REVIEW URRENT C OPINION
Pathogenesis of invasive fungal infections Carolina Garcia-Vidal, Diego Viasus, and Jordi Carratala`
Purpose of review Invasive fungal infection (IFI) is increasingly being recognized as a significant cause of morbidity and mortality in immunosuppressed patients. This review focuses on the latest literature reports concerning the pathogenesis of IFI in this population. Recent findings New virulence factors of Candida and Aspergillus have recently been identified. The past few months have brought significant advances in our understanding of how the immune system acts against fungal infection, especially with regard to the role of mucosa in the innate immune system, the arsenal of innate immune recognition receptors and the pathways connecting innate and adaptive immunity. Summary Knowledge of fungal pathogenesis and host immune response can help to optimize the management of fungal infections. Greater understanding of these processes may aid physicians in developing better prophylactic measures and antifungal or immunomodulatory therapies. Keywords aspergillosis, candidiasis, fungal infections, pathogenesis
INTRODUCTION
CANDIDA
The risk of invasive fungal infections (IFIs) in healthy individuals is low because the immune system prevents the development of invasive disease. However, IFIs are one of the leading infectionrelated causes of death among severely immunosuppressed patients and patients admitted to ICUs [1–4]. In fact, the rising incidence of IFI in developed societies in recent years is mainly linked to the increase in immunocompromised individuals, specifically, neutropenic patients with cancer, and recipients of solid organ or hematopoietic stem cell transplants. This close relationship between IFI and the immune system has stimulated efforts to understand the interactions between the host and the fungi. However, it remains hard to transfer the results of basic science research from bench to bedside. Basic investigators and clinical physicians should work together to understand how the immune system acts against the most common fungal pathogens and how we can use this knowledge to improve the clinical management of these infections. The purpose of this review is to summarize the latest information regarding the most significant Candida and Aspergillus virulence factors and the pathogenesis of IFI.
Candida species are normal commensals of humans and are frequently isolated from skin, gastrointestinal tract, and urine. There are more than 150 species of Candida, but few are pathogenic to humans. The most frequent species that cause invasive infections are C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei. The step from asymptomatic colonization to invasive infection may occur when the patient presents certain risk factors, the microorganism has virulence factors, or the host immune system is compromised.
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Candida virulence factors The pathogenicity of Candida species is mediated by a number of virulence factors that facilitate adherence to mucosa, the ability to evade host defenses, Infectious Disease Service, Hospital Universitari de Bellvitge, Institut d’Investigacio´ Biome`dica de Bellvitge (IDIBELL), University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain Correspondence to Dr Carolina Garcia-Vidal, Infectious Disease Service, Hospital Universitari de Bellvitge, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain. Tel: +34 932 607 625; fax: +34 932 607 637; e-mail:
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Pathogenesis of invasive fungal infections Garcia-Vidal et al.
KEY POINTS The pathogenicity of Candida and Aspergillus is mediated by a number of virulence factors that facilitate adherence to mucosa, the ability to evade host defenses, and the production of tissue-damaging hydrolytic enzymes.
emerging that Candida species are exposed to oxygen-limited microenvironments during fungal pathogenesis. The effects of oxygen on Candida– host interactions are likely to be multifaceted including among other things, changes in gene transcription, heme and ergosterol biosynthesis, and changes in cell wall and membrane structure [11 ,12,13]. &&
The innate defense is quite specific; this response is activated by pattern recognition receptors which are able to recognize conserved structures of microorganisms. The most important pattern recognition receptors are C-type lectin receptors (i.e., Dectin-1), pentraxin-3, Toll-like receptors, and NOD-like receptors (i.e., inflammasome). The Th1/Th2/Th17 responses are basic to the fight against fungal infection.
and the production of tissue-damaging hydrolytic enzymes. Candida’s capacity for mucosa adherence and biofilm formation is an important virulence factor. It confers significant resistance to antifungal therapy by limiting the penetration of substances through the matrix and protecting Candida from the host immune response. In this field, recent experiments have demonstrated that the production of biofilm is strongly dependent on the particular Candida strain involved and on the environmental conditions of infection [5–7]. Destruction of host tissues by Candida in the local environment may be facilitated by the release of hydrolytic enzymes such as secreted aspartyl proteinases (Saps), phospholipases, lipases, and hemolysins. It has recently been shown that C. albicans produces greater amounts of phospholipases than other Candida species [8,9]. However, the production of these enzymes is highly straindependent [6,8]. The ability of Candida to switch between yeast and hyphal growth forms is also related to virulence. A recent review [10 ] described that the morphological transition of C. albicans is linked to adhesion to epithelial and endothelial cells, invasion by endocytosis and mucosa penetration, iron acquisition from intracellular host sources, escape from phagocytes and the immune system, promotion of immune activation in mucosal tissues and the triggering of specific sepsis-like immune responses during systemic infection. Finally, understanding the dynamics of in-vivo fungal microenvironments encountered during infection and their relationship with fungal virulence is a recent focus of interest. Evidence is &
ASPERGILLUS The usual niches of Aspergillus are soil, air, food, and common decaying organic material. There are more than 200 recognized Aspergillus species. Among them, A. fumigatus is the most common cause of IFI, followed by A. flavus, A. terreus, A. niger, and A. nidulans. The infectious life cycle of Aspergillus begins with the production of conidia which are easily dispersed into the air. When they reach a permissive environment such as the lung of an immunosuppressed patient, they germinate and become hyphae, the invasive form of Aspergillus. Humans may inhale hundreds of conidia daily. Nevertheless, most people do not develop illness and present no evidence of antibody or cell-mediated acquired immunity to Aspergillus. This suggests that in regular conditions innate immunity is sufficient to clear this microorganism before acquired immunity is called upon. Invasive aspergillosis occurs mostly when the patient presents certain risk factors that imply a severe host immune system compromise.
Aspergillus virulence factors The virulence of Aspergillus depends on a combination of biological features of the fungus and the immune status of the host. The link between them is very strong, as demonstrated by the fact that the activation of the innate immune system may differ depending on the Aspergillus morphotype, growth stage, environment sensing, and species, and may represent a key factor in fungal pathogenicity [14]. Certain intrinsic characteristics of Aspergillus, however, contribute to virulence. Classically, it has been reported that the relatively small size of A. fumigatus conidia allows access deep into the alveoli. Moreover, A. fumigatus can grow between 37 and 508C, and is therefore more resistant and has better thermotolerance than other Aspergillus species. Aspergillus also secretes various proteases, hydrolases, and elastases with different functions. These enzymes may activate different pathways which have a direct effect on the expression of the virulence-related attributes of A. fumigatus [15,16].
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Pathogenesis and immune response
Iron is an essential nutrient for Aspergillus. To regulate iron load, Aspergillus employs siderophores, which are of great importance in fungal virulence. A recent review summarizes the relationship between iron homeostasis and Aspergillus virulence [17 ]. The central role of iron influences processes such as ergosterol biosynthesis, azole drug resistance, hypoxia adaptation, and the interaction with the host immune cells [18–21]. Finally, Aspergillus’ ability to adapt to oxygenlimited microenvironments also has a great impact on fungal pathogenesis [11 ]. In hypoxic conditions Aspergillus activates glycolysis, transcriptional downregulation of the tricarboxylic acid cycle, and oxidative phosphorylation, and produces secondary metabolites that promote lung inflammation, &&
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exacerbate the infection, and influence subsequent host immune response [22,23].
HOST IMMUNE SYSTEM RESPONSE TO FUNGAL INFECTION Figure 1 summarizes the immune system response against IFI. The physical barrier of the mucosa is the first line of defense. A very recent study highlights the role of pulmonary surfactant against Aspergillus infection in limiting inflammation by reducing host–fungal interactions [24 ]. Another recent study found that respiratory epithelial cells are activated by Aspergillus conidias and directly initiate innate immune response by secreting interferon (IFN)-b [25 ]. &
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Candida/Aspergillus
Colonization
Innate immune response 1st step: epithelial mucosa Invasion
Recognition of pathogen by different pattern recognition receptors (PRRs)
Macrophage and dendritic cellassociated PRRs (CLRs, TLRs , NLRs and inflammasomes)
Cytokine response Dendritic cell maduration and antigen presentation
Macrophages, neutrophils and monocytes
Soluble PRRs and mediators: CLRs/pentraxin-3 Complement/lysozymes/cationic peptides
Activation processes of degradation, oxidation and acidification
Adaptive immune response Response mediated by Th1, Th2, Th17 and Threg immunoglobulins
Fungi destruction
FIGURE 1. Outline of the host immune response to fungal infection. CLRs, C-type lectin receptors; NLRs, NOD-like receptors; TLRs, Toll-like receptors. 272
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Once fungi invade the mucosa, the host response is mediated by innate immune cells such as macrophages, dendritic cells, and monocytes, and by soluble mediators such as complement or different peptides. It has now been demonstrated that the innate defense is quite specific. The response is activated by a limited arsenal of soluble and innate cell-associated pattern recognition receptors (PRRs) which are able to recognize conserved structures of microorganisms called pathogen-associated molecular patterns (PAMPs). Well known fungal PAMPs include proteins and polysaccharides such as mannan, ß-glucan, and chitin. The most important soluble PRRs in the immune response against Candida are C-type lectin receptors (CLRs), and against Aspergillus infection opsonization with pentraxin-3 (PTX-3) is also critical. The most important cellassociated PRRs against Candida and Aspergillus are CLRs, Toll-like receptors (TLRs), and NOD-like receptors (NLRs), including the inflammasome.
Pattern recognition receptors The CLR family comprises transmembrane and soluble receptors that share a carbohydrate-recognition domain [26]. CLR receptors mainly recognize glucan and mannan. Dectin-1 is the most important CLR. Their deficiency causes an increased susceptibility to mucocutaneous fungal and IFIs, and this finding emphasizes the importance of specific CRLs in vivo [27,28]. Dectin-1 signaling is crucial for triggering phagocytosis and antifungal activity [29 ,30 ] and plays a key role in balancing the Th1/Th17 response [31]. PTX3 is secreted by macrophages and epithelial cells during Aspergillus infection. PTX3 binds galactomannan and coated conidia. This step is important because neutrophils take up PTX3-coated spores much more efficiently than uncoated spores [32]. Toll-like receptors are a family of nine PRRs associated with innate immune cells. The adaptor molecule MyD88 is a major signaling mechanism. The role of these receptors against fungal infection has been known for many years [30 ] and some genetic polymorphisms have been related to a higher risk of invasive aspergillosis [33]. Fungal recognition by this family has classically been associated with TLR2/6, TLR4, and TLR 9. TLR1 is also important in the host response against Candida, as demonstrated by the fact that three TLR1 polymorphisms have been associated with an increased susceptibility for candidemia [34 ]. A recent study found that genetic deficiency of TLR3 was also associated with susceptibility to aspergillosis in patients receiving stem-cell transplantation [35 ]. &&
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Finally, NLRs activate the caspase pathway. It has been recently shown that A. fumigatus conidia induce nuclear factor-kB activation in a NOD2dependent manner [36]. Intracellular inflammasome is a multimolecular complex including NLRP1 that has emerged as one of the most interesting PRRs in antifungal host defense [37,38,39 ,40 ]. NLRP1, NLRP3, and NLRC4 activate caspase-1, producing the secretion of interleukin (IL)-1ß and IL-18 and triggering an immune response mediated by Th17. Interestingly, this response is the result of the recognition of C. albicans hyphae by human macrophages. The yeast form does not activate the inflammasome, demonstrating that this pathway is probably important for discriminating between colonizing yeast and invasive hyphae [41]. Inflammasomes appear to be essential for preventing mucocutaneous Candida infection, but their role in preventing IFI is less clear. Recognition of fungi by the many PRRs is a highly complex and dynamic process. Recent evidence suggest that various PRRs have to work together to optimize ligand binding and signal transduction processes [42,43]. &&
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Innate immune cells and the link with adaptive response Neutrophils and macrophages play a major role in killing fungi, mainly by phagocytosis and lysis. But the most important antigen-presenting cells are dendritic cells, which play a vital role in linking innate and acquired immunity. Dendritic cells act by amplifying the innate immune response via the secretion of cytokines. This process helps to recruit and activate other leukocytes, and is responsible for initiating a T-cell response. Depending on the antigen presented, dendritic cells initiate responses by promoting the differentiation of T helper (Th) cells into Th1, Th2, Th17, or Treg cells. Th1 leads to the production of protective pro-inflammatory cytokines IFN-g, IL-6, and IL-12, which are essential for protection against fungal infections. The Th2 response is associated with the production of IL-4, IL-5, and IL-10 and with an impaired host defense against IFI. It has recently been shown that IL-33, a cytokine associated with Th2 immunity, can improve the antifungal activity of neutrophils by collaborative modulation of the signaling pathways of different PRRs [44 ]. The Th1/Th2 response is a dynamic process that primarily has an antifungal effect but also plays a key part in balancing pro-inflammatory and antiinflammatory signals. This activity is particularly important because the host inflammatory status is a vital factor in fungal pathogenesis [45].
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Pathogenesis and immune response
Apart from the classical Th1/Th2 response, Th17 cells have recently been shown to play a leading role in antifungal activity. Accumulating evidence has shown that the engagement of different PRRs by C. albicans in antigen-presenting cells results in the secretion of IL-1b, IL-23, and IL-6 [46,47]. These cytokines activate the Th17 lineage that expresses IL-17, IL-17F, and IL-22. These processes are crucial in mucosal immunity [38,39 ,41]. However, their role in defense against IFI remains unclear. Another recent study suggests that IL-17 may bind Candida directly and induce nutrient starvation conditions in the environment [48]. Finally, the role of acquired humoral mediated immunity in protecting against invasive aspergillosis has not been well defined. Recent studies have provided evidence that certain antibodies can modify the course of some IFIs, including candidiasis. Recently identified Candida antigens that have been shown to elicit protective antibodies include Saps, phosphoglycerate kinase, and fructose bisphosphate aldolase [49 ]. Antibodies such as heat shock protein 90 antibody improve outcomes in patients with invasive candidiasis in combination with liposomal amphotericin [50]. However, the clinical development of this antibody (Mycograb) has been discontinued. Progress is being made in the understanding of new mechanisms of antibody-mediated protection. &&
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It has recently been shown that iron starvation is the mechanism by which one Candida antibody (mAb) becomes cytotoxic and interferes with morphogenesis [51]. Additionally, Candida cell wall proteinderived peptides have been found to protect against disseminated candidiasis in mice [52]. Many more issues must be addressed before these findings can be applied in daily clinical practice. Experimental studies of the role of vaccines in protecting against Candida infections based on the use of recombinant Saps and glycan–peptide conjugates are currently underway [53].
LINK BETWEEN IMMUNOPATHOGENESIS AND CLINICAL RISK FACTORS FOR INVASIVE FUNGAL INFECTIONS Table 1 summarizes clinical risk factors for IFI and their relationship with fungal pathogenesis. Patients admitted to the ICU and those with severe immunosuppression have different predisposing factors for candidiasis. This means that physicians must adapt their strategies for preventing infection to particular patient groups. Factors associated with higher risk of candidiasis in ICU patients are mainly associated with the mucosa disruption caused by catheters and Candida overgrowth due to antibiotic pressure. In contrast, in severely immunosuppressed patients, factors predisposing for candidiasis
Table 1. Link between clinical risk factors for invasive fungal infections and immunopathogenesis Risk factors for IFI
Predisposing factor
Invasive candidiasis Colonization
Increased amount of Candida
Prior antibiotic treatment
Switch of the common microbial flora in digestive tract increases amount of Candida
Invasive aspergillosis Older age
Progressive replacement of Th1 response by Th2
Baseline illness
Kinetics of immune reconstitution of cytokine signaling networks may depends on baseline illness
Transplant procedures
Transplant procedures alter the host immune status Donor/receptor matching is key to modulating immunologic suppression
Respiratory viruses
Break down the bronchial mucosa facilitating Aspergillus invasion Immunomodulatory effects: secretion of IL-10
Number of blood transfusions
Highlight of Th2 response
Invasive candidiasis and aspergillosis Cytopenia
Dysfunction of innate immune response due to lack of cells
Graft-versus-host disease
Breaks the digestive mucosa facilitating Candida invasion Marked dysfunction in Th1/Th2 response
CMV
Immunomodulatory effects producing changes in lymphocytes and monocytes function Intrinsic secretion of IL-10
Corticosteroids
Complex dysregulation of immunity including inhibition of Th1 response and enhancement of Th2 response
CMV, cytomegalovirus; IFI, invasive fungal infection.
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directly reflect the compromise of the host immune response and are similar to those that predispose for aspergillosis. The most common risk factors for invasive aspergillosis are older age, transplant variables, cytopenia, graft-versus-host disease (GVHD), corticosteroids, cytomegalovirus (CMV) disease, respiratory viruses, and iron overload [2,3,54 ]. These factors suggest a scenario with a severe dysfunction of T-cell response, but also with a replacement of Th1 response by Th2, corroborating previous reports of the importance of this balance in basic research. In this regard, it is important to bear in mind that in cytopenia all the cells normally involved in the immune response are lacking. The cytokine signaling networks are altered in elderly patients and in some transplant procedures, a situation that tends to favor a Th2 over Th1 response [55–57]. CMV and respiratory virus have an immunomodulatory effect that promotes the Th2 response; in fact some viruses are able to produce IL-10 by themselves [54 ,58–60]. CMV and respiratory virus, moreover, alter the mucosa facilitating fungal invasion. Corticosteroids cause a complex dysregulation of immunity including inhibition of Th1 response and enhancement of Th2 response [61]. GVHD is strongly associated with corticosteroid use and Th cell dysfunction. Finally, blood transfusions are also associated with a down-regulation of the immune response, promoting Th2 [62].
by a grant FIS10/01318 from the Fondo de Investigacio´n Sanitaria del Instituto de Salud Carlos III (Madrid). Dr Carolina Garcia-Vidal is the recipient of a Juan de la Cierva research grant from the Instituto de Salud Carlos III, Madrid, Spain. Dr Viasus is the recipient of a research grant from the Spanish Network Research of Infectious Disease (REIPI) (RD06/0008/0022).
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CONCLUSION The development of IFI is closely related to the dysfunction of the immune system. Knowledge of fungal pathogenesis and host immune response can help optimize the management of these infections. Greater understanding of these processes may help physicians to develop better prophylaxis measures and antifungal or immunomodulatory therapies, but transferring the promising results obtained in experimental models to clinical practice remains a major challenge today. It has been demonstrated that some patients undergoing stem cell transplantation have intrinsic risk factors for invasive aspergillosis and that the immunogenetic study of donors may prevent this infection. How to incorporate these findings into patient care is an issue that should be addressed in future research. Acknowledgements The authors are supported by supported by Ministerio de Economı´a y Competitividad, Instituto de Salud Carlos III - co-financed by European Development Regional Fund ‘A way to achieve Europe’ ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015), and
Conflicts of interest There are no conflicts of interest.
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Volume 26 Number 3 June 2013
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