Featured
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| Open AccessThe vacuolar fusion regulated by HOPS complex promotes hyphal initiation and penetration in Candida albicans
The transition between yeast and hyphae is crucial for the pathogenicity of Candida albicans. Here, Liu et al. show that vacuole fusion is active during hyphal extension and that large vacuoles increase the mechanical forces of hyphae penetrating into organs.
- Yu Liu
- , Ruina Wang
- & Lan Yan
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Article
| Open AccessHyphal Als proteins act as CR3 ligands to promote immune responses against Candida albicans
Integrin CR3 (CD11b/CD18) is a receptor responsible for recognizing fungal β-glucan. Here, Zhou et al show that the Candida albicans Als family proteins are ligands for the CD11b I domain; an interaction which synergizes with β-glucan to activate CR3.
- Tingting Zhou
- , Norma V. Solis
- & Haoping Liu
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Article
| Open AccessA secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1
Triazole antifungals are widely used and exert their action by inhibiting ergosterol biosynthesis. Here, Rybak et al show that these drugs both inhibit ergosterol biosynthesis and induce accumulation of pathway intermediates that directly induce inhibition of sterol synthesis.
- Jeffrey M. Rybak
- , Jinhong Xie
- & Jarrod R. Fortwendel
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Article
| Open AccessEpidemiological, clinical, and genomic landscape of coccidioidomycosis in northeastern Brazil
Coccidioidomycosis, a WHO-listed mycosis, is neglected in South America. Analysis of 292 cases in Brazil, often tied to armadillo hunting, unveils unique disease patterns, environmental factors and pathogen genetics causing the disease.
- Kelsen Dantas Eulálio
- , Daniel R. Kollath
- & Marcus de Melo Teixeira
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Article
| Open AccessGlobal fungal-host interactome mapping identifies host targets of candidalysin
Candidalysin is a toxin secreted by Candida albicans. Although critical for pathogenesis, its intracellular targets are not well mapped. Here, Zhang et al screen for interacting proteins and identify that candidalysin can modulate the DNA damage repair pathway to promote fungal infection.
- Tian-Yi Zhang
- , Yao-Qi Chen
- & Ning-Ning Liu
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Article
| Open AccessTandem gene duplications contributed to high-level azole resistance in a rapidly expanding Candida tropicalis population
Candida tropicalis is a cause of invasive candidiasis infection in humans that has been increasingly associated with azole drug resistance. In this study, the authors investigate the genetic basis for azole resistance through analysis of whole-genome sequencing and multilocus sequence typing data.
- Xin Fan
- , Rong-Chen Dai
- & Meng Xiao
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Article
| Open AccessC-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity
Receptor dimerization can modulate immune responses during various microbial infections. Here, the authors show that C-type lectin receptor-2d (CLEC2D) negatively regulates antifungal immunity through forming homodimers or heterodimers with TLR2.
- Fan Li
- , Hui Wang
- & Xin-Ming Jia
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Article
| Open AccessCryptococcus neoformans adapts to the host environment through TOR-mediated remodeling of phospholipid asymmetry
Here, Ristow et al show that the environmental fungus Cryptococcus adapts to the higher carbon dioxide levels present in human tissue through activation of the Target-of-Rapamycin stress response pathway leading to reorganization of its outer membrane lipids and host adaptation.
- Laura C. Ristow
- , Andrew J. Jezewski
- & Damian J. Krysan
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Article
| Open AccessGenotypic diversity and unrecognized antifungal resistance among populations of Candida glabrata from positive blood cultures
Candida glabrata bloodstream infections are thought to be mostly caused by a single strain. Here, the authors describe genotypic and phenotypic diversity of Candida glabrata in ten individual blood cultures, and find diversity in drug susceptibility and virulence within patients.
- Hassan Badrane
- , Shaoji Cheng
- & M. Hong Nguyen
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Article
| Open AccessBridging of host-microbiota tryptophan partitioning by the serotonin pathway in fungal pneumonia
Serotonin regulates mood as well as intestinal homeostasis, but its role in lung immune homeostasis is less clear. Here, Renga et al. show that serotonin regulates immune and microbial metabolic functions in respiratory pneumonia, beyond its mood regulatory function, by modulating tryptophan metabolism in the cystic fibrosis lung.
- Giorgia Renga
- , Fiorella D’Onofrio
- & Luigina Romani
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Article
| Open AccessCD8+ tissue-resident memory T-cell development depends on infection-matching regulatory T-cell types
Type-1 regulatory T cells promoted the generation of CD8+ tissue-resident memory T (TRM) cells during intracellular infections in the gut. Here, the authors show that the establishment TRM cells more broadly depends on the presence of regulatory T cells matching the type of infection.
- Leandro Barros
- , Daryna Piontkivska
- & Cristina Ferreira
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Article
| Open AccessToll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen
Fungal pathogens are recognised and phagocytosed by macrophages in the early stages of infection. Here, Onyishi et al. identify a crosstalk between Toll Like Receptor 4 and Macrophage Scavenger Receptor 1 in the regulation of Cryptococcus neoformans uptake.
- Chinaemerem U. Onyishi
- , Guillaume E. Desanti
- & Robin C. May
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Article
| Open AccessT cell infiltration into the brain triggers pulmonary dysfunction in murine Cryptococcus-associated IRIS
Cryptococcus-associated immune reconstitution inflammatory syndrome is a condition found in immunocompromised patients on antiretroviral therapy and characterized by numerous symptoms, including pulmonary distress. Here, Kawano et al use a mouse model to characterize the processes underlying this pulmonary dysfunction.
- Tasuku Kawano
- , Jinyan Zhou
- & Makoto Inoue
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Article
| Open AccessReciprocal modulation of ammonia and melanin production has implications for cryptococcal virulence
Cryptococcus neoformans has numerous described virulence mechanisms including urease secretion and melanization. Here, Baker and Casadevall, describe the reciprocal relationship between these two factors and their contribution to infection.
- Rosanna P. Baker
- & Arturo Casadevall
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Article
| Open AccessPD-L1 negatively regulates antifungal immunity by inhibiting neutrophil release from bone marrow
Programmed death ligand 1 (PD-L1) suppresses host immunity during infection and microbial sepsis. Here, the authors show that PD-L1 does this by regulating the secretion of CXCL1 and CXCL2 to control neutrophil mobilization during Candida albicans infection.
- Yao Yu
- , Rong-Rong Wang
- & Xin-Ming Jia
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Article
| Open AccessStructural and functional analysis of EntV reveals a 12 amino acid fragment protective against fungal infections
Enterococcus faecalis has been reported to inhibit Candida albicans virulence via secretion of the bacteriocin EntV. Here, the authors present the crystal structure and characterise the antifungal properties of this peptide in numerous in vitro and in vivo assays.
- Melissa R. Cruz
- , Shane Cristy
- & Danielle A. Garsin
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Article
| Open AccessIL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis
The beta-glucan receptor EphA2 is known to maintain mucosal immunity. Here, its role in modulating renal immunopathology via IL-23 signalling and ferroptotic cell death during candidiasis is characterised.
- Nicolas Millet
- , Norma V. Solis
- & Marc Swidergall
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Article
| Open AccessInhibition of myeloid-derived suppressor cell arginase-1 production enhances T-cell-based immunotherapy against Cryptococcus neoformans infection
Cryptococcus neoformans causes opportunistic infection and potentially lethal immunopathology but therapeutic options are limited. Here the authors implicate myeloid derived suppressor cells during C. neoformans infection and suggest targeting arginase-1 production as a potential therapeutic strategy.
- Ya-Nan Li
- , Zhong-Wei Wang
- & Xin-Ming Jia
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Article
| Open AccessTargeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation
There is an urgent need for novel strategies to combat life-threatening fungal infections. Here, Revie et al. identify a compound that induces alterations in fungal membranes, synergizes with azole antifungals against the pathogen Candida albicans, and inhibits virulence traits and biofilm formation in animal models of infection.
- Nicole M. Revie
- , Kali R. Iyer
- & Leah E. Cowen
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Article
| Open AccessInnate immune responses against the fungal pathogen Candida auris
Candida auris is a multidrug-resistant human fungal pathogen responsible for nosocomial outbreaks worldwide. Here, the authors identify differential innate immune responses induced by C. auris and Candida albicans in vitro and in vivo, which correlate with structural features of the cell wall.
- Yuanyuan Wang
- , Yun Zou
- & Dongsheng Zhou
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Article
| Open AccessCandida albicans evades NK cell elimination via binding of Agglutinin-Like Sequence proteins to the checkpoint receptor TIGIT
Natural killer cells have emerged as critical immune cells in the response to fungal infection. Here the authors identify how Candida albicans evades the natural killer cell response via expression of ligands that directly modify the natural killer cell response and can be therapeutically targeted to restore the anti-Candida immunity.
- Yoav Charpak-Amikam
- , Tom Lapidus
- & Ofer Mandelboim
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Article
| Open AccessIn vivo imaging of invasive aspergillosis with 18F-fluorodeoxysorbitol positron emission tomography
Current diagnostic methods for invasive aspergillosis are time-consuming and poorly sensitive. Here, the authors show that positron emission tomography with 2-deoxy-2-18F-fluorosorbitol can visualize Aspergillus fumigatus infection of the lungs, brain and muscles in mouse models, and can distinguish pulmonary aspergillosis from other diseases such as Staphylococcus aureus infection and lung cancer.
- Dong-Yeon Kim
- , Ayoung Pyo
- & Jung-Joon Min
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Article
| Open AccessPhagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis
Dectin-1 is a critical component of the innate sensing repertoire which is involved in pattern based recognition of fungal pathogens. Here the authors show that intramembrane proteolysis is involved in the regulation of the antifungal host response by termination of the phagosomal signalling of Dectin-1.
- Torben Mentrup
- , Anna Yamina Stumpff-Niggemann
- & Bernd Schröder
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Article
| Open AccessSerum amyloid P component is an essential element of resistance against Aspergillus fumigatus
Serum Amyloid P is a humoral component with established roles in the response to bacterial infection and regulation of tissue remodeling. Here the authors provide evidence to a further crucial role of serum amyloid P in the context of fungal pathogen Aspergillus fumigatus.
- Andrea Doni
- , Raffaella Parente
- & Alberto Mantovani
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Article
| Open AccessStructural specificities of cell surface β-glucan polysaccharides determine commensal yeast mediated immuno-modulatory activities
Yeast form part of the host microbiome with known impact on host immunity. Here the authors identify and investigate the impact of commensal yeast-derived polysaccharides in modulating host inflammation, and show its potential for inhibiting inflammation in a number of models of inflammatory diseases.
- Changhon Lee
- , Ravi Verma
- & Sin-Hyeog Im
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Article
| Open AccessAntibody-guided in vivo imaging of Aspergillus fumigatus lung infections during antifungal azole treatment
Invasive pulmonary aspergillosis is a life-threatening fungal lung disease devoid of specific rapid diagnosis and with limited therapeutic options. Here, the authors show how state-of-the-art imaging approaches can enable specific diagnosis and therapy monitoring of this infection.
- Sophie Henneberg
- , Anja Hasenberg
- & Nicolas Beziere
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Article
| Open AccessTAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response
TAGAP gene variants are linked to human autoimmunity. Here the authors identify TAGAP as a Dectin-1 and EphB2-binding protein mediating antifungal innate immune signaling and cytokine production, and demonstrate TAGAP in non-T cells promotes Th17 response in mouse models of infection and autoimmunity.
- Jianwen Chen
- , Ruirui He
- & Chenhui Wang
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Article
| Open AccessFungal dissemination is limited by liver macrophage filtration of the blood
Patients with liver diseases are at increased risk of fungal infections. Here the authors show that Kupffer cells are critical for the filtration of fungi out of the blood and thereby for liver-mediated protection against disseminating fungal infection.
- Donglei Sun
- , Peng Sun
- & Meiqing Shi
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Article
| Open AccessCandidalysin activates innate epithelial immune responses via epidermal growth factor receptor
Candida albicans is an opportunistic fungus primarily affecting immunocompromised patients. Here, the authors identify a novel mechanism of host immune stimulation and highlight candidalysin and EGFR signalling components as potential targets for prophylactic and therapeutic intervention of mucosal candidiasis.
- Jemima Ho
- , Xuexin Yang
- & Julian R. Naglik
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Article
| Open AccessCoordinated host-pathogen transcriptional dynamics revealed using sorted subpopulations and single macrophages infected with Candida albicans
The outcomes of the interactions between individual host cells and pathogens are heterogeneous. Here, the authors assess transcriptional variability in both host and pathogen during infection of macrophages with the fungus Candida albicans, using sorted subpopulations and single macrophages.
- José F. Muñoz
- , Toni Delorey
- & Christina A. Cuomo
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Article
| Open AccessStructural basis for species-selective targeting of Hsp90 in a pathogenic fungus
The chaperone Hsp90 is a potential target for the development of drugs against fungal pathogens. Here the authors determine the structure of the Hsp90 nucleotide-binding domain from Candida albicans, which they use to design an inhibitor and demonstrate its selectivity for the fungal enzyme, both biochemically and in cells.
- Luke Whitesell
- , Nicole Robbins
- & Leah E. Cowen
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Article
| Open AccessMicroglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits
The potential links between infections and neurodegenerative disorders are unclear. Here, Wu et al. present a mouse model of low-grade candidemia characterized by highly localized cerebritis, accumulation of amyloid precursor protein and beta peptides, and mild memory impairment that resolves with fungal clearance.
- Yifan Wu
- , Shuqi Du
- & David B. Corry
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Article
| Open AccessSingle human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis
Late diagnosis and ineffective treatment of fungal infections lead to high mortality. Here, Rudkin et al. generate anti-Candida human monoclonal antibodies with diagnostic and therapeutic potential, by expressing recombinant antibodies from genes cloned from B cells of patients suffering candidiasis.
- Fiona M. Rudkin
- , Ingrida Raziunaite
- & Neil A. R. Gow
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Review Article
| Open AccessMolecular diagnostics in medical mycology
Diagnosing fungal infections poses a number of unique problems. In this Review, Wickes and Wiederhold discuss molecular technologies used for fungal identification, and the problems associated with their development and implementation in today’s clinical microbiology laboratories.
- Brian L. Wickes
- & Nathan P. Wiederhold
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Article
| Open AccessThe fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes
Phagocytic cells of the innate immune system play critical roles in defence against invading pathogens including the opportunistic pathogen Candida albicans. Here the authors show that C. albicans derived Candidalysin in addition to being a cell-damaging toxin to mononuclear phagocytes is a trigger of NLRP3 inflammasome activation in these cells.
- Lydia Kasper
- , Annika König
- & Bernhard Hube
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Article
| Open AccessLung colonization by Aspergillus fumigatus is controlled by ZNF77
Aspergillus fumigatus regularly colonises the lungs but in the context of respiratory disease can be associated with increased pathology. Here the authors show mutations in ZNF77 result in altered bronchial epithelial characteristics and enhanced fungal burden.
- Sara Gago
- , Nicola L. D. Overton
- & Paul Bowyer
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Article
| Open AccessIron restriction inside macrophages regulates pulmonary host defense against Rhizopus species
Mucormycosis is a life-threatening respiratory fungal infection that typically occurs in patients with abnormalities in iron metabolism. Here the authors show that iron restriction inside the phagosome of macrophages is an essential component of the host defense against Rhizopus, the main species causing mucormycosis.
- Angeliki M. Andrianaki
- , Irene Kyrmizi
- & Georgios Chamilos
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Article
| Open AccessAzole-induced cell wall carbohydrate patches kill Aspergillus fumigatus
Azole antifungals inhibit fungal ergosterol biosynthesis. Here, Geißel et al. show that the fungicidal activity of azoles involves excessive synthesis of cell wall carbohydrates at defined spots along the hyphae, leading to formation of membrane invaginations and eventually rupture of the plasma membrane.
- Bernadette Geißel
- , Veronika Loiko
- & Johannes Wagener
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Article
| Open AccessGenetic deficiency of NOD2 confers resistance to invasive aspergillosis
NOD2 has been shown to be crucial for immune recognition of Aspergillus infection. Here the authors show that a common NOD2 genetic variant associated with Crohn’s disease is associated with reduced risk of disease due to enhanced antifungal activates of monocytes and macrophages.
- Mark S. Gresnigt
- , Cristina Cunha
- & Frank L. van de Veerdonk
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Article
| Open AccessIdentification of the fungal ligand triggering cytotoxic PRR-mediated NK cell killing of Cryptococcus and Candida
Natural killer (NK) cells has been show to mediate fungi killing via the activating receptor NKp30, but the fungal target for NKp30 is still unclear. Here the authors show, using atomic force microscopy and live cell imaging, that β-1,3-glucan is expressed by Cryptococcus neoformans and Candida albicans and responsible for NKp30-mediated NK killing.
- Shu Shun Li
- , Henry Ogbomo
- & Christopher H. Mody
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Article
| Open AccessGalectin-3 impacts Cryptococcus neoformans infection through direct antifungal effects
The protein Galectin-3 modulates host immunity and plays roles during infections. Here, Almeida et al. show that this protein contributes to host defence against infection with the fungal pathogen Cryptococcus neoformans by inhibiting fungal growth and inducing lysis of fungal extracellular vesicles.
- Fausto Almeida
- , Julie M. Wolf
- & Arturo Casadevall
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Article
| Open AccessAn integrated genomic and transcriptomic survey of mucormycosis-causing fungi
Fungi of the order Mucorales can cause life-threatening infections. Here, Chibucos et al. present genomic and transcriptomic analyses of a diverse set of Mucorales fungi, shedding light on their evolution and identifying potential therapeutic targets in the pathogens and the host.
- Marcus C. Chibucos
- , Sameh Soliman
- & Vincent M. Bruno
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Article
| Open AccessPrevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance
The fungal pathogen Candida glabrata readily acquires resistance to multiple types of antifungal drugs. Here, Healey et al. show that C. glabrataclinical isolates often carry mutations in a gene involved in DNA mismatch repair, and this is associated with increased propensity to develop antifungal resistance.
- Kelley R. Healey
- , Yanan Zhao
- & David S. Perlin
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Article
| Open AccessGenome analysis of three Pneumocystis species reveals adaptation mechanisms to life exclusively in mammalian hosts
Pneumocystis jirovecii is a fungus that can cause life-threatening pneumonia in immunocompromised patients. Here, the authors sequence the genomes of P. jirovecii and two other Pneumocystisspecies, and show the unexpected absence of chitin (a near universal fungal cell wall component).
- Liang Ma
- , Zehua Chen
- & Joseph A. Kovacs
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Article
| Open AccessMHC variation sculpts individualized microbial communities that control susceptibility to enteric infection
Composition of the gut microbiota is regulated by IgA antibodies which are produced under the control of MHCII-restricted B cells. Here the authors show that MHCII polymorphisms sculpt bacterial composition of the gut, which influences a host’s susceptibility to enteric Salmonellainfection.
- Jason L. Kubinak
- , W. Zac Stephens
- & June L. Round
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Autophagy enhances NFκB activity in specific tissue macrophages by sequestering A20 to boost antifungal immunity
Immune activation must be carefully tuned to respond to infection and restrained to prevent tissue damage. Here the authors show that autophagy has a role in the immune response to Candida albicans, activating NFκB in macrophages by sequestering the NFκB inhibitor A20.
- Masashi Kanayama
- , Makoto Inoue
- & Mari L. Shinohara
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Article
| Open AccessCo-infection alters population dynamics of infectious disease
Co-infection of plants with multiple pathogen strains is predicted to alter disease dynamics. Here, Susi et al.use experimental and natural population data to show that co-infected host plants spread more disease and cause more devastating epidemics than singly infected hosts.
- Hanna Susi
- , Benoit Barrès
- & Anna-Liisa Laine
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Reciprocal functions of Cryptococcus neoformans copper homeostasis machinery during pulmonary infection and meningoencephalitis
The fungus Cryptococcus neoformans can cause lethal meningoencephalitis in humans after initiating infection in the lung. Here, the authors describe the roles played by two C. neoformanscopper transporters in pathogen’s survival during lung and brain infection.
- Tian-Shu Sun
- , Xiao Ju
- & Chen Ding
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Article
| Open Access‘Division of labour’ in response to host oxidative burst drives a fatal Cryptococcus gattii outbreak
Outbreak strains of the pathogenic fungus Cryptococcus gattii display an increased ability to form tubular mitochondria. Here, Voelz et al.show that mitochondrial tubularization is induced by host reactive oxygen species within macrophages and facilitates rapid growth of neighbouring fungal cells.
- Kerstin Voelz
- , Simon A. Johnston
- & Robin C. May