Fungi make fun guys.

In a recent Cell study, Leonardi et al. show that commensal mucosa-associated gut fungi profoundly impact host immunity, epithelial barrier function, and, unexpectedly, neuroimmune modulation of social behavior. All of these events are controlled by fungal-induced activation of type 17 cytokines that act on both epithelial cells and neurons.

Effective Barriers: The Role of NKT Cells and Innate Lymphoid Cells in the Gut.

The critical role of commensal microbiota in regulating the host immune response has been established. In addition, it is known that host-microbial interactions are bidirectional, and this interplay is tightly regulated to prevent chronic inflammatory disease. Although many studies have focused on the role of classic T cell subsets, unconventional lymphocytes such as NKT cells and innate lymphoid cells also contribute to the regulation of homeostasis at mucosal surfaces and influence the composition of the intestinal microbiota. In this review, we discuss the mechanisms involved in the cross-regulation between NKT cells, innate lymphoid cells, and the gut microbiota. Moreover, we highlight how disruptions in homeostasis can lead to immune-mediated disorders.

Fungal Dysbiosis in Children with Celiac Disease.

BACKGROUND: Although intestinal fungi are known to interact with the immune system, the relationship between intestinal fungi and childhood celiac disease (CeD), an immune-mediated condition, has rarely been reported. AIMS: The aim of this study was to describe gut fungal profiles in a cohort of children with new-onset CeD. METHODS: Mucosal and fecal samples were collected from children with CeD and controls and subjected to metagenomics analysis of fungal microbiota communities. DNA libraries were sequenced using Illumina HiSeq platform 2 × 150 bp. Bioinformatic analysis was performed to quantify the relative abundance of fungi. Shannon alpha diversity metrics and beta diversity principal coordinate (PCo) analyses were calculated, and DESeq tests were performed between celiac and non-celiac groups. RESULTS: Overall more abundant taxa in samples of children with CeD included Tricholomataceae, Saccharomycetaceae, Saccharomycetes Saccharomyces cerevisiae, and Candida, whereas less abundant taxa included Pichiaceae, Pichia kudriavzevii, Pneumocystis, and Pneumocystis jirovecii. Alpha diversity between CeD and control individuals did not differ significantly, and beta diversity PCo analysis showed overlap of samples from CeD and controls for both fecal or mucosal samples; however, there was a clear separation between mucosal and fecal overall samples CONCLUSIONS: We report fungal dysbiosis in children with CeD, suggesting a possible role in the pathogenesis of CeD. Further larger, controlled, prospective and longitudinal studies are needed to verify the results of this study and clarify the functional role of fungi in CeD.

Comprehensive Gene Expression Signature Using RNA-Seq in Airways of Mouse Model of Severe Asthma with Fungal Sensitization.

INTRODUCTION: Inhalation of fungal allergens induces airway epithelial damage following airway inflammation and excessive mucus secretion, which can lead to severe asthma with fungal sensitization (SAFS). Comprehensive gene expression analysis in Alternaria-exposed mouse airways, a model of SAFS, has not been conducted. METHODS: BALB/c mice received intranasal administration of Alternaria extract or phosphate-buffered saline twice a week for 6 weeks. Lung sections and bronchoalveolar lavage fluid were obtained to assess airway inflammation. RNA-Seq in the central airway was performed, and gene ontology (GO) analysis and gene set enrichment analysis (GSEA) were conducted for pathway analyses. An in vitro experiment using human airway epithelial cell 16HBE14o- was performed to validate the RNA-Seq findings. RESULTS: Eosinophilic airway inflammation with mucus overproduction and airway remodeling was observed in mice exposed to Alternaria. RNA-Seq analysis revealed 403 upregulated and 108 downregulated genes in airways of Alternaria-exposed mice. In GO analysis, the functions of immunoglobulin (Ig) receptor binding, Ig production, inflammatory response, and T-cell activation were upregulated, while those of keratinization and defense response to other organisms were downregulated. GSEA revealed positive enrichment in T-cell receptor complex, immunological synapse, antigen binding, mast cell activation, and Ig receptor binding, and negative enrichment in keratinization and cornification in Alternaria-exposed mice relative to control. Alternaria exposure to 16HBE14o- cells validated the downregulation of epithelial keratinization-related genes, including SPRR1A, SPRR1B, and KRT6B. CONCLUSION: RNA-Seq analysis showed that Alternaria exposure induced inflammatory response and impaired defense mechanisms in mice airway epithelium, which might be therapeutic targets for SAFS.

Mold, Mycotoxins and a Dysregulated Immune System: A Combination of Concern?

Fungi represent one of the most diverse and abundant eukaryotes on earth. The interplay between mold exposure and the host immune system is still not fully elucidated. Literature research focusing on up-to-date publications is providing a heterogenous picture of evidence and opinions regarding the role of mold and mycotoxins in the development of immune diseases. While the induction of allergic immune responses by molds is generally acknowledged, other direct health effects like the toxic mold syndrome are controversially discussed. However, recent observations indicate a particular importance of mold/mycotoxin exposure in individuals with pre-existing dysregulation of the immune system, due to exacerbation of underlying pathophysiology including allergic and non-allergic chronic inflammatory diseases, autoimmune disorders, and even human immunodeficiency virus (HIV) disease progression. In this review, we focus on the impact of mycotoxins regarding their impact on disease progression in pre-existing immune dysregulation. This is complemented by experimental in vivo and in vitro findings to present cellular and molecular modes of action. Furthermore, we discuss hypothetical mechanisms of action, where evidence is missing since much remains to be discovered.

Two NLR immune receptors acquired high-affinity binding to a fungal effector through convergent evolution of their integrated domain.

A subset of plant NLR immune receptors carry unconventional integrated domains in addition to their canonical domain architecture. One example is rice Pik-1 that comprises an integrated heavy metal-associated (HMA) domain. Here, we reconstructed the evolutionary history of Pik-1 and its NLR partner, Pik-2, and tested hypotheses about adaptive evolution of the HMA domain. Phylogenetic analyses revealed that the HMA domain integrated into Pik-1 before Oryzinae speciation over 15 million years ago and has been under diversifying selection. Ancestral sequence reconstruction coupled with functional studies showed that two Pik-1 allelic variants independently evolved from a weakly binding ancestral state to high-affinity binding of the blast fungus effector AVR-PikD. We conclude that for most of its evolutionary history the Pik-1 HMA domain did not sense AVR-PikD, and that different Pik-1 receptors have recently evolved through distinct biochemical paths to produce similar phenotypic outcomes. These findings highlight the dynamic nature of the evolutionary mechanisms underpinning NLR adaptation to plant pathogens.

Commensal bacteria and fungi differentially regulate tumor responses to radiation therapy.

Studies suggest that the efficacy of cancer chemotherapy and immunotherapy is influenced by intestinal bacteria. However, the influence of the microbiome on radiation therapy is not as well understood, and the microbiome comprises more than bacteria. Here, we find that intestinal fungi regulate antitumor immune responses following radiation in mouse models of breast cancer and melanoma and that fungi and bacteria have opposite influences on these responses. Antibiotic-mediated depletion or gnotobiotic exclusion of fungi enhances responsiveness to radiation, whereas antibiotic-mediated depletion of bacteria reduces responsiveness and is associated with overgrowth of commensal fungi. Further, elevated intratumoral expression of Dectin-1, a primary innate sensor of fungi, is negatively associated with survival in patients with breast cancer and is required for the effects of commensal fungi in mouse models of radiation therapy.

The Emerging Role of Mast Cells in Response to Fungal Infection.

Mast cells (MCs) have been considered as the core effector cells of allergic diseases. However, there are evidence suggesting that MCs are involved in the mechanisms of fungal infection. MCs are mostly located in the border between host and environment and thus may have easy contact with the external environmental pathogens. These cells express receptors which can recognize pathogen-associated molecular patterns such as Toll-like receptors (TLR2/4) and C-type Lectins receptors (Dectin-1/2). Currently, more and more data indicate that MCs can be interacted with some fungi (Candida albicans, Aspergillus fumigatus and Sporothrix schenckii). It is demonstrated that MCs can enhance immunity through triggered degranulation, secretion of cytokines and chemokines, neutrophil recruitment, or provision of extracellular DNA traps in response to the stimulation by fungi. In contrast, the involvement of MCs in some immune responses may lead to more severe symptoms, such as intestinal barrier function loss, development of allergic bronchial pulmonary aspergillosis and increased area of inflammatory in S. schenckii infection. This suggests that MCs and their relevant signaling pathways are potential treatment regimens to prevent the clinically unwanted consequences. However, it is not yet possible to make definitive statements about the role of MCs during fungal infection and/or pathomechanisms of fungal diseases. In our article, we aim to review the function of MCs in fungal infections from molecular mechanism to signaling pathways, and illustrate the role of MCs in some common host-fungi interactions.

The Role of IL-17-Producing Cells in Cutaneous Fungal Infections.

The skin is the outermost layer of the body and is exposed to many environmental stimuli, which cause various inflammatory immune responses in the skin. Among them, fungi are common microorganisms that colonize the skin and cause cutaneous fungal diseases such as candidiasis and dermatophytosis. The skin exerts inflammatory responses to eliminate these fungi through the cooperation of skin-component immune cells. IL-17 producing cells are representative immune cells that play a vital role in anti-fungal action in the skin by producing antimicrobial peptides and facilitating neutrophil infiltration. However, the actual impact of IL-17-producing cells in cutaneous fungal infections remains unclear. In this review, we focused on the role of IL-17-producing cells in a series of cutaneous fungal infections, the characteristics of skin infectious fungi, and the recognition of cell components that drive cutaneous immune cells.

Tissue-Resident Memory T Cells in Antifungal Immunity.

Fungi are an integral part of the mammalian microbiota colonizing most if not all mucosal surfaces and the skin. Maintaining stable colonization on these surfaces is critical for preventing fungal dysbiosis and infection, which in some cases can lead to life threatening consequences. The epithelial barriers are protected by T cells and additional controlling immune mechanisms. Noncirculating memory T cells that reside stably in barrier tissues play an important role for host protection from commensals and recurrent pathogens due to their fast response and local activity, which provides them a strategic advantage. So far, only a few specific examples of tissue resident memory T cells (TRMs) that act against fungi have been reported. This review provides an overview of the characteristics and functional attributes of TRMs that have been established based on human and mouse studies with various microbes. It highlights what is currently known about fungi specific TRMs mediating immunosurveillance, how they have been targeted in preclinical vaccination approaches and how they can promote immunopathology, if not controlled. A better appreciation of the host protective and damaging roles of TRMs might accelerate the development of novel tissue specific preventive strategies against fungal infections and fungi-driven immunopathologies.

Characterization of antifungal C-type lectin receptor expression on murine epithelial and endothelial cells in mucosal tissues.

Our data reveal that selection of enzymes for generating single cell suspensions from murine tissues influences detection of surface expression of antifungal CLRs. Using a method that most preserves receptor expression, we show that non-myeloid expression of antifungal CLRs is limited to MelLec on endothelial cells in murine mucosal tissues.

RALDH Activity Induced by Bacterial/Fungal Pathogens in CD16+ Monocyte-Derived Dendritic Cells Boosts HIV Infection and Outgrowth in CD4+ T Cells.

HIV reservoirs persist in gut-homing CD4+ T cells of people living with HIV and receiving antiretroviral therapy, but the antigenic specificity of such reservoirs remains poorly documented. The imprinting for gut homing is mediated by retinoic acid (RA), a vitamin A-derived metabolite produced by dendritic cells (DCs) exhibiting RA-synthesizing (RALDH) activity. RALDH activity in DCs can be induced by TLR2 ligands, such as bacterial peptidoglycans and fungal zymosan. Thus, we hypothesized that bacterial/fungal pathogens triggering RALDH activity in DCs fuel HIV reservoir establishment/outgrowth in pathogen-reactive CD4+ T cells. Our results demonstrate that DCs derived from intermediate/nonclassical CD16+ compared with classical CD16- monocytes exhibited superior RALDH activity and higher capacity to transmit HIV infection to autologous Staphylococcus aureus-reactive T cells. Exposure of total monocyte-derived DCs (MDDCs) to S. aureus lysates as well as TLR2 (zymosan and heat-killed preparation of Listeria monocytogenes) and TLR4 (LPS) agonists but not CMV lysates resulted in a robust upregulation of RALDH activity. MDDCs loaded with S. aureus or zymosan induced the proliferation of T cells with a CCR5+integrin ß7+CCR6+ phenotype and efficiently transmitted HIV infection to these T cells via RALDH/RA-dependent mechanisms. Finally, S. aureus- and zymosan-reactive CD4+ T cells of antiretroviral therapy-treated people living with HIV carried replication-competent integrated HIV-DNA, as demonstrated by an MDDC-based viral outgrowth assay. Together, these results support a model in which bacterial/fungal pathogens in the gut promote RALDH activity in MDDCs, especially in CD16+ MDDCs, and subsequently imprint CD4+ T cells with gut-homing potential and HIV permissiveness. Thus, nonviral pathogens play key roles in fueling HIV reservoir establishment/outgrowth via RALDH/RA-dependent mechanisms that may be therapeutically targeted.

Insights on the Functional Role of Beta-Glucans in Fungal Immunity Using Receptor-Deficient Mouse Models.

Understanding the host anti-fungal immunity induced by beta-glucan has been one of the most challenging conundrums in the field of biomedical research. During the last couple of decades, insights on the role of beta-glucan in fungal disease progression, susceptibility, and resistance have been greatly augmented through the utility of various beta-glucan cognate receptor-deficient mouse models. Analysis of dectin-1 knockout mice has clarified the downstream signaling pathways and adaptive effector responses triggered by beta-glucan in anti-fungal immunity. On the other hand, assessment of CR3-deficient mice has elucidated the compelling action of beta-glucans in neutrophil-mediated fungal clearance, and the investigation of EphA2-deficient mice has highlighted its novel involvement in host sensing and defense to oral mucosal fungal infection. Based on these accounts, this review focuses on the recent discoveries made by these gene-targeted mice in beta-glucan research with particular emphasis on the multifaceted aspects of fungal immunity.

Immune properties of invertebrate phenoloxidases.

Melanin production from different types of phenoloxidases (POs) confers immunity from a variety of pathogens ranging from viruses and microorganisms to parasites. The arthropod proPO expresses a variety of activities including cytokine, opsonin and microbiocidal activities independent of and even without melanin production. Proteolytic processing of proPO and its activating enzyme gives rise to several peptide fragments with a variety of separate activities in a process reminiscent of vertebrate complement system activation although proPO bears no sequence similarity to vertebrate complement factors. Pathogens influence proPO activation and thereby what types of immune effects that will be produced. An increasing number of specialised pathogens - from parasites to viruses - have been identified who can synthesise compounds specifically aimed at the proPO-system. In invertebrates outside the arthropods phylogenetically unrelated POs are participating in melanization reactions obviously aimed at intruders and/or aberrant tissues.

Immunomodulating Effects of Fungal Beta-Glucans: From Traditional Use to Medicine.

The importance of a well-functioning and balanced immune system has become more apparent in recent decades. Various elements have however not yet been uncovered as shown, for example, in the uncertainty on immune system responses to COVID-19. Fungal beta-glucans are bioactive molecules with immunomodulating properties. Insights into the effects and function of beta-glucans, which have been used in traditional Chinese medicine for centuries, advances with the help of modern immunological and biotechnological methods. However, it is still unclear into which area beta-glucans fit best: supplements or medicine? This review has highlighted the potential application of fungal beta-glucans in nutrition and medicine, reviewing their formulation, efficacy, safety profile, and immunomodulating effects. The current status of dietary fungal glucans with respect to the European scientific requirements for health claims related to the immune system and defense against pathogens has been reviewed. Comparing the evidence base of the putative health effects of fungal beta-glucan supplements with the published guidance documents by EFSA on substantiating immune stimulation and pathogen defense by food products shows that fungal beta-glucans could play a role in supporting and maintaining health and, thus, can be seen as a good health-promoting substance from food, which could mean that this effect may also be claimed if approved. In addition to these developments related to food uses of beta-glucan-containing supplements, beta-glucans could also hold a novel position in Western medicine as the concept of trained immunity is relatively new and has not been investigated to a large extent. These innovative concepts, together with the emerging success of modern immunological and biotechnological methods, suggest that fungal glucans may play a promising role in both perspectives, and that there are possibilities for traditional medicine to provide an immunological application in both medicine and nutrition.

Zearalenone and the Immune Response.

Zearalenone (ZEA) is an estrogenic fusariotoxin, being classified as a phytoestrogen, or as a mycoestrogen. ZEA and its metabolites are able to bind to estrogen receptors, 17ß-estradiol specific receptors, leading to reproductive disorders which include low fertility, abnormal fetal development, reduced litter size and modification at the level of reproductive hormones especially in female pigs. ZEA has also significant effects on immune response with immunostimulatory or immunosuppressive results. This review presents the effects of ZEA and its derivatives on all levels of the immune response such as innate immunity with its principal component inflammatory response as well as the acquired immunity with two components, humoral and cellular immune response. The mechanisms involved by ZEA in triggering its effects are addressed. The review cited more than 150 publications and discuss the results obtained from in vitro and in vivo experiments exploring the immunotoxicity produced by ZEA on different type of immune cells (phagocytes related to innate immunity and lymphocytes related to acquired immunity) as well as on immune organs. The review indicates that despite the increasing number of studies analyzing the mechanisms used by ZEA to modulate the immune response the available data are unsubstantial and needs further works.

Sensitization against Fungi in Patients with Airway Allergies over 20 Years in Germany.

BACKGROUND: Fungal spores are ubiquitous allergens. Severe forms of asthma are particularly highly associated with fungal sensitization. National and international asthma guidelines recommend the implementation of allergen immunotherapy if indicated. Thus, detection and treatment of relevant allergies are key components of primary care of these patients. OBJECTIVES: The aims of the study were (i) to investigate trends in the prevalence of sensitization to twelve fungi in central Germany over the last 20 years and (ii) to dissect specific sensitization patterns among the 3 most important fungi: Aspergillus, Alternaria, and Cladosporium. METHODS: This single-center study evaluated skin prick test (SPT) results of 3,358 patients with suspected airway allergies over a period of 20 years (1998-2017). RESULTS: While 19.2% of all study patients had positive test results to at least 1 of the 3 fungi (Alternaria, Aspergillus, or Cladosporium) in the first study decade, this rate increased to 22.5% in the second decade. Slight increases in sensitization rates to almost all fungi were observed over the 20-year period. In the last decade, polysensitization to Alternaria, Aspergillus, and Cladosporium increased significantly. Sensitization to fungi is age-dependent and peaks in the age-group of 21-40 years during the second decade. CONCLUSION: Fungi are relevant allergens for perennial and seasonal allergy symptoms. We currently recommend including Aspergillus, Alternaria, and Cladosporium in the standard series of SPTs for airway allergies.

Microbiological profile in chronic granulomatous disease patients in a single Brazilian primary immunodeficiency center.

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency. Infections of lung, skin, lymph nodes, and liver are the hallmark of CGD and frequently the initial manifestation of the disease. The aim of the present paper is to describe the sites of infections and their causative agents in 38 pediatric patients with CGD. METHODS: This retrospective, single-center cohort study included CGD patients followed at the allergy and immunology unit of a tertiary hospital in São Paulo, Brazil over the last 40 years. Sites of infections and their causative agents were described. RESULTS: Thirty-eight patients were included (36 males). The median age of onset of symptoms was 45 days (ranging from 7 days-7 years), and the median age at diagnosis was 23 months (ranging from 1 month-12 years). In all, 31.6% of the patients reported a family history of child deaths and 21% (eight cases) had another male family member with CGD. The most common infections were pneumonia (81.6%), skin infections (50.0%), adenitis (42.1%), and liver abscess (23.7%); 188 cultures were positive (85.6% bacteria; 14.4% fungi). The most prevalent bacterial agents were Staphylococcus sp. (12.4%), Staphylococcus aureus (11.2%), and Klebsiella pneumoniae (9.3%). Aspergillus sp. and Candida sp. were 56% and 22.2% of the isolated fungi, respectively. Mycobacterium tuberculosis was isolated in 5.6% and Mycobacterium bovis in one patient (0.9%). CONCLUSION: Staphylococcus sp., Staphylococcus aureus, and Aspergillus sp. were the most frequent agents found in this cohort. M. tuberculosis should be considered in endemic area. Detection of infectious agents drives to the adequate treatment and benefits the evolution of patients with CGD.

Cell wall-associated effectors of plant-colonizing fungi.

Plant-colonizing fungi secrete a cocktail of effector proteins during colonization. After secretion, some of these effectors are delivered into plant cells to directly dampen the plant immune system or redirect host processes benefitting fungal growth. Other effectors function in the apoplastic space either as released proteins modulating the activity of plant enzymes associated with plant defense or as proteins bound to the fungal cell wall. For such fungal cell wall-bound effectors, we know particularly little about their molecular function. In this review, we describe effectors that are associated with the fungal cell wall and discuss how they contribute to colonization.