Contents:
Immune responses to fungal pathogens. Immune responses to bacteria. Chronic Obstructive Pulmonary Disease. Biofilms and their role in pathogenesis. Ulcerative colitis and Trichuris infection. Microbial infection in cystic fibrosis. Vulvovaginal candidiasis thrush Oral candidiaisis mouth infection Disseminated candidiasis sepsis. Fungal infection in HIV-infected persons. Overview of host defences in fungal infections. Clin Infect Dis ; Epidemiology of nosocomial fungal infections.
Clin Microbiol Rev ; 9: Candida and Aspergillus infections in immunocompromised patients: Rev Infect Dis ; Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med ; Mucociliary clearance in the airways. Pulmonary defence mechanisms against opportunistic fungal pathogens In: Immunology of Fungal Diseases. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus.
J Clin Invest ; Antibacterial components in bronchoalveolar lavage fluid from healthy individuals and sarcoidosis patients. Epithelial antibiotics induced at sites of inflammation.
Science ; The T cell response against fungal infections. Curr Opin Immunol ; 9: Polak A, Hartman PG. Antifungal chemotherapy - are we winning?. Prog Drug Res ; Disseminated hyalohyphomycosis caused by a novel human pathogen, Fusarium napiforme. J Clin Microbiol ; Sirisantha V, Sirisantha T. Disseminated Penicillium marneffei infection in human immunodeficiency infected children.
Pediatr Infect Dis J ; Clin Microbiol Rev ; 8: Recombinant Aspergillus fumigatus allergens: From the nucleotide sequences to clinical applications. Int Arch Allergy Immunol ; Automated specific IgE assay with recombinant allergens: Clin Exp Allergy ; Skin test reactivity to 2 recombinant Aspergillus fumigatus allergens in A. J Allergy Clin Immunol ; Disease-specific recombinant allergens for the diagnosis of allergic bronchopulmonary aspergillosis. Int Immunol ; Differential IgE recognition of recombinant Aspergillus fumigatus allergens by cystic fibrosis patients with allergic bronchopulmonary aspergillosis or Aspergillus allergy.
Eur J Immunol ; Ann Intern Med ; Clin Chest Med ; Hood S, Denning DW. Treatment of fungal infections in AIDS. J Antimicrob Chemother ; Killing of Aspergillus spores depends on the anatomical source of the macrophage. Infect Immun ; Pathogenesis of pulmonary aspergillosis. Granulocytopenia versus Cyclosporin and methylprednisolone-induced immunosuppression.
Epithelial shedding - restitution as a causative process in airway inflammation. Asmundsson T, Kilburn KH. Mechanisms of respiratory tract clearance In: Springfield, IL, Charles C. Thomas, ; pp. Mucociliary clearance in patients with cystic fibrosis and in normal subjects. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus: Observations on these two lines of defence in vivo and in vitro with human and mouse phagocytes.
Medzhitov R, Janeway CA. Relationship to the eosinophil-active cytokines interleukin IL -5, granulocyte macrophage-colony-stimulating factor, and IL Curr Opin Immunol ; 2: Cytokine cross-talk between phagocytic cells and lymphocytes: J Cell Biochem ; Cytokine gene expression in human peripheral blood mononuclear cells stimulated by mannoprotein constituents from Candida albicans. Burrell R, Rylander R.
A critical review of the role of precipitins in hypersensitivity pneumonitis. Eur J Respir Dis ; Antibodies, killer toxins and antifungal immunoprotection: Immunol Today ; Crameri R, Walter G. Selective enrichment and high-throughput screening of phage surface-displayed cDNA libraries from complex allergenic systems. Comb Chem High Throughput Screen ; 2: Tapping allergen-repertoires by advanced cloning technologies. IgE-mediated reaction to autoantigens in allergic diseases.
Humoral and cell-mediated autoimmunity in allergy to Aspergillus fumigatus. J Exp Med ; Humoral and cell-mediated autoimmune reactions to human acidic ribosomal P 2 protein in individuals sensitized to Aspergillus fumigatus P 2 protein. Production and function of cytokines in natural and acquired immunity to Candida albicans infection.
Microbiol Rev ; View this article with LENS. Vol 19 Issue 1 Table of Contents. Table of Contents Index by author. Thank you for your interest in spreading the word on European Respiratory Society. You are going to email the following Allergy and immunity to fungal infections and colonization. Allergy and immunity to fungal infections and colonization. Ventilatory response to exercise in cardiopulmonary disease. STAT3 is involved in the signal transduction pathway required for the expression of many cytokine receptors, and patients bearing STAT3 mutations have almost no T H 17 lymphocytes and fail to produce IL [ 16 — 18 ].
CGD is another condition characterized by marked increased susceptibility to invasive bacterial and fungal infections. The fungal infections are mainly represented by Aspergillus , with the interesting observation of a high proportion owing to A. CGD is caused by mutations in one of the proteins of the nicotinamide adenine dinucleotide phosphate oxidase complex. Mutations in all five subunits of this complex have been described gp91phox, p47phox, p22phox, p67phox and p40phox , which result in the loss of function of the complex and defective production of reactive oxygen species.
In addition, hematopoietic stem cell transplantation may offer a longer-term solution for CGD patients [ 38 ], whereas gene therapy using retroviral vectors has also been proposed as a future intervention [ 39 ]. More research is required to evaluate the long-term safety and effectiveness of gene therapy.
In addition to these classical immunodeficiencies, new studies have described novel forms of immunodeficiency based on defects in specific receptors or their associated intracellular pathways. Among these, one of the most severe is the defect in CARD9—the adaptor molecule crucial for inducing the intracellular signalling of C-type lectin receptors. Defects in CARD9 are associated with significantly increased susceptibility to invasive fungal infections, which is mediated through multiple immunological defects [ 40 , 41 ].
Complete functional defects in one of the important C-type lectin receptors, dectin-1, have also been described to be associated with mucosal Candida infections [ 42 , 43 ], but the relatively common prevalence of this mutation and the mild clinical presentation suggest this should be regarded as a mutation associated with an increased susceptibility risk, rather than as a classical primary immunodeficiency. These mutations are most often loss-of-function recessive polymorphisms. Several epidemiological investigations have assessed the role of TLR polymorphisms for the susceptibility to disseminated candidiasis.
The AspGly TLR4 polymorphism has been proposed to act as a susceptibility trait for systemic candidiasis [ 56 ] and the AspGln TLR2 polymorphism resulted in an altered cytokine profile in patients with Candida sepsis [ 57 ]. However, the hypothesis that these polymorphisms are involved in susceptibility to candidemia could not be confirmed in a much larger cohort of individuals, including patients and matched controls [ 45 ].
Similarly, no role of TLR4 polymorphisms in vaginal colonization with Candida spp. Common genetic variants associated with increased susceptibility to Candida infections. MBL, mannose binding lectin. Studies dedicated to identifying common genetic variants that predispose to bloodstream Candida infections have revealed a significant role for non-synonymous polymorphisms in TLR1 [ 45 ]. These TLR1 polymorphisms result in loss-of-function of the receptor, defective pattern recognition of the pathogens, and decreased cytokine production. In the same cohort of patients with candidemia, persistence of fungemia was shown to be associated with promoter polymorphisms in the cytokine genes ILB and IL [ 47 ].
These polymorphisms affect cytokine transcription and thereby influence the IL and IL production capacity of innate immune cells [ 61 — 65 ]. The persistence of infection was demonstrated to correlate with decreased IL and increased IL production induced by the presence of Candida , which may result in inhibition of the T H 1 response that is known to be crucial for anti- Candida systemic immunity [ 66 , 67 ]. In agreement with this, a decreased production of T H 2 cytokines such as IL-4 owing to genetic variation in the IL4 gene also leads to protective effects [ 68 , 69 ].
Multiple studies have been dedicated to investigate the role of mannose binding lectin MBL deficiency in infections with Candida spp. Indeed, genetic associations of MBL deficiency with infection risk have been observed in cohorts of patients with candidemia, abdominal infections and RVVC [ 48 — 50 , 68 ]. Oropharyngeal candidiasis OPC , a mucosal colonization of the mouth and upper digestive tract, is frequently observed in patients that are infected with HIV.
A recent study assessed the potential role of genetic variants of pattern recognition receptors in susceptibility to OPC in West African HIV patients, and revealed an IS genetic variant of dectin-1 that was specific for African populations [ 44 ]. The genetic studies on Candida infections described above are variable in terms of size of patient cohorts and statistical power.
While some of the studies had relatively large cohorts, with appropriate statistical analysis, others were based on relatively small numbers of patients and this limited the robustness of the conclusions. Although some of the reported genetic associations were supported by functional studies that provided mechanistic explanations for the increased susceptibility to infection, the common lack of genetic validation of these genetic associations underlines the importance of future studies with appropriate statistical power using independent cohorts of patients.
In addition to the classical candidate-based approaches for investigating susceptibility to fungal infections, recent methodological advances have permitted the initiation of discovery-based genomic approaches to identify novel genetic variants that impact on fungal disease. Recently, the first genome-wide association study GWAS on a fungal infection was published [ 55 ], in which the authors analysed and compared single-nucleotide polymorphisms SNPs in patients with candidemia and a large cohort of healthy volunteers.
The combination of two or more risk alleles in these two genes resulted in an almost fold increase in the risk for candidemia [ 55 ].
CD58, and adhesion molecule on antigen-presenting cells, appeared to be involved in the inhibition of Candida germination, whereas TAGAP was needed for optimal Candida -induced cytokine production [ 55 ]. More studies are needed to validate these findings, to expand the depth of these genomic approaches to more genetic variants, and to perform GWASs also in other fungal infections.
Such studies may pave the way for future clinical decisions based on personalized SNP profiling. Recent years have witnessed a revolution in our understanding of how the microbiome composition impacts the health status of the host [ 74 ]. For example, a recent study in mice showed that dietary coconut oil reduced C. Candida colonization is also influenced by quantitative and qualitative aspects of the microbiome, such as Lactobacilli that inhibit fungal adhesion and growth by producing H 2 O 2 and bacteriocin-like compounds [ 76 ].
Another example through which microbiome products influence fungal colonization is that of the production of short-chain fatty acids by Lactobacilli that can also inhibit fungal growth [ 77 ]. Some bacteria such as Pseudomonas aeruginosa and Enterococcus faecalis can inhibit C. Supporting this, in a Caenorhabditis elegans infection model, E. Direct and indirect influences of the microbiome on the physiology of fungal pathogen growth and the innate immune response as described in the text. In short, colonization with Candida does not induce the production of cytokines.
Upon invasion, Candida activates tissue macrophages to induce production of chemokines and cytokines. This, in turn, will recruit and activate other immune cells from the bloodstream, such as monocytes or neutrophils that will ingest and kill the pathogens.
Activations of dendritic cells will also lead to antigen presentation and activation of T-helper responses that, in turn, will aid pathogen elimination. Mice treated with the short-chain fatty acid propionate, a product of the metabolism of dietary fermentable fibres by many gut microorganisms, have numerous immune alterations, including enhanced generation of macrophage and dendritic cell precursors, increased number of dendritic cells in the lungs and reduced T H 2 effector function [ 84 ].
Lactobacilli in the gut use tryptophan as their energy source and produce indolealdehyde in the process. Thus, bacterial components of the microbiome can influence immune responses in the gut and in the lung. The microbiome composition in humans has also been demonstrated to influence the immune response against C. Acinetobacter , whereas some of the regular skin microbiome genera e. Corynebacteria have a much lower prevalence than in controls. This pathological colonization with Gram-negative bacteria can, in turn, suppress S.
The vaginal microbiome of patients with vulvovaginal candidiasis is highly variable, and could not be described by any single profile [ 87 ]. In terms of abundance, fungi are relatively rare on human skin [ 88 ], and the fungal microbiome has yet to be researched in detail.
When the normal immune balance is disturbed, e. Indeed, antibiotic treatment in mice causes an altered gut microbiome that coincides with outgrowth of commensal Candida species in the gut [ 90 ]. In addition, genetic factors contribute to mycobiome composition. Fr example, in dectin-1 deficient mice, there is an altered gut mycobiome, which subsequently increases the susceptibility to experimental colitis [ 91 ]. Oral mycobiome analysis revealed that C. Candida colonization is negatively correlated with the abundance of Pichia farinosa —a near relative of Candida boidinii.
Pichia -conditioned medium is a medium in which the yeast Pichia has been grown and then removed by filtration. Interestingly, Pichia- conditioned medium inhibits Candida growth and biofilms, and in a murine oral candidiasis model, Pichia- conditioned medium lowered the infection score, fungal burden and tongue epithelial damage [ 92 ]. This study provides proof of principle that investigating the relationship between the bacteriome and mycobiome, or between various components of the mycobiome, can both provide new insights into the pathology of a disease and can lead to novel antifungal approaches [ 92 ].
Fungal infections are more prevalent and often more serious than have been appreciated, and investment is required in basic research and public engagement to address the clinical challenge they impose. Although new antifungals and better diagnostics are under development, the impact of currently available tools and interventions on mortality rates owing to fungal infection has not changed significantly in recent years.