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.     

小鼠念珠菌感染模型和抗感染免疫

目前,临床相关的小鼠念珠菌感染疾病模型种类日益增多.与早期小鼠念珠菌感染模型相比,近期感染模型与临床上免疫抑制机会性念珠菌感染患者的感染方式、感染的发展进程、临床表现、靶器官临床病理组织学特征更相近.建立了特定免疫缺陷小鼠(如转基因/基因敲除小鼠等);感染源从白色念珠菌转向非白念珠菌(如近平滑念珠菌、光滑念珠菌等);感染方式从局部口腔-消化道感染逐步转变为血源性深部多器官组织感染.特定模型的建立更深入地探讨了宿主-念珠菌感染源之间相互的免疫机制.细胞介导的免疫反应在宿主抗念珠菌感染免疫反应中占主导,吞噬细胞直接杀伤真菌;细胞分化为Th1和Th2型细胞,分泌相关细胞因子进行免疫调控.体液免疫中一些保护性抗体也具有一定的保护作用.     

白念珠菌对宿主的黏附机制

白念珠菌对宿主的黏附是白念珠菌感染过程的关键的第一步,因此阐明白念珠菌对宿主的黏附机制对探索新的方法预防和治疗白念珠菌感染至关重要。近年来,研究者们从白念珠菌的表面结构、黏附素以及黏附相关基因等方面对白念珠菌与宿主的黏附机制进行了大量研究。该文就白念珠菌对宿主的黏附机制进行综述。     

白念珠菌黏附基因的研究进展

白念珠菌能引起免疫力低下患者的皮肤黏膜和全身系统性持续感染,对宿主组织的黏附是其侵入和感染的先决条件。对白念珠菌黏附相关基因的研究有助于揭示白念珠菌的致病机制。近年来,越来越多的研究者从黏附基因的结构、影响其表达的因素以及黏附机制等方面进行了研究。本文就黏附基因的相关研究进展进行综述,旨在为新型抗真菌药物和白念珠菌疫苗的研究提供参考。     

白念珠菌的形态发生与致病性

白念珠菌是一种广泛存在于人体内的共生真菌,也是人类最常见的机会性致病真菌,可引起浅表感染甚至威胁生命的系统性感染。白念珠菌具有很强的形态可塑性,而且这种形态可塑性与致病性密切相关。白念珠菌在侵染的过程中可以进行酵母、假菌丝和真菌丝之间的形态转换。除此之外,white形态、opaque形态、gray形态和GUT细胞在宿主不同的部位具有生长繁殖优势。本文总结了白念珠菌各种形态特征以及它们与致病性之间的联系,同时我们也简述了宿主环境因素调控这些形态的发生与转换的机理。     

白念珠菌感染分子机制研究

白念珠菌是临床上最常见的条件致病真菌。白念珠菌在感染宿主时会遭遇机械阻碍(如上皮细胞),生物、化学和物理拮抗(如胆汁、黏液、p H)及宿主免疫细胞(如吞噬细胞)的杀伤。白念珠菌生物化学、形态学的灵活性及逃逸宿主天然免疫的能力对其发挥致病性至关重要。该文就白念珠菌感染宿主过程中涉及的分子机制做一综述,为进一步探索新的治疗药物提供参考。     

白念珠菌侵袭宿主毒力因子研究进展

白念珠菌是一种寄生于人类黏膜表面的条件致病菌,是导致免疫功能低下人群侵袭性真菌感染的主要病原菌。白念珠菌形成侵袭性感染的过程主要分为黏附、侵袭、播散、形成感染灶等步骤,其中黏附和侵袭过程最为关键。黏附是白念珠菌入侵宿主的前提,该过程主要依赖于细胞壁表面的黏附素。侵袭阶段主要与菌丝形成、细胞壁表面毒力蛋白表达和蛋白水解酶分泌增加有关。形成菌丝是白念珠菌侵袭宿主的关键因素,主要由细胞内cAMP/PKA和MAPK等信号通路调控;侵袭素主要位于白念珠菌细胞壁表面,可以协助其穿刺宿主上皮细胞、诱导内吞作用;白念珠菌还可分泌多种蛋白水解酶,它能够破坏宿主组织细胞,协助白念珠菌形成感染灶。该文主要对白念珠菌黏附和侵袭宿主过程中关键的毒力因子进行综述,为理解白念珠菌致病机制以及选择潜在的药物靶点提供参考。     

抗黏膜白念珠菌感染的固有免疫研究进展

白念珠菌是条件致病性真菌,常导致黏膜念珠菌感染。固有免疫应答在宿主抗黏膜念珠菌感染中起主要作用。最新研究结果揭示上皮细胞、中性粒细胞、巨噬细胞和IL-17生产型固有细胞在黏膜念珠菌感染中的发挥了重要作用。现从固有免疫分子和固有免疫细胞两方面探讨黏膜念珠菌感染的固有免疫研究进展。     

固有免疫系统识别白念珠菌的分子机制研究进展

白念珠菌是引起机体浅部和深部真菌感染的主要致病菌。机体通过固有免疫细胞表面的模式识别受体(pattern recognition receptors,PRRs),与白念珠菌细胞壁表面的病原相关模式分子(pathogen associated molecular patterns,PAMPs)结合,激活机体固有免疫应答。机体和白念珠菌的相互作用可以有效抵抗白念珠菌侵袭,清除白念珠菌感染,但当机体免疫力低下时,白念珠菌会持续引发感染,引起慢性黏膜念珠菌病,严重时可以引发系统性白念珠菌感染危及生命。部分模式识别受体如Dectin-1还通过影响Th17细胞的分化,对白念珠菌的适应性免疫应答发挥一定的作用。该文将对已发现的能够识别白念珠菌的模式识别受体,以及这些受体在机体抗白念珠菌感染中的作用进行讨论。     

白念珠菌致病相关的水解酶

白念珠菌是一种重要的人类致病性真菌,其致病机制与多种因素有关.水解酶是白念珠菌最重要的毒力因子之一,在其入侵宿主过程中起关键作用.白念珠菌水解酶包括分泌型天冬氨酸蛋白酶、磷脂酶和脂肪酶,介导白念珠菌的表型转换、对宿主组织的黏附及对宿主免疫系统的干预,使其能够入侵宿主组织和逃避宿主的免疫防御机制.该文我们综述了白念珠菌水解酶的生物学属性和致病机制的研究进展.     

An integrated model of the recognition of Candida albicans by the innate immune system

The innate immune response was once considered to be a limited set of responses that aimed to contain an infection by primitive 'ingest and kill' mechanisms, giving the host time to mount a specific humoral and cellular immune response. In the mid-1990s, however, the discovery of Toll-like receptors heralded a revolution in our understanding of how microorganisms are recognized by the innate immune system, and how this system is activated. Several major classes of pathogen-recognition receptors have now been described, each with specific abilities to recognize conserved bacterial structures. The challenge ahead is to understand the level of complexity that underlies the response that is triggered by pathogen recognition. In this Review, we use the fungal pathogen Candida albicans as a model for the complex interaction that exists between the host pattern-recognition systems and invading microbial pathogens.     

Innate versus adaptive immunity in Candida albicans infection

Candida albicans is a common opportunistic pathogen, causing both superficial and systemic infection. Clinical observations indicate that mucocutaneous infections are commonly associated with defective cell-mediated immune responses, whereas systemic infection is more frequently seen in patients with deficiencies in neutrophil number or function. Analysis of mechanisms of host resistance against gastrointestinal and oral infection in mouse models has demonstrated an absolute dependence on CD4(+) T cells, although clearance also involves phagocytic cells. Both IL-12 and TNF-alpha appear to be important mediators, but mouse strain-dependent variations in susceptibility to infection may be related to T-cell enhancement of production of phagocytic cells by the bone marrow. In murine systemic infection, the role of innate and adaptive responses is less well defined. Studies in immunodeficient and T-cell-depleted mice suggest that clearance of the yeast may be predominantly a function of the innate response, whereas the adaptive response may either limit tissue damage or have the potential to cause immunopathology, depending on the host genetic context in which the infection takes place.     

Candida-host cell receptor-ligand interactions

The interaction of Candida species with their cognate host receptors is a key factor in the pathogenesis of different types of candidiasis. The recognition of different forms of Candida albicans by Toll-like receptors 2 and 4 on mononuclear leukocytes has recently been discovered to determine the function and activity of regulatory T-cells, determine the balance of Type 1 and Type 2 cytokines and, thereby, influence the antifungal activity of both the innate and adaptive immune response. Different forms of C. albicans are also recognized by different lectins that are expressed on the surface macrophages. C. albicans and Candida glabrata express the ALS (agglutinin-like sequence) and EPA (epithelial adhesin) families of adhesins, respectively. A key difference between C. glabrata and C. albicans is that EPA expression in C. glabrata is governed by sub-telomeric silencing, whereas ALS expression in C. albicans is regulated by other mechanisms.     

Animal models of mucosal Candida infection

Rodent models of oral, vaginal and gastrointestinal Candida infection are described and discussed in terms of their scientific merits. The common feature of all experimental mucosal Candida infections is the need for some level of host immunocompromise or exogenous treatment to ensure quantitatively reproducible disease. A growing literature describes the contributions of such candidiasis models to our understanding of certain aspects of fungal virulence and host response to mucosal Candida albicans challenge. Evidence to date shows that T-lymphocyte responses dominate host immune defences to oral and gastrointestinal challenge, while other, highly compartmentalized responses defend vaginal surfaces. By contrast the study of C. albicans virulence factors in mucosal infection models has only begun to unravel the complex of attributes required to define the difference between strongly and weakly muco-invasive strains.     

Antifungal Activity of Schinifoline Against Candida Albicans in Caenorhabditis Elegans

Zanthoxylum schinifolium has been used as spices and traditional medicine in China for hundreds of years. A variety of active substances have been isolated from Zanthoxylum schinifolium using biological and chemical techniques. Among these substances, the effect of schinifoline has gradually attracted much attention. Candida albicans is one of the most common pathogens isolated from the gastrointestinal tract, vagina, and mouth in healthy individuals. In a healthy population, there are various mechanisms in host, such as the microbial flora, the epithelial barriers, and the innate immune system, that can control the presence of Candida albicans. However, when host immunity is compromised, an invasive fungal infection is more likely to occur. In this study, we explored the antifungal activity of schinifoline against Candida albicans in Caenorhabditis elegans. To determine the optimal concentration of schinifoline, we investigated the lifespan, defecation cycle and locomotion behavior of Caenorhabditis elegans after treatment with schinifoline. In addition, we examined colony formation in the intestine of Caenorhabditis elegans after Candida albicans infection. The results indicated that 100 and 200 mg/L of schinifoline could prolonged the lifespan, shorten the defecation cycle and increased the locomotion behavior of Caenorhabditis elegans, with 100 mg/L of schinifoline being the optimal concentration. Moreover, 100 mg/L of schinifoline increased the lifespan of Caenorhabditis elegans after infection and inhibited the colony formation of Candida albicans in Caenorhabditis elegans intestine. Therefore, we concluded that schinifoline exhibits anti-fungal effects and its potential use as natural drugs should be further explored in future studies.     

Live imaging of disseminated candidiasis in zebrafish reveals role of phagocyte oxidase in limiting filamentous growth

Candida albicans is a human commensal and a clinically important fungal pathogen that grows in both yeast and hyphal forms during human infection. Although Candida can cause cutaneous and mucosal disease, systemic infections cause the greatest mortality in hospitals. Candidemia occurs primarily in immunocompromised patients, for whom the innate immune system plays a paramount role in immunity. We have developed a novel transparent vertebrate model of candidemia to probe the molecular nature of Candida-innate immune system interactions in an intact host. Our zebrafish infection model results in a lethal disseminated disease that shares important traits with disseminated candidiasis in mammals, including dimorphic fungal growth, dependence on hyphal growth for virulence, and dependence on the phagocyte NADPH oxidase for immunity. Dual imaging of fluorescently marked immune cells and fungi revealed that phagocytosed yeast cells can remain viable and even divide within macrophages without germinating. Similarly, although we observed apparently killed yeast cells within neutrophils, most yeast cells within these innate immune cells were viable. Exploiting this model, we combined intravital imaging with gene knockdown to show for the first time that NADPH oxidase is required for regulation of C. albicans filamentation in vivo. The transparent and easily manipulated larval zebrafish model promises to provide a unique tool for dissecting the molecular basis of phagocyte NADPH oxidase-mediated limitation of filamentous growth in vivo.     

Effects of interferon-γ and granulocyte colony-stimulating factor on antifungal activity of human polymorphonuclear neutrophils against Candida albicans grown as biofilms or planktonic cells

Candida albicans is a leading cause of biofilm-related infections. As Candida biofilms are recalcitrant to host defenses, we sought to determine the effects of interferon-γ and granulocyte colony-stimulating factor, two pro-inflammatory cytokines, on the antifungal activities of human polymorphonuclear neutrophils (PMNs) against C. albicans biofilms, using an in vitro biofilm model. Priming of PMNs by these cytokines augmented fungal damage of planktonic cells; however, priming of PMNs did not have the same effect against Candida biofilms. Biofilm phenotype appears to play an important role in protecting C. albicans from the innate immune system.