelial cells, and passage through the blood brain 58 barrier inside immune cells. However, we hypothesised that blood vessel blockage and 59 haemorrhagic dissemination might be an alternative mechanism. 60Cryptococcus neoformans is an opportunistic fungal pathogen causing life threatening 61 cryptococcal meningitis in severely immunocompromised patients. C. neoformans is a 62 significant pathogen of HIV/AIDs positive individuals with cryptococcal meningitis ultimately 63 responsible for 15% of all AIDS related deaths worldwide (6). C . neoformans has 64 previsously been suggested to disseminate from the blood stream into the brain through 65 different routes, including transcytosis, and by...

Glucuronoxylomannan intranasal challenge prior toCryptococcus neoformanspulmonary infection enhances cerebral cryptococcosis in rodents

“…Mice lacking claudin-18, a TJ protein highly expressed in airway tissues, exhibited increased susceptibility to C. deneoformans infection through massive multiplication of yeast cells with poor granulomatous responses, reduced production of interferon-γ, and acidification of the alveolar space despite increased presence of immune cells such as CD4 + T cells [37]. In addition, GXM has detrimental effects on endothelial cells associated with blood vessels including alterations of adhesion molecules important for the migration of leukocytes to fight off the infection [38,39] and vascular vasodilation [40] following cryptococcal infection, which increases vessel tension and promotes fungal dissemination [40].…”

“…Likewise, GXM localized in blood vessels in brain parenchyma, and its deposition may have serious implications in the maintenance of the host BBB integrity. Vascular GXM accumulation and fungal occlusion have been described as responsible of infarction and hemorrhagic dissemination in CME patients [43,44] and animal models [40], respectively.…”