Pathogen and host genetics underpinning cryptococcal disease

Coelho, Carolina; Farrer, Rhys A.

doi:10.1016/bs.adgen.2020.02.001

Cited by 10 publications

(8 citation statements)

References 285 publications

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“…Healthy individuals acquire C. neoformans infections from environmental sources, and 56-70% of healthy children ages 1-10 years have serum antibodies against C. neoformans proteins 2 . Such early seropositivity suggests individuals frequently come into contact with C. neoformans and that infection in healthy individuals is either cleared or persists in latent, asymptomatic form 3,4 . Dissemination from airways requires C. neoformans to cross a series of tissue barriers to exit the airways, enter the bloodstream, and cross the blood-brain barrier where it causes meningoencephalitis 5 .…”

Section: Introductionmentioning

confidence: 99%

Cryptococcus neoformans rapidly invades the murine brain by sequential breaching of airway and endothelial tissues barriers, followed by engulfment by microglia

Francis,

Liddle,

Camacho

et al. 2023

Preprint

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The fungusCryptococcus neoformanscauses lethal meningitis in humans with weakened immune systems and is estimated to account for 10-15% of AIDS-associated deaths worldwide. There are major gaps in our understanding of how this environmental fungus evades the immune system and invades the mammalian brain before the onset of overt symptoms. To investigate the dynamics ofC. neoformanstissue invasion, we mapped early fungal localisation and host cell interactions at early times in infected brain, lung, and upper airways using mouse models of systemic and airway infection. To enable this, we developed anin situimaging pipeline capable of measuring large volumes of tissue while preserving anatomical and cellular information by combining thick tissue sections, tissue clarification, and confocal imaging. Made possible by these techniques, we confirm high fungal burden in mouse upper airway turbinates after nasal inoculation. Surprisingly, most yeasts in turbinates were titan cells, indicating this microenvironment enables titan cell formation with faster kinetics than reported in mouse lungs. Importantly, we observed one instance of fungal cells enmeshed in lamina propria of upper airways, suggesting penetration of airway mucosa as a possible route of tissue invasion and dissemination to the bloodstream. We extend previous literature positing bloodstream dissemination ofC. neoformans, via imagingC. neoformanswithin blood vessels of mouse lungs and finding viable fungi in the bloodstream of mice a few days after intranasal infection, suggesting that bloodstream access can occur via lung alveoli. In a model of systemic cryptococcosis, we show that as early as 24 h post infection, majority ofC. neoformanscells traversed the blood-brain barrier, and are engulfed or in close proximity to microglia. Our work establishes thatC. neoformanscan breach multiple tissue barriers within the first days of infection. This work presents a new method for investigating cryptococcal invasion mechanisms and demonstrates microglia as the primary cells responding to C. neoformans invasion.

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Section: Introductionmentioning

confidence: 99%

Cryptococcus neoformans rapidly invades the murine brain by sequential breaching of airway and endothelial tissues barriers, followed by engulfment by microglia

Francis,

Liddle,

Camacho

et al. 2023

Preprint

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“…Cryptococcus species are present in a range of environments, especially soil and in association with trees and decaying wood. A number of Cryptococcus species, most notably Cryptococcus neoformans and Cryptococcus gattii , also cause opportunistic infections of humans [ 1 ]. C. neoformans and related species belong to a large group of Tremellomycetes that are commonly associated with bird droppings.…”

Section: Introductionmentioning

confidence: 99%

Genomic epidemiology of a Cryptococcus neoformans case cluster in Glasgow, Scotland, 2018

et al. 2021

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In 2018, a cluster of two cases of cryptococcosis occurred at the Queen Elizabeth University Hospital (QEUH) in Glasgow, Scotland (UK). It was postulated that these cases may have been linked to pigeon droppings found on the hospital site, given there have been previous reports of Cryptococcus neoformans associated with pigeon guano. Although some samples of pigeon guano taken from the site yielded culturable yeast from genera related to Cryptococcus, they have since been classified as Naganishia or Papiliotrema spp., and no isolates of C. neoformans were recovered from either the guano or subsequent widespread air sampling. In an attempt to further elucidate any possible shared source of the clinical isolates, we used whole-genome sequencing and phylogenetic analysis to examine the relationship of the two Cryptococcus isolates from the QEUH cases, along with two isolates from sporadic cases treated at a different Glasgow hospital earlier in 2018. Our work demonstrated that these four clinical isolates were not clonally related; while all isolates were from the VNI global lineage and of the same mating type (MATα), the genotypes of the two QEUH isolates were separated by 1885 base changes and belonged to different sub-lineages, recently described as the intercontinental sub-clades VNIa-93 and VNIa-5. In contrast, one of the two sporadic 2018 clinical isolates was determined to belong to the VNIb sub-lineage and the other classified as a VNIV/VNI hybrid. Our work demonstrated that the two 2018 QEUH isolates and the two prior C. neoformans clinical isolates were all genetically distinct. It was not possible to determine whether the QEUH genotypes stemmed from independent sources or from the same source, i.e. pigeons carrying different genotypes, but it should be noted that whilst members of allied genera within the Tremellomycetes were isolated from the hospital environment, there were no environmental isolations of C. neoformans.

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“…C. decagatti has rarely been isolated, and there are few reports worldwide 3,48 . It was first named genotype VGIIIc 3,49 but recently renamed VGVI 50,51 . Recently, a case report of cryptococcosis caused by C. decagattii in Argentina was published in a patient belonging to a community living in huts made of branches in close physical contact with nature and domestic animals 48 .…”

Section: Discussionmentioning

confidence: 99%

Multilocus sequence typing of strains from the Cryptococcus gattii species complex from different continents

Bellet

Roger

Krasteva

et al. 2021

Mycoses

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Background Cryptococcus neoformans and Cryptococcus gattii species complexes are pathogens causing cryptococcal meningitis, a fungal infection that leads to death unless treated. Worldwide, it is estimated to kill over 180,000 individuals annually. Objectives We aim to investigate the molecular diversity of C. gattii isolates from strains isolated from 1995 to the present day from different continents. Method In this study, we analysed the molecular diversity by MLST and antifungal susceptibility by using the broth microdilution method according to the CLSI M27‐A4 protocol of a total of 26 strains from Cryptococcus gattii species complex from both clinical and environmental sources. Results Genotyping showed that most of the strains (17/26; 65.4%) belonged to serotype B and were distributed between three genotypes: VGI (13/17; 76.5%), VGII (3/17; 17.6%) and VGVI (1/17; 5.9%). The serotype C strains (9/26; 34.6%) were distributed between the VGIII (1/9; 11.1%) and VGIV (8/9; 88.9%) genotypes. The 26 strains belonged to 17 different MLST subtypes, and we highlight four new MLST genotypes (ST553, 554, 555 and 556). The two environmental strains were identified as serotype B and genotype VGI, but were of ST 51 and 154. All isolates have wild‐type MIC of fluconazole and flucytosine. Regarding amphotericin B, five VGI strains showed MICs to AMB equal to 1 µg/ml, and according to the ECV for these genotypes, they were considered non‐wild‐type strains. Conclusions The current study reveals the genetic diversity and new sequence types among strains from the C. gattii complex species.

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Pathogen and host genetics underpinning cryptococcal disease

Cited by 10 publications

References 285 publications

Cryptococcus neoformans rapidly invades the murine brain by sequential breaching of airway and endothelial tissues barriers, followed by engulfment by microglia

Cryptococcus neoformans rapidly invades the murine brain by sequential breaching of airway and endothelial tissues barriers, followed by engulfment by microglia

Genomic epidemiology of a Cryptococcus neoformans case cluster in Glasgow, Scotland, 2018

Multilocus sequence typing of strains from the Cryptococcus gattii species complex from different continents

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