Candida albicans isolates with different genomic backgrounds display a differential response to macrophage infection

Few human pathogens possess the ability exhibited by Candida albicans to colonize and cause symptomatic infections at different body sites. The host immune system is the major factor determining whether this opportunistic yeast behaves as a commensal or as a pathogen, since C. albicans strains appear capable of expressing similar virulence factors in response to specific body-district cues. This report provides evidence showing that C. albicans isolates with diverse genomic backgrounds (b and c karyotypes) differently modulate their pathogenic potential when assayed in cocultures with human monocytic derived macrophages (THP-1 cells). Striking differences were observed in the ability to undergo bud-hypha transition, a relevant C. albicans virulence factor, between b and c karyotypes (P<0.0001) upon their internalization by macrophages. All c types were able to develop hyphal forms, resist intracellular killing, replicate, and escape from macrophages. The b type isolates, which were shown to be more efficiently ingested by THP-1 cells than the c type strains (P=0.013), were susceptible to intracellular killing and predominantly found as blastoconidia inside macrophages. Despite their different intracellular disposition, both b and c type isolates were equally able to undergo morphogenesis and to express NRG1 and HWP1 genes, markers of the bud-hypha transition program, during in vitro propagation. Since macrophages play a critical role in the host resistance to C. albicans, the different response of b and c isolates to macrophage infection suggests that the c type strains are better suited to behave as a more virulent strain cluster.     

Immunosensing during colonization by Candida albicans: does it take a village to colonize the intestine?

Candida albicans, an opportunistic fungal pathogen and a component of the normal flora of the gastrointestinal tract, is a frequent colonizer of humans. Is C. albicans capable of sensing the immune status of its host, a process we term immunosensing, and, if so, how? C. albicans causes serious disease only in immunocompromised hosts and therefore the ability to immunosense would be advantageous to an organism. We propose a speculative model whereby, during colonization, C. albicans produces phenotypic variants that vary in relative concentration depending on host status. One variant is optimized for persistence as a commensal, whereas the other variant has higher capacity to initiate pathogenic interactions. When the ratio of the two variants changes, the pathogenic potential of the population changes. The critical element of this model is that the C. albicans colonizing population is not uniform but is composed of subpopulations of phenotypic variants that are advantageous under different host conditions.     

Candida albicans iron acquisition within the host

As a commensal and opportunistic pathogen, Candida albicans possesses a range of determinants that contribute to survival, persistence and virulence. Among this repertoire of fitness and virulence attributes are iron acquisition factors and pathways, which allow fungal cells to gain this essential mineral in the iron-poor environment of the host. The aim of this review is to present the strategies used by C. albicans to exploit host iron reservoirs and their impact on C. albicans pathogenicity. Because iron in the human host is mostly linked to host proteins, pathogens such as C. albicans must possess mechanisms to gain iron from these proteins. Here, we introduce the most important groups of human proteins, including haemoglobin, transferrin, lactoferrin and ferritin, which contain iron and that are potential iron sources for invading microorganisms. We then summarize and discuss the known and proposed strategies by which C. albicans exploits or may exploit iron from host proteins and compare these with strategies from other pathogenic microorganisms.     

A drug-sensitive genetic network masks fungi from the immune system

Fungal pathogens can be recognized by the immune system via their beta-glucan, a potent proinflammatory molecule that is present at high levels but is predominantly buried beneath a mannoprotein coat and invisible to the host. To investigate the nature and significance of "masking" this molecule, we characterized the mechanism of masking and consequences of unmasking for immune recognition. We found that the underlying beta-glucan in the cell wall of Candida albicans is unmasked by subinhibitory doses of the antifungal drug caspofungin, causing the exposed fungi to elicit a stronger immune response. Using a library of bakers' yeast (Saccharomyces cerevisiae) mutants, we uncovered a conserved genetic network that is required for concealing beta-glucan from the immune system and limiting the host response. Perturbation of parts of this network in the pathogen C. albicans caused unmasking of its beta-glucan, leading to increased beta-glucan receptor-dependent elicitation of key proinflammatory cytokines from primary mouse macrophages. By creating an anti-inflammatory barrier to mask beta-glucan, opportunistic fungi may promote commensal colonization and have an increased propensity for causing disease. Targeting the widely conserved gene network required for creating and maintaining this barrier may lead to novel broad-spectrum antimycotics.     

Candida albicans modulates host defense by biosynthesizing the pro-resolving mediator resolvin E1

Candida albicans is an opportunistic fungal pathogen of humans that resides commensally on epithelial surfaces, but can cause inflammation when pathogenic. Resolvins are a class of anti-inflammatory lipids derived from omega-3 polyunsaturated fatty acids (PUFA) that attenuate neutrophil migration during the resolution phase of inflammation. In this report we demonstrate that C. albicans biosynthesizes resolvins that are chemically identical to those produced by human cells. In contrast to the trans-cellular biosynthesis of human Resolvin E1 (RvE1), RvE1 biosynthesis in C. albicans occurs in the absence of other cellular partners. C. albicans biosynthesis of RvE1 is sensitive to lipoxygenase and cytochrome P450 monoxygenase inhibitors. We show that 10nM RvE1 reduces neutrophil chemotaxis in response to IL-8; 1nM RvE1 enhanced phagocytosis of Candida by human neutrophils, as well as intracellular ROS generation and killing, while having no direct affect on neutrophil motility. In a mouse model of systemic candidiasis, RvE1 stimulated clearance of the fungus from circulating blood. These results reveal an inter-species chemical signaling system that modulates host immune functions and may play a role in balancing host carriage of commensal and pathogenic C. albicans.     

Importance of the Candida albicans cell wall during commensalism and infection

An imbalance of the normal microbial flora, breakage of epithelial barriers or dysfunction of the immune system favour the transition of the human pathogenic yeast Candida albicans from a commensal to a pathogen. C. albicans has evolved to be adapted as a commensal on mucosal surfaces. As a commensal it has also acquired attributes, which are necessary to avoid or overcome the host defence mechanisms. The human host has also co-evolved to recognize and eliminate potential fungal invaders. Many of the fungal genes that have been the focus of this co-evolutionary process encode cell wall components. In this review, we will discuss the transition from commensalism to pathogenesis, the key players of the fungal cell surface that are important for this transition, the role of the morphology and the mechanisms of host recognition and response.     

抗白念珠菌感染的疫苗及抗体研究进展

白念珠菌是与人类共生的条件致病真菌,能引起免疫力低下患者皮肤黏膜和全身系统性持续感染.系统性念珠菌病是引起免疫力低下患者死亡的主要原因之一.由于临床缺乏念珠菌病的早期诊疗手段、可用的抗真菌药物种类有限且毒副作用大、耐药菌株越来越普遍、新药研发难度大等因素,抗真菌治疗依然面临着严峻挑战.目前有较多研究者致力于阐明白念珠菌感染的宿主免疫应答机制,并试图研发抗白念珠菌感染的免疫治疗方法,使免疫治疗有望成为预防和治疗真菌感染的有效手段.该文将几种抗白念珠菌感染的疫苗和抗体研究进展作简要概述,旨在为新型抗白念珠菌感染疫苗及抗体的研究提供参考.     

Sensing the host environment: recognition of hemoglobin by the pathogenic yeast Candida albicans

Adhesion to host cells and tissues is important for several steps in the pathogenesis of disseminated Candida albicans infections. Although such adhesion is evident in vivo and for C. albicans grown in vitro in complex medium, some adhesive activities are absent when cultures are grown in defined media. However, addition of hemoglobin to defined media restores binding and adhesion to several host proteins. This activity of hemoglobin is independent of iron acquisition and is mediated by a cell surface hemoglobin receptor. In addition to regulating expression of adhesion receptors, hemoglobin rapidly induces expression of several genes. One of these, a heme oxygenase, allows the pathogen to utilize exogenous heme or hemoglobin to acquire iron and to produce the cytoprotective molecules alpha-biliverdin and carbon monoxide. The specific recognition of and responses to hemoglobin demonstrate a unique adaptation of C. albicans to be both a commensal and an opportunistic pathogen in humans.     

HIV aspartyl protease inhibitors as promising compounds against Candida albicans André Luis Souza dos Santos

Cells of Candida albicans (C. albicans) can invade humans and may lead to mucosal and skin infections or to deep-seated mycoses of almost all inner organs, especially in immunocompromised patients. In this context, both the host immune status and the ability of C. albicans to modulate the expression of its virulence factors are relevant aspects that drive the candidal susceptibility or resistance; in this last case, culminating in the establishment of successful infection known as candidiasis. C. albicans possesses a potent armamentarium consisting of several virulence molecules that help the fungal cells to escape of the host immune responses. There is no doubt that the secretion of aspartyl-type proteases, designated as Saps, are one of the major virulence attributes produced by C. albicans cells, since these hydrolytic enzymes participate in a wide range of fungal physiological processes as well as in different facets of the fungal-host interactions. For these reasons, Saps clearly hold promise as new potential drug targets. Corroborating this hypothesis, the introduction of new anti-human immunodeficiency virus drugs of the aspartyl protease inhibitor-type (HIV PIs) have emerged as new agents for the inhibition of Saps. The introduction of HIV PIs has revolutionized the treatment of HIV disease, reducing opportunistic infections, especially candidiasis. The attenuation of candidal infections in HIV-infected individuals might not solely have resulted from improved immunological status, but also as a result of direct inhibition of C. albicans Saps. In this article, we review updates on the beneficial effects of HIV PIs against the human fungal pathogen C. albicans, focusing on the effects of these compounds on Sap activity, growth behavior, morphological architecture, cellular differentiation, fungal adhesion to animal cells and abiotic materials, modulation of virulence factors, experimental candidiasis infection, and their synergistic actions with classical antifungal agents.     

Environmental sensing and signal transduction pathways regulating morphopathogenic determinants of Candida albicans.

Candida albicans is an opportunistic fungal pathogen that is found in the normal gastrointestinal flora of most healthy humans. However, under certain environmental conditions, it can become a life-threatening pathogen. The shift from commensal organism to pathogen is often correlated with the capacity to undergo morphogenesis. Indeed, under certain conditions, including growth at ambient temperature, the presence of serum or N-acetylglucosamine, neutral pH, and nutrient starvation, C. albicans can undergo reversible transitions from the yeast form to the mycelial form. This morphological plasticity reflects the interplay of various signal transduction pathways, either stimulating or repressing hyphal formation. In this review, we provide an overview of the different sensing and signaling pathways involved in the morphogenesis and pathogenesis of C. albicans. Where appropriate, we compare the analogous pathways/genes in Saccharomyces cerevisiae in an attempt to highlight the evolution of the different components of the two organisms. The downstream components of these pathways, some of which may be interesting antifungal targets, are also discussed.     

Dressed to impress: impact of environmental adaptation on the Candida albicans cell wall

Candida albicans is an opportunistic fungal pathogen of humans causing superficial mucosal infections and life‐threatening systemic disease. The fungal cell wall is the first point of contact between the invading pathogen and the host innate immune system. As a result, the polysaccharides that comprise the cell wall act as pathogen associated molecular patterns, which govern the host–pathogen interaction. The cell wall is dynamic and responsive to changes in the external environment. Therefore, the host environment plays a critical role in regulating the host–pathogen interaction through modulation of the fungal cell wall. This review focuses on how environmental adaptation modulates the cell wall structure and composition, and the subsequent impact this has on the innate immune recognition of C. albicans.     

Immune-deficient Drosophila melanogaster: a model for the innate immune response to human fungal pathogens

We explored the host-pathogen interactions of the human opportunistic fungus Candida albicans using Drosophila melanogaster. We established that a Drosophila strain devoid of functional Toll receptor is highly susceptible to the human pathogen C. albicans. Using this sensitive strain, we have been able to show that a set of specific C. albicans mutants of different virulence in mammalian infection models are also impaired in virulence in Drosophila and remarkably display the same rank order of virulence. This immunodeficient insect model also revealed virulence properties undetected in an immunocompetent murine model of infection. The genetic systems available in both host and pathogen will enable the identification of host-specific components and C. albicans genes involved in the host-fungal interplay.     

营养感应与白念珠菌致病机制研究进展

营养元素是白念珠菌定植和致病的关键因素之一,作为人体真菌微生物组的一部分,白念珠菌能够特异性感应宿主微环境中营养物质的变化,及时做出适应性反应,为其生长、繁殖和侵袭宿主提供营养支持;同时白念珠菌还能反馈作用于人体,在机体免疫力低下或肠道菌群失调时由共生菌转化为致病菌引发严重的念珠菌病。目前关于营养感应与白念珠菌致病的分子机制已经有很多研究。本文概述了近年来营养感应与白念珠菌致病机制的相关研究结果,总结了碳源、氮源、磷营养以及多种金属元素在白念珠菌致病过程中发挥的作用,旨在为系统认识白念珠菌致病机制以及开发新型抗真菌药物提供新的研究思路。     

Non-lytic expulsion/exocytosis of Candida albicans from macrophages

Candida albicans is an opportunistic pathogen and is recognised and phagocytosed by macrophages. Using live-cell imaging, non-lytic expulsion/exocytosis of C. albicans from macrophages is demonstrated for the first time. Following complete expulsion, both the phagocyte and pathogen remain intact and viable. Partial engulfment of hyphal C. albicans without macrophage lysis is also demonstrated. These observations underpin the complexity of interactions between C. albicans and innate immune cells.     

白念珠菌生物被膜形成的遗传调控机制

白念珠菌是人体重要的条件性致病真菌。形态的多样性和可塑性是白念珠菌典型的生物学特征,这与它的致病性、宿主适应能力以及有性生殖过程密切相关。白念珠菌生物被膜(Biofilm)是由不同形态细胞(包括酵母型、菌丝和假菌丝)以及胞外基质组成的致密结构,也是毒性和耐药性形成的重要因子。生物被膜对抗真菌药物、宿主免疫系统和环境胁迫因子等都表现出较强的抵抗力和耐受性,是临床上病原真菌感染防治的重大挑战。随着基因表达谱和遗传操作技术的发展,白念珠菌生物被膜的形成及其耐药性的获得所依赖的遗传调控通路和分子调控机制越来越清楚。主要包括MAPK和cAMP介导的信号途径以及Bcr1和Tec1等因子介导的转录调控。此外,白念珠菌生物被膜的形成与形态转换和有性生殖之间存在密切的联系。文中综述了白念珠菌生物被膜形成的遗传调控机制,重点介绍了细胞壁相关蛋白、转录因子和交配型对该过程的调控以及生物被膜的耐药机制。