Immunity to fungal infections

Fungal diseases represent an important paradigm in immunology, as they can result from either a lack of recognition by the immune system or overactivation of the inflammatory response. Research in this field is entering an exciting period of transition from studying the molecular and cellular bases of fungal virulence to determining the cellular and molecular mechanisms that maintain immune homeostasis with fungi. The fine line between these two research areas is central to our understanding of tissue homeostasis and its possible breakdown in fungal infections and diseases. Recent insights into immune responses to fungi suggest that functionally distinct mechanisms have evolved to achieve optimal host-fungus interactions in mammals.     

Immunity to glycolipid antigens in microbial infections.

T cells recognize ligands of different chemical structures. Recently, it has become clear that also self glycosphingolipids and bacterial lipoglycans may act as T cell stimulatory ligands. This type of antigen recognition is restricted by the non-polymorphic CD1 molecules, which have a structure resembling that of classical MHC molecules. Glycolipids insert their hydrophobic lipid tails in two pockets below the antigen-binding groove and position their hydrophilic heads on the external part of CD1 molecules. TCR interacts with these carbohydrates and discriminates their structural variations. Glycolipid-specific T cells may provide protection during bacterial and parasite infection probably with different mechanisms: by secreting pro-inflammatory lymphokines, by the direct killing of infected target cells, and by helping specific B cells in Ig production. Lipoglycans represent excellent candidates for new anti-microbial vaccines due to their wide distribution in the microbial world and their structural composition which does not change and thus cannot give rise to escape mutants. Moreover, these vaccines might induce anti-microbial protective T cell responses in the whole population due to the non-polymorphic nature of CD1 presenting molecules.     

Immunotherapy for fungal infections

Invasive fungal infections have become a major cause of mortality in immunocompromised individuals. Despite the current availability of number of highly active antifungal agents, overall mortality remains around 40%. Importantly, it is clear that a failure to restore host immunity leads to worse outcomes. These observations provide clear rationale for the development of novel immunotherapies to improve outcomes in immunocompromised individuals with invasive fungal infections. In this article we summarise the key advances that have been made in the field of immunotherapy for fungal infections in recent years, with a particular focus on clinical studies of interferon-γ therapy, adoptive T cell therapy, and gene therapy for chronic granulomatous disorder. In addition a number of pre-clinical approaches are reviewed.     

Drosophila innate immunity and response to fungal infections

The fruit fly Drosophila melanogaster is an important model for the analysis of the interaction between host immune systems and fungal pathogens. Recent experiments have extended our understanding of the Toll-based signalling pathway critical to response to fungal infections, and identified new elements involved in cellular and humoral-based defences. The fly immune system shows remarkable sophistication in its ability to discriminate among pathogens, and the powerful genetics available to researchers studying the adult fly response, and the ability to manipulate cultured phagocytic cell lines with RNAi, are allowing researchers to dissect the molecular details of the process.     

Immunity against Staphylococcus aureus cutaneous infections

Complications arising from cutaneous and soft tissue infections with Staphylococcus aureus are a major clinical problem owing to the high incidence of these infections and the widespread emergence of antibiotic-resistant bacterial strains. If prophylactic vaccines or immunotherapy for certain patient populations are to be developed as an alternative to antibiotics, it will be essential to better understand the immune mechanisms that provide protection against S. aureus skin infections. Recent discoveries have identified a key role for interleukin-1 (IL-1)- and IL-17-mediated immune responses in promoting neutrophil recruitment to the site of infection in the skin, a process that is required for host defence and bacterial clearance. This Review describes these new insights and discusses their potential impact on immune-based therapies and vaccination strategies.     

Antibody-mediated protective immunity in fungal infections

The host response to fungal infection is the result of a complex interaction between the pathogen and the host's innate and adaptive immune system. Cell-mediated immunity is widely considered to be critical for the successful outcome of fungal infections. However, in recent years numerous studies have established that certain antibodies may play an important role in host immunoprotection against pathogenic fungi, through interaction with different cellular targets, such as mannans, heat shock proteins, capsular polysaccharides, surface proteins, and yeast killer toxin receptors, with mechanisms of action sometimes still undefined. This review summarizes the latest findings on the role of different types of antibodies in the antifungal defense against infections caused by epidemiologically important fungi, such as Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum, and others. New perspectives of antibody-mediated therapy, based on the availability of monoclonal and recombinant antibodies as well as genetically engineered antibody fragments of defined specificity, will be also envisaged and discussed.     

深部真菌感染临床特点分析

目的了解深部真菌感染患者的性别、年龄、感染部位、住院科室、菌种分布及真菌耐药情况,为临床防治真菌感染提供研究依据。方法收集荆州市中心医院2009年1月至2009年12月微生物实验室分离的真菌446株,采用科马嘉显色琼脂及API220C Aux鉴定系统鉴定,并使用ATMTMFUNGUS3真菌药敏卡进行体外药敏试验。结果临床真菌感染男性占72%,以老年患者为主,大于60岁者占54.9%;感染的真菌主要分布于呼吸内科和ICU,分别占35.5%、24.9%;主要感染部位为呼吸道,占91.3%;主要菌种为白假丝酵母菌、热带念株菌、近平滑假丝酵母菌、光滑念株菌和克柔念株菌,分别占64.2%、13.2%、9.6%、7.6%和5.4%;合并细菌感染的感染真菌100株,占22.2%,细菌中以革兰阴杆性菌为主,占96%;药敏试验结果显示真菌对各抗真菌药具有较好的敏感性。结论临床真菌感染已日益突出,以呼吸科及ICU患者老年男性为主,儿童真菌感染亦不容忽视,感染菌种以白假丝酵母菌和热带念株菌为主,临床应加强对这些真菌感染的预防和监测,防止真菌感染。     

Studying fungal pathogens of humans and fungal infections: fungal diversity and diversity of approaches

Seminal work by Louis Pasteur revealed the contribution of fungi – yeasts and microsporidia to agroindustry and disease in animals, respectively. More than 150 years later, the impact of fungi on human health and beyond is an ever-increasing issue, although often underestimated. Recent studies estimate that fungal infections, especially those caused by Candida, Cryptococcus and Aspergillus species, kill more than one million people annually. Indeed, these neglected infections are in general very difficult to cure and the associated mortality remains very high even when antifungal treatments exist. The development of new antifungals and diagnostic tools that are both necessary to fight fungal diseases efficiently, requires greater insights in the biology of the fungal pathogens of humans in the context of the infection, on their epidemiology, and on their role in the human mycobiota. We also need a better understanding of the host immune responses to fungal pathogens as well as the genetic basis for the increased sensitivity of some individuals to fungal infections. Here, we highlight some recent progress made in these different areas of research, in particular based on work conducted in our own laboratories. These progresses should lay the ground for better management of fungal infections, as they provide opportunities for better diagnostic, vaccination, the development of classical antifungals but also strategies for targeting virulence factors or the host.     

Immunity to non-cerebral severe malaria is acquired after one or two infections

In areas of stable transmission, clinical immunity to mild malaria is acquired slowly, so it is not usually effective until early adolescence. Life-threatening disease is, however, restricted to a much younger age group, indicating that resistance to the severe clinical consequences of infection is acquired more quickly. Understanding how rapidly immunity develops to severe malaria is essential, as severe malaria should be the primary target of intervention strategies, and predicting the result of interventions that reduce host exposure will require consideration of these dynamics. Severe disease in childhood is less frequent in areas where transmission is the greatest. One explanation for this is that infants experience increased exposure to infection while they are protected from disease, possibly by maternal antibody. They therefore emerge from this period of clinical protection with considerably more immunity than those who experience lower transmission intensities. Here we use this data, assuming a period of clinical protection, to estimate the number of prior infections needed to reduce the risk of severe disease to negligible levels. Contrary to expectations, one or two successful infective bites seem to be all that is necessary across a broad range of transmission intensities.     

Cytokines in the treatment of fungal infections

The incidence of invasive fungal infections in the immunocompromized host has increased during the past decade. Even the recently developed antifungal drugs are unable to cure these infections in patients with severely impaired host defense mechanisms. Cytokines have great potential to augment host resistance and as adjunctive therapy of invasive mycoses. We discuss the mechanisms of host defense against invasive candidiasis, aspergillosis, and cryptococcosis, and review the use of cytokines and growth factors in this setting. Interleukin-1 has been shown effective in an animal model of disseminated candidiasis, even during severe granulocytopenia. Interferon- has been very effective as a modulator of resistance against a variety of fungal infectionsin vitro. The effect of interferon- against disseminated candidiasis has been demonstrated in a mouse model. Activation of neutrophils is the main mechanism by which interferon- enhances the elimination ofCandida, and consequently the agent is not effective in severly granulocytopenic animals. Data on the role of colony-stimulating factors against fungal pathogens are accumulating, and trials with these agents for hematologic patients with invasive fungal infections are now being performed.Abbreviations CGD chronic granulomatous disease - G-CSF granulocyte colony-stimulating factor - M-CSF monocyte colony-stimulating factor - GM-CSF granulocyte-monocyte colony-stimulating factor - IFN- interferon-gamma - IL interleukin - LAK lymphokine-activated killer - LPS lipopolysaccharide - MDP muramyl dipeptide - NK natural killer - PMN polymorphonuclear leukocytes - rh recombinant human - ROI reactive oxygen intermediates - TNF tumor necrosis factor     

院内深部真菌感染92例临床分析

目的探讨院内深部真菌感染的临床表现、感染相关因素及诊断治疗措施.方法对1993年1月至2002年12月间经微生物检查证实的92例院内深部真菌感染的病例临床资料进行回顾性分析.结果在92例患者中,肺部疾病26例,糖尿病19例,血液病及肿瘤19例,外科手术后13例,消化系统疾病6例,慢性肾脏病6例,风湿性疾病3例.主要感染真菌为白色念珠菌和酵母菌.感染相关因素:长时间应用广谱抗生素病人65例,应用糖皮质激素22例,应用免疫抑制剂18例,应用气管切开或气管内插管以及中心静脉留置导管17例,进行血液净化治疗的9例.治疗痊愈59例(64.1%),好转10例(10.9%),死亡23例(25%).结论白色念珠菌是院内深部真菌感染的主要致病菌株,有逐年增加趋势,病死率高.与长时间应用广谱抗生素及免疫抑制剂等有相关性.