Molecular and clinical characterization of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) in Iranian non-Jewish patients: report of two novel AIRE gene pathogenic variants

Objective Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is a rare autosomal recessive systemic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Incidence of this genetic disorder is estimated at 1/90,000–200,000 worldwide and 1/6500–9000 in genetically isolated populations such as Iran. Here, we investigated AIRE gene mutations in eight independent Iranian non-Jewish families. Methods We sequenced the coding regions of the AIRE gene and documented mutations which were further confirmed in respective parents. Results In total, 11 cases from 8 independent families were recruited. Mucosal candidiasis, Addison’s disease and hypoparathyroidism were the most common clinical manifestations in these patients. One novel homozygous splice acceptor mutation (c.308-1G>C), and one novel heterozygous stop-gain mutation (c.1496delC) combined with a known heterozygous c.232T>C missense mutation were found. Moreover, we observed previously described splice donor (c.1095+2T>A), frameshift (c.967-979del), stop-gain (c.415C>T), and missense (c.62C>T) mutations among the patients. All results were co-segregated in parents. Conclusion Here, we reported two novel mutations in the AIRE gene leading to APECED. Our data could provide insight into the phenotypic and genotypic spectrum of APECED in the non-Jewish Iranian population. These findings, in addition to future functional assays, can elucidate disease-causing mechanisms related to the AIRE gene and assist in genetic counseling and diagnosis.

Recurrent vulvovaginal candidiasis during COVID-19 pandemic: medical algorithm

The review article presents data on the prevalence of candidiasis of various localization against the history of coronavirus infection (COVID-19). The predisposing factors for the development and recurrence of candidiasis in patients after therapy for coronavirus infection have been analysed. Candida is one of the most common pathogens in intensive care units (ICUs), affecting 6 to 10% of patients, and some studies have reported an increasing trend in the prevalence of candidemia. The literature data that we analysed showed that the most common types of fungal infection among patients with a severe course of COVID-19 were C. albicans, then C. auris, C. glabrata, C. parapsilosis, C. tropicalis, S. cerevisiae, C. krusei and Rhodotorula spp. Candida non-albicans species, in particular C. glabrata, C. auris, were the most common causes of death. The previous treatment regimens for patients with COVID-19 included antibiotics, but at present time corticosteroids are more often used, which have an immunosuppressive effect and, accordingly, predispose to the development of candidiasis. The epithelial injury caused by SARS-CoV-2 also enables Candida to attach to the basement membrane, subsequently triggering the development of mucosal candidiasis. As the systemic and local candidiasis are conditioned by common immune mechanisms that are affected by coronavirus infection, vulvovaginal candidiasis (VVC) may recur during COVID-19 therapy. The timely diagnosis and treatment of fungal infections in patients who underwent COVID-19 are crucial for achieving a positive clinical outcome. The article provides an algorithm for the management of patients with recurrent VVC, the principles of action of antifungal drugs, their acceptability and efficacy.

Case Report: Disseminated Talaromyces marneffei Infection in a Patient With Chronic Mucocutaneous Candidiasis and a Novel STAT1 Gain-of-Function Mutation

Chronic mucocutaneous candidiasis (CMC) is a disorder of recurrent or persistent chronic noninvasive symptomatic infections of the skin, nails and mucous membranes. This disorder is primarily caused by Candida albicans. Many factors, including primary immunodeficiencies, can make a host more susceptible to CMC. Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations are the most common genetic etiologies of CMC. We describe a case of CMC with disseminated Talaromyces marneffei infection caused by a new pathogenic Y287N mutation at amino acid 287 in the coiled-coiled domain of STAT1, which was identified using whole-exome sequencing. Position 287 might be a hot spot for missense mutations because several amino acid substitutions were found there. Flow cytometry suggested that the Y287N mutation might reduce the expression of IL-17 of Th17 cells in peripheral blood mononuclear cells stimulated by phorbol myristate acetate and ionomycin. The STAT1 Y287N GOF mutation may be the direct cause of recurrent cutaneous and mucosal candidiasis, including the T. marneffei infection in this patient.

Critically Appraising the Significance of the Oral Mycobiome

Recent efforts to understand the oral microbiome have focused on its fungal component. Since fungi occupy a low proportion of the oral microbiome biomass, mycobiome studies rely on sequencing of internal transcribed spacer (ITS) amplicons. ITS-based studies usually detect hundreds of fungi in oral samples. Here, we review the oral mycobiome, critically appraising the significance of such large fungal diversity. When harsh lysis methods are used to extract DNA, 2 oral mycobiome community types (mycotypes) are evident, each dominated by only 1 genus, either Candida or Malassezia. The rest of the diversity in ITS surveys represents low-abundance fungi possibly acquired from the environment and ingested food. So far, Candida is the only genus demonstrated to reach a significant biomass in the oral cavity and clearly shown to be associated with a distinct oral ecology. Candida thrives in the presence of lower oral pH and is enriched in caries, with mechanistic studies in animal models suggesting it participates in the disease process by synergistically interacting with acidogenic bacteria. Candida serves as the main etiological agent of oral mucosal candidiasis, in which a Candida-bacteriome partnership plays a key role. The function of other potential oral colonizers, such as lipid-dependent Malassezia, is still unclear, with further studies needed to establish whether Malassezia are metabolically active oral commensals. Low-abundance oral mycobiome members acquired from the environment may be viable in the oral cavity, and although they may not play a significant role in microbiome communities, they could serve as opportunistic pathogens in immunocompromised hosts. We suggest that further work is needed to ascertain the significance of oral mycobiome members beyond Candida. ITS-based surveys should be complemented with other methods to determine the in situ biomass and metabolic state of fungi thought to play a role in the oral environment.

A Review on Candidiasis resistance current drug development process in its prevention and treatment

A fungal infection caused by Candida albicans leads to illness and death worldwide. This review mainly focused upon Vulvovaginal Candidiasis that is a common fungal infection seen in women, especially during pregnancy; Candida species cause diseases, particularly in immunocompromised patients. This type of infection occurred during the nonsterile environment. The different types of candidiasis mentioned in this review are Mucosal Candidiasis, Oropharyngeal Candidiasis, Vulvovaginal Candidiasis, Cutaneous Candidiasis, Invasive Candidiasis, Disseminated candidiasis, and Candidemia. New approaches like vaccination, antibodies, cytokine therapy, amphotericin-B loaded nanofiber, mucoadhesive are required to improve the result of the patients suffering from infections. New insights into the mechanism of anticandidal host response have contributed to the design of novel immunotherapy. The systemic and topical treatment is carried. The novel drug therapy is given in order to avoid the resistivity developed by fungus. Diagnosis is made by different techniques like direct examination and Culture Method. The other examination methods used are Pathogen-related tests, mannan tests, nucleic acid-based assays. Amphotericin–B loaded nanofibers and liposomes are developed and even certain plant extracts are using as an antifungal drug which is safer to use the future trends used for the study are Echinocandins, the latest class of drug used for the antifungal and drug act as a fungicidal that has low drug-drug interaction which makes first-line treatment for invasive candidiasis particularly. The different class of drugs has been used for the treatment are discussed with Azoles that are used in the treatment with a combination of the other class drugs.

The Dysbiosis and Inter-Kingdom Synergy Model in Oropharyngeal Candidiasis, a New Perspective in Pathogenesis

As more information emerges on oral microbiota using advanced sequencing methodologies, it is imperative to examine how organisms modulate the capacity of each other to colonize or trigger infection. Most mouse models of oral C. albicans infection have focused on interactions with single bacterial species. Thus, little is known about the microbiome-mediated interactions that control the switch of C. albicans from commensalism to infection. Evidence is accumulating that in immunosuppression where mucosal candidiasis is more prevalent, there is an altered oral bacterial microbiome with reduced diversity, but not an altered mycobiome. Oropharyngeal candidiasis in immunosuppressed humans and mice is associated with a further reduction in oral bacterial diversity and a dysbiotic shift with significant enrichment of streptococcal and enterococcal species. Our recent studies in a cancer chemotherapy mouse model supported the combined profound effect of immunosuppression and C. albicans in reducing oral bacterial diversity and provided the first direct evidence that these changes contribute to pathogenesis, representing dysbiosis. There is still a gap in understanding the relationship between Candida and the oral bacterial microbiome. We propose that certain oral commensal bacteria contribute to fungal pathogenesis and we identify gaps in our understanding of the mechanisms involved in this cooperative virulence.

Small-Molecule Morphogenesis Modulators Enhance the Ability of 14-Helical β-Peptides To PreventCandida albicansBiofilm Formation

ABSTRACTCandida albicansis an opportunistic fungal pathogen responsible for mucosal candidiasis and systemic candidemia in humans. Often, these infections are associated with the formation of drug-resistant biofilms on the surfaces of tissues or medical devices. Increased incidence ofC. albicansresistance to current antifungals has heightened the need for new strategies to prevent or eliminate biofilm-related fungal infections. In prior studies, we designed 14-helical β-peptides to mimic the structural properties of natural antimicrobial α-peptides (AMPs) in an effort to develop active and selective antifungal compounds. These amphiphilic, cationic, helical β-peptides exhibited antifungal activity against planktonicC. albicanscells and inhibited biofilm formationin vitroandin vivo. Recent studies have suggested the use of antivirulence agents in combination with antifungals. In this study, we investigated the use of compounds that targetC. albicanspolymorphism, such as 1-dodecanol, isoamyl alcohol, and farnesol, to attempt to improve β-peptide efficacy for preventingC. albicansbiofilms. Isoamyl alcohol, which prevents hyphal formation, reduced the minimum biofilm prevention concentrations (MBPCs) of β-peptides by up to 128-fold. Combinations of isoamyl alcohol and antifungal β-peptides resulted in less than 10% hemolysis at the antifungal MBPCs. Overall, our results suggest potential benefits of combination therapies comprised of morphogenesis modulators and antifungal AMP peptidomimetics for preventingC. albicansbiofilm formation.