Antigen-Specific Th17 Cells Are Primed by Distinct and Complementary Dendritic Cell Subsets in Oropharyngeal Candidiasis

Candida spp. can cause severe and chronic mucocutaneous and systemic infections in immunocompromised individuals. Protection from mucocutaneous candidiasis depends on T helper cells, in particular those secreting IL-17. The events regulating T cell activation and differentiation toward effector fates in response to fungal invasion in different tissues are poorly understood. Here we generated a Candida-specific TCR transgenic mouse reactive to a novel endogenous antigen that is conserved in multiple distant species of Candida, including the clinically highly relevant C. albicans and C. glabrata. Using TCR transgenic T cells in combination with an experimental model of oropharyngeal candidiasis (OPC) we investigated antigen presentation and Th17 priming by different subsets of dendritic cells (DCs) present in the infected oral mucosa. Candida-derived endogenous antigen accesses the draining lymph nodes and is directly presented by migratory DCs. Tissue-resident Flt3L-dependent DCs and CCR2-dependent monocyte-derived DCs collaborate in antigen presentation and T cell priming during OPC. In contrast, Langerhans cells, which are also present in the oral mucosa and have been shown to prime Th17 cells in the skin, are not required for induction of the Candida-specific T cell response upon oral challenge. This highlights the functional compartmentalization of specific DC subsets in different tissues. These data provide important new insights to our understanding of tissue-specific antifungal immunity.     

Unravelling fungal immunity through primary immune deficiencies

Fungal infections affect individuals with an impaired immune system and are on the increase, often with serious consequences. Recent studies in patients with primary immune deficiencies (PIDs) have led to important breakthroughs in our understanding of the different, mutually exclusive pathways underlying immunity to mucocutaneous as opposed to invasive fungal infections. Patients with defects affecting segments of innate (dectin-1, CARD9, IL12RB1) or adaptive immunity (interleukin (IL)17-F, IL-17 receptor, STAT1, STAT3, antibodies to Th-17 cytokines) that disrupt the Th-17 pathway, are unable to clear superficial Candida or Dermatophyte infections and suffer with chronic mucocutaneous candidiasis (CMC). Patients with defects affecting phagocyte function (oxidative killing, neutropenia) or a severely impaired immune system are at risk of developing invasive, often fatal fungal disease with Aspergillus, Candida, Cryptococcai and other fungi. PIDs are hugely beneficial in promoting our knowledge of fungal immunity and provide important contributions toward evidence-based diagnosis and improved patient care.     

Atorvastatin inhibits osteoclastogenesis by decreasing the expression of RANKL in the synoviocytes of rheumatoid arthritis

IL-17 and related cytokines are direct and indirect targets of selective immunosuppressive agents for the treatment of autoimmune diseases and other diseases of pathologic inflammation. Insights into the potential adverse effects of IL-17 blockade can be drawn from the experience of patients with deficiencies in the IL-17 pathway. A unifying theme of susceptibility to mucocutaneous candidiasis is seen in both mice and humans with a variety of genetic defects that converge on this pathway. Mucocutaneous candidiasis is a superficial infection of mucosal, nail or skin surfaces usually caused by the fungal pathogen Candida albicans. The morbidity of the disease includes significant pain, weight loss and secondary complications, including carcinoma and aneurysms. This review describes the known human diseases associated with chronic mucocutaneous candidiasis (CMC) as well as the known and proposed connections to IL-17 signaling. The human diseases include defects in IL-17 signaling due to autoantibodies (AIRE deficiency), receptor mutations (IL-17 receptor mutations) or mutations in the cytokine genes (IL17F and IL17A). Hyper-IgE syndrome is characterized by elevated serum IgE, dermatitis and recurrent infections, including CMC due to impaired generation of IL-17-producing Th17 cells. Mutations in STAT1, IL12B and IL12RB1 result in CMC secondary to decreased IL-17 production through different mechanisms. Dectin-1 defects and CARD9 defects result in susceptibility to C. albicans because of impaired host recognition of the pathogen and subsequent impaired generation of IL-17-producing T cells. Thus, recent discoveries of genetic predisposition to CMC have driven the recognition of the role of IL-17 in protection from mucosal fungal infection and should guide counseling and management of patients treated with pharmacologic IL-17 blockade.     

Immunological basis of anti‐Candida vaccines focused on synthetically prepared cell wall mannan‐derived manno‐oligomers

The increasing incidence of diseases caused by Candida species and complications in individuals with impaired immunity require new strategies for candidiasis treatment and prevention. The available therapies are often of limited effectiveness in immunocompromised patients, resulting in treatment failures, chronic infections and high mortality rates. Research directed at identifying the composition of an effective vaccine is required. Mannan forms the outermost layer of the Candida cell wall and has an essential role in modulation of anti‐Candida host immune responses. Therefore, Candida cell wall mannan and synthetically prepared manno‐oligomer‐based glycoconjugates are the foci of attention in vaccine candidate development. Almost all of the existing human vaccines mediate protection through neutralizing antibodies. Th1‐based and/or Th17‐based cellular immune responses, rather than antibody‐mediated immunity, mediate protection against candidiasis. Findings of published studies indicate that analysis of cellular immune responses as well as antibody responses is necessary when assessing the immunomodulatory properties of manno‐oligomer‐based glycoconjugates that are potential anti‐Candida vaccine candidates.     

Mucocutaneous candidiasis: the IL-17 pathway and implications for targeted immunotherapy

IL-17 and related cytokines are direct and indirect targets of selective immunosuppressive agents for the treatment of autoimmune diseases and other diseases of pathologic inflammation. Insights into the potential adverse effects of IL-17 blockade can be drawn from the experience of patients with deficiencies in the IL-17 pathway. A unifying theme of susceptibility to mucocutaneous candidiasis is seen in both mice and humans with a variety of genetic defects that converge on this pathway. Mucocutaneous candidiasis is a superficial infection of mucosal, nail or skin surfaces usually caused by the fungal pathogen Candida albicans. The morbidity of the disease includes significant pain, weight loss and secondary complications, including carcinoma and aneurysms. This review describes the known human diseases associated with chronic mucocutaneous candidiasis (CMC) as well as the known and proposed connections to IL-17 signaling. The human diseases include defects in IL-17 signaling due to autoantibodies (AIRE deficiency), receptor mutations (IL-17 receptor mutations) or mutations in the cytokine genes (IL17F and IL17A). Hyper-IgE syndrome is characterized by elevated serum IgE, dermatitis and recurrent infections, including CMC due to impaired generation of IL-17-producing Th17 cells. Mutations in STAT1, IL12B and IL12RB1 result in CMC secondary to decreased IL-17 production through different mechanisms. Dectin-1 defects and CARD9 defects result in susceptibility to C. albicans because of impaired host recognition of the pathogen and subsequent impaired generation of IL-17-producing T cells. Thus, recent discoveries of genetic predisposition to CMC have driven the recognition of the role of IL-17 in protection from mucosal fungal infection and should guide counseling and management of patients treated with pharmacologic IL-17 blockade.     

Understanding Vulvovaginal Candidiasis Through a Community Genomics Approach

Vulvovaginal candidiasis (VVC), predominantly caused by Candida albicans, is one of the most common types of infectious vaginitis. Extensive study has been directed toward understanding host defenses against this infection, and results remain inconclusive. While many have examined the role of innate and cell-mediated immunity, as well as Candida-specific antibodies and the anti-Candida activity of vaginal epithelial cells, little attention has been given to one of the most important players: the vaginal microbiota. Exploring changes in species composition and gene expression within the vaginal community using high-throughput genomic technologies is invaluable to fully understanding Candida pathogenesis and host response to infection. This integrative perspective of pathogenesis, host response and microbial influence are critical to our ability to improve routine gynecologic care and treatment of vaginal infections.     

念珠菌—上皮细胞互作研究进展

念珠菌作为共生菌定植于机体黏膜表面,一般情况下并不引起感染,但当机体出现免疫力下降或微生态失衡等状况时,可引发口咽念珠菌病、外阴阴道念珠菌病等黏膜感染。对于念珠菌黏膜感染的治疗,虽然抗菌药物是不可或缺的因素,但宿主自身的免疫力,尤其是黏膜上皮细胞作为抵御念珠菌感染的第一道防线,发挥着重要作用。本文将念珠菌—上皮细胞相互作用研究进展作一综述。     

Patients with Primary Immunodeficiencies: How Are They at Risk for Fungal Disease?

Purpose of Review

In this review, we focus on the inborn errors of immunity known to render the host susceptible to fungal infections, including candidias, aspergillosis, dermatophytosis, phaeohyphomycosis, pneumocystosis, fusariosis, cryptococcosis, and endemic mycoses.

Recent Findings

Classically, the burden of fungal disease in humans is believed to be carried by patients with a secondary immunodeficiency, either due to malignancy, to chemotherapy, to an immunocompromised state post hematopoietic stem cell transplantation, or to treatment with anti-cytokine therapies. However, in the last decade, the study of patients affected by fungal infections without any overt risk factors has led to the unraveling of several monogenic defects of human immunity to fungi. The study of these inborn errors of immunity has added vastly to our comprehension of antifungal immunity. For example, the role of IL-17 immunity in human defense against mucocutaneous candidiasis has been extensively characterized through the analysis of IL-17F, IL-17RA, IL-17Rc, ACT1, RORγT and, indirectly, CARD9 deficiency.

Summary

Many monogenic causes of susceptibility to superficial and/or invasive fungal infections have been recently unraveled. Most of these inborn errors of immunity associate with a specific type of fungal infection, and such a defect should always be suspected and sought in patients affected by fungal infection in the absence of predisposing factors.

     

A Review of the Ultrastructural Features of Superficial Candidiasis

Commensal yeast Candida causes opportunistic infections ranging from superficial lesions to disseminated mycoses in compromised patients. Superficial candidiasis, the commonest form of candidal infections, primarily affects the mucosa and the skin where Candida lives as a commensal. Conversion of candidal commensalism into opportunism at the fungal–epithelial interface is still ill-defined. Nevertheless, fungal virulence mechanisms such as adhesion to epithelia, morphogenesis, production of secretory hydrolytic enzymes, and phenotypic switching are thought to contribute in the process of pathogenesis. On the other hand, host responses in terms of immunity and local epithelial responses are actively involved in resisting the fungal challenge at the advancing front of the infection. Ultrastructural investigations using electron microscopy along with immunohistochemistry, cytochemistry, etc. have helped better viewing of Candida–host interactions. Thus, studies on the ultrastructure of superficial candidiasis have revealed a number of fungal behaviors and associated host responses such as adhesion, morphogenesis (hyphae and appresoria formation), thigmotropism, production and distribution of extracellular enzymes, phagocytosis, and epithelial changes. The purpose of this review is to sum up most of the ultrastructural findings of Candida–host interactions and to delineate the important pathological processes underlying superficial candidiasis.     

Invasive Fungal Infection in Primary Immunodeficiencies Other Than Chronic Granulomatous Disease

Purpose of review

We aimed to review invasive fungal infections complicating primary immunodeficiencies (PID).

Recent findings

Several PID predisposing to fungal infections were recently deciphered. CARD9 deficiency selectively predisposes to fungal infections including candidiasis, aspergillosis, deep dermatophytosis, and phaeohyphomycosis, with frequent central nervous system location, especially after Candida infection. Patients with heterozygous STAT1 gain-of-function mutations are mostly predisposed to chronic mucocutaneous candidiasis but may also display, even though less frequently, invasive fungal infections. Aspergillosis complicating STAT3 deficiency is also a major concern in patients with lung cavities. Antifungal prophylaxis is recommended in this first group of patients. Previously well-reported PID are known to predispose to fungal infections, such as genetic defects impairing the IL-12/IFN-γ axis can predispose to cryptococcosis, and dimorphic fungal infections.

Summary

Patients developing invasive fungal infections including candidiasis, aspergillosis, cryptococcosis, phaeohyphomycosis, pneumocystosis, or disseminated infections caused by dimorphic fungi, without known underlying risk factors, should be explored immunogenetically in order to diagnose primary immunodeficiencies, even in the absence of previous other infectious episodes.

     

IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal skin host defense against Candida albicans

IL-23 and Th17 cells play important roles in host defense against systemic infections with extracellular bacteria and fungi, although their roles in immunity against localized skin infections are less well defined. Here, the contributions of IL-23 and Th17 cytokines in host defense against cutaneous Candida albicans infection were evaluated. Mice deficient in IL-23 or IL-17A demonstrated delayed healing and decreased IL-17A production after skin infection with C. albicans compared with wild-type mice or mice deficient in IL-12 or IL-22. Histologic examination revealed epidermal hyperplasia overlying infected dermis four days postinoculation in wild-type mice. In IL-23-deficient mice, fungal burden was greater in skin, neither IL-17A nor IL-22 mRNAs were expressed postinfection, and these mice demonstrated only minimal epidermal hyperplasia. Exogenous recombinant IL-17A injected at the site of skin infection promoted more rapid healing of candidiasis in both wild-type mice and mice deficient in IL-23 and IL-12. Taken together, these results demonstrate that IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal host defense against cutaneous candidiasis. In addition, recombinant IL-17A may serve as a potential therapy to enhance healing in individuals with chronic cutaneous candidiasis.     

Farnesol promotes epithelial cell defense against Candida albicans through Toll-like receptor 2 expression,interleukin-6 and human β-defensin 2 production

Farnesol, a quorum-sensing molecule, regulates virulence and morphogenesis in Candida albicans and is involved in various human pathologies including oral candidiasis. Oral epithelial cells are involved in innate immunity against Candida infections via Toll-like receptors (TLRs) and inflammatory mediators. We investigated the effects of farnesol on host cells and its possible synergistic interaction with gingival epithelial cells against C. albicans infection by studying the expression of TLR2, 4 and 6. The production of IL-6, IL-8, and human β-defensins 1 and 2 was also examined using engineered human oral mucosa tissue put in contact with various concentrations of farnesol with and without C. albicans. Our findings indicate that 24 h after contact with C. albicans, epithelial cells expressed more TLR2 than did non-infected cells. The addition of exogenous farnesol upregulated the TLR2 expression by the gingival epithelial cells in the presence or absence of C. albicans. In contrast, TLR4 was down regulated when farnesol was added to the tissue with or without C. albicans. Finally, farnesol alone was shown to have no effect on TLR6, yet in the presence of both C. albicans and farnesol, TLR6 expression was down regulated. Farnesol modulated TLR2 expression by the epithelial cells following tissue contact with C. albicans. This effect was paralleled by IL-6 but not IL-8 secretion. Farnesol’s effect on innate immunity was strengthened by its capacity to increase human β-defensin 2 production, and by the efficacy of β-defensin against C. albicans growth. Overall results showed that exogenous farnesol promoted epithelial cell defense against C. albicans infection through the involvement of TLR2, IL-6, and human β-defensin 2.     

Immunomodulatory Agents as Adjunctive Therapy for the Treatment of Resistant Candida Species

Invasive Candida infections have increased fivefold over the past 20 years. During this time, the incidence of antifungal resistance and infection due to non-albicans species has risen with the increasing use of broad spectrum antifungals. As few new antifungal agents are in development, strategies to improve outcomes in the treatment of Candida infections are sorely needed. The use of immunotherapy to augment the host immune response as an adjunctive treatment for Candida infections is a potentially robust and promising approach. The purpose of this review is to focus on new developments in the use of adjunctive immunotherapy for the treatment of Candida infections, and discuss the potential impact of antifungal resistance on the host immune response.     

CARD9-Dependent Neutrophil Recruitment Protects against Fungal Invasion of the Central Nervous System

Candida is the most common human fungal pathogen and causes systemic infections that require neutrophils for effective host defense. Humans deficient in the C-type lectin pathway adaptor protein CARD9 develop spontaneous fungal disease that targets the central nervous system (CNS). However, how CARD9 promotes protective antifungal immunity in the CNS remains unclear. Here, we show that a patient with CARD9 deficiency had impaired neutrophil accumulation and induction of neutrophil-recruiting CXC chemokines in the cerebrospinal fluid despite uncontrolled CNS Candida infection. We phenocopied the human susceptibility in Card9 ^-/- mice, which develop uncontrolled brain candidiasis with diminished neutrophil accumulation. The induction of neutrophil-recruiting CXC chemokines is significantly impaired in infected Card9 ^-/- brains, from both myeloid and resident glial cellular sources, whereas cell-intrinsic neutrophil chemotaxis is Card9-independent. Taken together, our data highlight the critical role of CARD9-dependent neutrophil trafficking into the CNS and provide novel insight into the CNS fungal susceptibility of CARD9-deficient humans.     

Fungal Infections in Phagocytic Defects

Delineating the infection susceptibility of primary immunodeficiencies allows insight into host immunity. Filamentous mold infections are seen most frequently in chronic granulomatous disease, a neutrophil disorder characterized by impaired superoxide production. Mucocutaneous candidiasis occurs in disorders of impaired interleukin (IL)-17 and IL-22 signaling, such as seen in autosomal dominant hyper-IgE (Job’s) syndrome and in disorders with autoantibodies to these cytokines. The endemic dimorphic fungi are in part controlled by disorders of the IL-12/interferon (IFN)-γ pathway, such as IFN-γ receptor and STAT1 defects. Understanding the pathways involved in these primary immunodeficiency disorders will also provide insight into these infections in secondary immunodeficiencies and allow guidance for novel therapies.     

Clonal Strain Persistence of Candida albicans Isolates from Chronic Mucocutaneous Candidiasis Patients

Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency disorder characterised by susceptibility to chronic Candida and fungal dermatophyte infections of the skin, nails and mucous membranes. Molecular epidemiology studies of CMC infection are limited in number and scope and it is not clear whether single or multiple strains inducing CMC persist stably or are exchanged and replaced. We subjected 42 C. albicans individual single colony isolates from 6 unrelated CMC patients to multilocus sequence typing (MLST). Multiple colonies were typed from swabs taken from multiple body sites across multiple time points over a 17-month period. Among isolates from each individual patient, our data show clonal and persistent diploid sequence types (DSTs) that were stable over time, identical between multiple infection sites and exhibit azole resistant phenotypes. No shared origin or common source of infection was identified among isolates from these patients. Additionally, we performed C. albicans MLST SNP genotype frequency analysis to identify signatures of past loss of heterozygosity (LOH) events among persistent and azole resistant isolates retrieved from patients with autoimmune disorders including CMC.     

Insights from human studies into the host defense against candidiasis

Candida spp. are the most common cause of mucosal and disseminated fungal infections in humans. Studies using mutant strains of mice have provided initial information about the roles of dectin-1, CARD9, and Th17 cytokines in the host defense against candidiasis. Recent technological advances have resulted in the identification of mutations in specific genes that predispose humans to develop candidal infection. The analysis of individuals with these mutations demonstrates that dectin-1 is critical for the host defense against vulvovaginal candidiasis and candidal colonization of the gastrointestinal tract. They also indicate that CARD9 is important for preventing both mucosal and disseminated candidiasis, whereas the Th17 response is necessary for the defense against mucocutaneous candidiasis. This article reviews the recent studies of genetic defects in humans that result in an increased susceptibility to candidiasis and discusses how these studies provide new insight into the host defense against different types of candidal infections.     

The Acute Neutrophil Response Mediated by S100 Alarmins during Vaginal Candida Infections Is Independent of the Th17-Pathway

Vulvovaginal candidiasis (VVC) caused by Candida albicans affects a significant number of women during their reproductive ages. Clinical observations revealed that a robust vaginal polymorphonuclear neutrophil (PMN) migration occurs in susceptible women, promoting pathological inflammation without affecting fungal burden. Evidence to date in the mouse model suggests that a similar acute PMN migration into the vagina is mediated by chemotactic S100A8 and S100A9 alarmins produced by vaginal epithelial cells in response to Candida. Based on the putative role for the Th17 response in mucosal candidiasis as well as S100 alarmin induction, this study aimed to determine whether the Th17 pathway plays a role in the S100 alarmin-mediated acute inflammation during VVC using the experimental mouse model. For this, IL-23p19^−/−, IL-17RA^−/− and IL-22^−/− mice were intravaginally inoculated with Candida, and vaginal lavage fluids were evaluated for fungal burden, PMN infiltration, the presence of S100 alarmins and inflammatory cytokines and chemokines. Compared to wild-type mice, the cytokine-deficient mice showed comparative levels of vaginal fungal burden and PMN infiltration following inoculation. Likewise, inoculated mice of all strains with substantial PMN infiltration exhibited elevated levels of vaginal S100 alarmins in both vaginal epithelia and secretions in the vaginal lumen. Finally, cytokine analyses of vaginal lavage fluid from inoculated mice revealed equivalent expression profiles irrespective of the Th17 cytokine status or PMN response. These data suggest that the vaginal S100 alarmin response to Candida does not require the cells or cytokines of the Th17 lineage, and therefore, the immunopathogenic inflammatory response during VVC occurs independently of the Th17-pathway.