Persistent Fungal Infection Research Articles

Harnessing Machine Learning to Uncover Hidden Patterns in Azole-Resistant CYP51/ERG11 Proteins.

Fungal resistance is a public health concern due to the limited availability of antifungal resources and the complexities associated with treating persistent fungal infections. Azoles are thus far the primary line of defense against fungi. Specifically, azoles inhibit the conversion of lanosterol to ergosterol, producing defective sterols and impairing fluidity in fungal plasmatic membranes. Studies on azole resistance have emphasized specific point mutations in CYP51/ERG11 proteins linked to resistance. Although very insightful, the traditional approach to studying azole resistance is time-consuming and prone to errors during meticulous alignment evaluation. It relies on a reference-based method using a specific protein sequence obtained from a wild-type (WT) phenotype. Therefore, this study introduces a machine learning (ML)-based approach utilizing molecular descriptors representing the physiochemical attributes of CYP51/ERG11 protein isoforms. This approach aims to unravel hidden patterns associated with azole resistance. The results highlight that descriptors related to amino acid composition and their combination of hydrophobicity and hydrophilicity effectively explain the slight differences between the resistant non-wild-type (NWT) and WT (nonresistant) protein sequences. This study underscores the potential of ML to unravel nuanced patterns in CYP51/ERG11 sequences, providing valuable molecular signatures that could inform future endeavors in drug development and computational screening of resistant and nonresistant fungal lineages.

Clinical presentation, diagnosis, and treatment of chronic granulomatous disease.

Chronic granulomatous disease (CGD) is caused by an impaired respiratory burst reaction in phagocytes. CGD is an X-linked (XL) (caused by pathogenic variants in CYBB) or autosomal recessive inborn error of immunity (caused by pathogenic variants in CYBA, NCF1, NCF2, or CYBC1). Female carriers of XL-CGD and unfavorable lyonization may present with the partial or full picture of CGD. Patients with CGD are at increased risk for invasive bacterial and fungal infections of potentially any organ, but especially the lymph nodes, liver, and lungs. Pathogens most frequently isolated are S. aureus and Aspergillus spp. Autoinflammation is difficult to control with immunosuppression, and patients frequently remain dependent on steroids. To diagnose CGD, reactive oxygen intermediates (O2 - or H2O2) generated by the NADPH oxidase in peripheral blood phagocytes are measured upon in vitro activation with either phorbol-12-myristate-13-acetate (PMA) and/or TLR4 ligands (E. coli or LPS). Conservative treatment requires strict hygienic conduct and adherence to antibiotic prophylaxis against bacteria and fungi, comprising cotrimoxazole and triazoles. The prognosis of patients treated conservatively is impaired: for the majority of patients, recurrent and/or persistent infections, autoinflammation, and failure to thrive remain lifelong challenges. In contrast, cellular therapies (allogeneic stem cell transplantation or gene therapy) can cure CGD. Optimal outcomes in cellular therapies are observed in individuals without ongoing infections or inflammation. Yet cellular therapies are the only curative option for patients with persistent fungal infections or autoinflammation.

Non-wounding contact-based Inoculation of fruits with fungal pathogens in postharvest

BackgroundFungal pathogens significantly impact the quality of fruits and vegetables at different stages of the supply chain, leading to substantial food losses. Understanding how these persistent fungal infections occur and progress in postharvest conditions is essential to developing effective control strategies.ResultsIn this study, we developed a reliable and consistent inoculation protocol to simulate disease spread from infected fruits to adjacent healthy fruits during postharvest storage. We tested different combinations of relevant fruit commodities, including oranges, tomatoes, and apples, against impactful postharvest pathogens such as Penicillium digitatum, Penicillium italicum, Botrytis cinerea, and Penicillium expansum. We assessed the efficacy of this protocol using fruits treated with various postharvest methods and multiple isolates for each pathogen. We optimized the source of infected tissue and incubation conditions for each fruit-pathogen combination. Disease incidence and severity were quantitatively evaluated to study infection success and progression. At the final evaluation point, 80% or higher disease incidence rates were observed in all trials except for the fungicide-treated oranges inoculated with fungicide-susceptible Penicillium spp. isolates. Although disease incidence was lower in that particular scenario, it is noteworthy that the pathogen was still able to establish itself under unfavorable conditions, indicating the robustness of our methodology. Finally, we used multispectral imaging to detect early P. digitatum infections in oranges before the disease became visible to the naked eye but after the pathogen was established.ConclusionsWe developed a non-invasive inoculation strategy that can be used to recreate infections caused by contact or nesting in postharvest. The observed high disease incidence and severity values across fruit commodities and fungal pathogens demonstrate the robustness, efficacy, and reproducibility of the developed methodology. The protocol has the potential to be tailored for other pathosystems. Additionally, this approach can facilitate the study of fruit-pathogen interactions and the assessment of innovative control strategies.

Nanoemulsion Carriers for Ocular Fungal Infection: Main Emphasis on Keratomycosis.

Keratomycosis, also termed fungal keratitis (FK), is an invasive eye condition for which there is a lack of available effective treatment due to pharmacological shortages and vital ocular obstacles. This severe corneal infection typically suppurates and eventually ulcerates, ultimately causing blindness or decreased vision. According to epidemiological studies, FK is more common in warm, humid places with an agricultural economy. The use of nanoemulsion carriers for ocular fungal infection has been promoting better treatment and patient compliance. The persistent fungal infection like FK, affecting particularly the stroma heralds complications thereby posing difficulty in diagnosis and treatment. To help treat refractory cases and improve outcomes, recently targeted drug delivery techniques and novel antifungal drugs shall be explored. A delay in diagnosis may cause corneal fungal infections to have irreversible consequences, which cannot be avoided. However, infections can develop into ocular perforation even after receiving intense care. The commonly used chemotherapy for FK is based on topical (natamycin 5% is typically first-line therapy) and systemic administration of azole drugs. To address the problems related to better treatment, various nanoemulsion carriers were discussed. Novel drug delivery systems based on nanoemulsions are a viable therapeutic option for treating keratomycosis and may be a candidate method for overcoming obstacles in the treatment of many other ocular illnesses when combined with different hydrophobic medicines. With a brief explanation of the pathogenesis, this article seeks to give readers a thorough analysis of current trends, various treatment choices, and care strategies for fungal keratitis.

A Novel Interleukin 17 Receptor A Mutation in a Child with Chronic Mucocutaneous Candidiasis and Staphylococcal Skin Infections.

Chronic mucocutaneous candidiasis leads to persistent or recurrent fungal infections of the nail, skin, oral, and genital mucosa. Impaired interleukin 17-mediated immunity is a cause of chronic mucocutaneous candidiasis. We aimed to show the pathogenicity of a novel interleukin 17 receptor A mutation through functional studies. After next-generation sequencing analysis showed the interleukin 17 receptor A variant, we confirmed the variant by Sanger sequencing and functional validation of the variant by flow cytometry. We present the case of a 6-year-old male patient who presented with recurrent oral and genital Candida infections and eczema. He had staphylococcal skin lesions, fungal susceptibility, and eczema. The patient carried a novel homozygous nonsense [(c.787C> T) (p.Arg263Ter)] mutation in the interleukin 17 receptor A gene. Sanger sequencing confirmed the variant and revealed the segregation of the variant in the family. We used flow cytometry to detect interleukin 17 receptor A protein expression in peripheral blood mononuclear cells from patients and measured Th17 cell percentage. We observed low interleukin 17 receptor A protein expression in patient peripheral blood mononuclear cells, decreased CD4+ interleukin 17+ cell percentage, and decreased interleukin 17F expression in CD4+ cells compared to healthy controls. Innate immune defects may lead to chronic recurrent fungal and bacterial infections of the skin, mucosa, and nails. Generally, genetic and functional analysis is needed in addition to basic immunological tests.

Anti-Candidal Activity of Reboxetine and Sertraline Antidepressants: Effects on Pre-Formed Biofilms.

Reboxetine (REB) and sertraline (SER) are antidepressants. The antifungal potential of these drugs against planktonic Candida has been recently reported with limited data about their effects on Candidal biofilms. Biofilms are self-derived extracellular matrixes produced by the microbial population that is attached to biotic surfaces, such as vaginal and oral mucosa, or abiotic surfaces, such as biomedical devices, resulting in persistent fungal infections. The commonly prescribed antifungals, azoles, are usually less effective when biofilms are formed, and most of the prescribed antifungals are only fungistatic. Therefore, the current study investigates the antifungal potentials of REB and SER, alone and in combination with fluconazole (FLC) and itraconazole (ITR) against Candidal biofilms. Using proper controls, Candida species (Candida albicans, C. albicans; Candida krusei, C. krusei; and Candida glabrata, C. glabrata) were used to form biofilms in 96-well microplates. Serial dilutions corresponding to concentrations ranging from 2 to 4096 µg/mL of the target drugs (REB, SER, FLC, ITR) were prepared and added to the plates. Impairment of the biofilm biomass and biofilm metabolic viability was detected using the crystal violet (CV) assay and 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, respectively. In the checkerboard assay, the sessile fractional inhibitory concentration index (SFICI) was calculated to evaluate the effects of drug combinations. SER was more effective in reducing the biomass than REB for C. albicans and C. glabrata, but both were equal for C. krusei. For the reduction in metabolic activity in C. albicans and C. glabrata, SER had a slight advantage over REB. In C. krusei, REB was slightly more potent. Overall, FLC and ITR were almost equal and produced more significant reductions in metabolic activity when compared to SER and REB, except for C. glabrata, where SER was almost equal to FLC. Synergism was detected between REB + FLC and REB + ITR against biofilm cells of C. albicans. Synergism was detected between REB + ITR against biofilm cells of C. krusei. Synergism was detected between REB + FLC and REB + ITR against biofilm cells of C. albicans, C. krusei, and C. glabrata. The results of the present study support the potential of SER and REB as anti-Candidal biofilm agents that are beneficial as a new antifungal to combat Candidal resistance.

Primary immunodeficiency disorders (PID) or inborn errors of immunity : preliminary work West Africa Côte d’Ivoire

Abstract The immune system is a particularly sophisticated protection system. As a true guardian of our health, the immune system defends our body against external or internal aggressions. Sometimes, the immune system is not able to fight because it lacks or does not function properly causing an ineffective or absent immune response. Although more than 400 diseases exist, there is no data available in our country. We analyze through a retrospective study carried out in the pediatric department at Hospital University Center, in Abidjan, between February and April 2022, involving 93 PID suspect children, the epidemiological, clinical, paraclinical and therapeutic aspects. The average age of our patients was 2 years with extremes of 22 days to 15 years, with a male predominance: sex ratio of 1.45. The predominant geographical origin was Abidjan (85.32%). Consanguinity was found in 12.9%, death in siblings was found in 3.49% of patients. The most common clinical manifestations were repeated respiratory infections (60.71%), fever (16%), severe infections at least twice a year (13.04%), persistent fungal infections (12.90), thrive retardation in 48.7%. Abnormalities such as hyperleukocytosis (42.4%), neutropenia (29.23%), lymphopenia (16.44%), thrombocytopenia (38.36%) and mostly anemia (62.36%) were noted. Phagocytosis deficiency combined immune deficiencies and humoral deficiencies were respectively found at 95.16%, 89.78%.79.03%. This work draws attention to the importance of PID which are often underdiagnosed, with absent or delayed treatment and poor prognosis. It is important to build a cohort with confirmed data to better support children with PID in our country. no support

Photosensitizer-Polypeptide Conjugate for Effective Elimination of Candida albicans Biofilm.

Persistent fungal infections caused by biofilms seriously endanger human health. In this study, a photosensitizer-polypeptide conjugate (PPa-cP) comprising a photosensitizer, pyropheophorbide a (PPa), and a cationic polypeptide (cP) is readily synthesized for effective antifungal and antibiofilm treatment. Compared with free PPa, the cationic PPa-cP shows enhanced binding ability to the negatively charged surface of Candida albicans (C. albicans) through electrostatic interactions. As a result, PPa-cP exhibits effective antifungal efficiency against both C. albicans and fluconazole-resistant C. albicans in vitro under light irradiation. The minimum inhibitory concentration (MIC) of PPa-cP for both C. albicans and fluconazole-resistant C. albicans is 1µm. In addition, PPa-cP also shows improved penetration in a C. albicans biofilm, thus effectively eliminating the C. albicans biofilm by photodynamic effects. More importantly, PPa-cP demonstrats significantly enhanced therapeutic effects in a fluconazole-resistant C. albicans-infected rat model with minimal side effects. In conclusion, the current work presents an effective strategy to combat biofilm infections associated with biomedical equipment.

Differential diagnosis of chronic diarrhea in patients with HIV infection

Today, when the whole world is overwhelmed by the coronavirus pandemic, few people remember that it was AIDS that was called the plague of the twentieth century. The manifestations of the acquired immunodeficiency syndrome are the terminal stage of infection of the body with the human immunodeficiency virus, which belongs to retroviruses and leads to the development of secondary immunodeficiency. The first case of HIV infection in adults was described in 1981 in America. A young homosexual came to one of the hospitals in the city of San Francisco with a persistent fungal infection. Some time after the treatment, the young man developed pneumonia, from the complications of which he soon died. The human immunodeficiency virus got its name only in 1982, and the disease caused by it began to be called the acquired immunodeficiency syndrome. At present, there are more than 40 million infected people in the world, 2/3 of whom live in Africa; in total, since the beginning of the epidemic, almost 100 million people have been infected with HIV, and the number of victims has doubled the number of people who died in the First World War. Despite the fact that this infection is not airborne or transmitted by contact, the growth rate of this disease continues to shock. Thus, about 5 thousand people get infected with HIV every day in the world; annually about 1 million die from complications of this disease. It should be noted that only 71% of those infected are aware of their status, all the rest continue to serve as a potential source of the spread of this terrible infection.

Chronic mucocutaneous Candidiasis caused by a novel STAT1 mutation: a report of 4 patients

Background: Chronic mucocutaneous Candidiasis (CMCC) is characterized by recurrent or persistent fungal infections of the skin, nails, and oral and genital mucosae. There are several underlying genetic causes for CMCC, with mutations in Signal Transducer and Activator of Transcription-1 (STAT1) accounting for the majority of cases. Aim: To broaden the genotypic spectrum of CMCC caused by STAT1 mutations. Methods: We evaluated a young patient and her family with CMCC. Immune workup and targeted gene sequencing were performed. Results: The proband presented at 7 years of age with persistent oral thrush. Immune evaluation revealed her cellular and humoral immunity to be within normal range. Given that her family history was significant for oral lesions in father, siblings, and paternal family members, STAT1 gene sequencing was performed. A novel heterozygous missense c.G799A, predicting a p. Ala267Thr amino acid change within the coiled-coil domain, was identified in our patient and 3 of her family members. Conclusion: Gain-of-function mutations in STAT1 have been associated with a variety of phenotypes, ranging from isolated CMCC to severe fatal combined immunodeficiency, mycobacterial infections, autoimmune disorders, as well as malignancy and aneurysms. Here, we describe a novel STAT1 mutation, c.G799A, resulting in a very mild phenotype of isolated CMCC in 4 members of one kindred. Statement of novelty: We describe 4 patients with a mild phenotype of CMCC caused by a novel STAT1 heterozygous mutation.

NADPH oxidase correction by mRNA transfection of apheresis granulocytes in chronic granulomatous disease

AbstractGranulocytes from patients with chronic granulomatous disease (CGD) have dysfunctional phagocyte reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase that fails to generate sufficient antimicrobial reactive oxidative species. CGD patients with severe persistent fungal or bacterial infection who do not respond to antibiotic therapy may be given apheresis-derived allogeneic granulocyte transfusions from healthy volunteers to improve clearance of intractable infections. Allogeneic granulocyte donors are not HLA matched, so patients who receive the donor granulocyte products may develop anti-HLA alloimmunity. This not only precludes future use of allogeneic granulocytes in an alloimmunized CGD recipient, but increases the risk of graft failure of those recipients who go on to need an allogeneic bone marrow transplant. Here, we provide the first demonstration of efficient functional restoration of CGD patient apheresis granulocytes by messenger RNA (mRNA) electroporation using a scalable, Good Manufacturing Practice–compliant system to restore protein expression and NADPH oxidase function. Dose-escalating clinical-scale in vivo studies in a nonhuman primate model verify the feasibility, safety, and persistence in peripheral blood of infusions of mRNA-transfected autologous granulocyte-enriched apheresis cells, supporting this novel therapeutic approach as a potential nonalloimmunizing adjunct treatment of intractable infections in CGD patients.

Nitric Oxide Regulates Macrophage Fungicidal Activity via S-nitrosylation of Dectin-1.

Introduction: Recognition of fungal surface β-glucan by pattern recognition receptor Dectin-1 is a critical process for fungal clearance in the lung. In humans, persistent fungal infection is observed in individuals with particular Dectin-1 polymorphism. We have identified that nitric oxide (NO) modifies critical cysteines in pattern recognition molecules to disassemble and alter protein function. There is a hydrophobic S-nitrosylation motif present in surfactant protein-D (SP-D) that is also present in Dectin-1. We hypothesized that Dectin-1 can be modified by nitrosative stress potentially leading to impairment of fungal clearance.Materials and Methods: Recombinant Dectin-1 was incubated with l-nitrosocysteine (L-SNOC) and S-nitrosylated Dectin-1 was detected by Biotin-switch assay. Cells of a murine macrophage line (Raw 264.7) were incubated with S-nitroso-glutathione (GSNO) and Dectin-1 shedding from the cell surface was determined by Western blot. Dectin-1 quaternary structure was determined by native gel electrophoresis. Dectin-1 function was assayed by NF-κB activity and IL-6 mRNA real-time polymerase chain reaction (PCR). Phagocytic activity was measured by fluorescence labeled zymosan beads.Results: Dectin-1 was S-nitrosylated by l-nitrosocysteine (L-SNOC) in vitro, as determined by Biotin-switch assay, resulting in structural disruption. We used Western blotting and flow cytometry to demonstrate that incubation of a murine macrophage cell line (Raw 264.7 cells) with GSNO reduced the surface Dectin-1 expression as a result of shedding to the media. The shedding of Dectin-1 is due to formation of S-nitrosothiol (SNO)-Dectin-1 and disruption of the Dectin-1 oligomeric complex. GSNO also induces Dectin-1 shedding from the cell surface. The functional significance of GSNO treatment of macrophages is shown by reduced β-glucan-mediated signaling in terms of NF-κB function and IL-6 expression. Finally, it was demonstrated that GSNO treatment reduces the capability of macrophages to phagocytose zymosan.Conclusions: These data provide mechanistic data to support the role of Dectin-1 nitrosylation as a mediator of reduced fungal clearance in the face of increased NO exposure.

Recurrent Vulvovaginal Candidiasis: An Immunological Perspective.

Vulvovaginal candidiasis (VVC) is a widespread vaginal infection primarily caused by Candida albicans. VVC affects up to 75% of women of childbearing age once in their life, and up to 9% of women in different populations experience more than three episodes per year, which is defined as recurrent vulvovaginal candidiasis (RVVC). RVVC results in diminished quality of life as well as increased associated healthcare costs. For a long time, VVC has been considered the outcome of inadequate host defenses against Candida colonization, as in the case of primary immunodeficiencies associated with persistent fungal infections and insufficient clearance. Intensive research in recent decades has led to a new hypothesis that points toward a local mucosal overreaction of the immune system rather than a defective host response to Candida colonization. This review provides an overview of the current understanding of the host immune response in VVC pathogenesis and suggests that a tightly regulated fungus–host–microbiota interplay might exert a protective role against recurrent Candida infections.

Ucuùba (Virola surinamensis) Fat-Based Nanostructured Lipid Carriers for Nail Drug Delivery of Ketoconazole: Development and Optimization Using Box-Behnken Design.

Ucuùba fat is fat obtained from a plant found in South America, mainly in Amazonian Brazil. Due to its biocompatibility and bioactivity, Ucuùba fat was used for the production of ketoconazole-loaded nanostructured lipid carriers (NLC) in view of an application for the treatment of onychomycosis and other persistent fungal infections. The development and optimization of Ucuùba fat-based NLC were performed using a Box-Behnken design of experiments. The independent variables were surfactant concentration (% w/v), liquid lipids concentration (% w/v), solid lipids concentration (% w/v), while the outputs of interest were particle size, polydispersity index (PDI) and drug encapsulation efficiency (EE). Ucuùba fat-based NLC were produced and the process was optimized by the development of a predictive mathematical model. Applying the model, two formulations with pre-determined particle size, i.e., 30 and 85 nm, were produced for further evaluation. The optimized formulations were characterized and showed particle size in agreement to the predicted value, i.e., 33.6 nm and 74.6 nm, respectively. The optimized formulations were also characterized using multiple techniques in order to investigate the solid state of drug and excipients (DSC and XRD), particle morphology (TEM), drug release and interactions between the formulation components (FTIR). Furthermore, particle size, surface charge and drug loading efficiency of the formulations were studied during a one-month stability study and did not show evidence of significant modification.

Novel Drug Delivery Strategies for the Treatment of Onychomycosis.

Onychomycosis accounts for 50% of all nail disease cases and is commonly caused by dermatophytes. It was primarily considered a cosmetic problem but has been garnering attention lately due to its persistent nature and difficult treatment with relapses. With prolonged treatment duration and high cost involved in treating onychomycosis, several attempts have been made in overcoming the rigid nail barrier. The conventional treatment of onychomy-cosis involves oral and topical therapy. The oral antifungal agents though quite effective, are hepato-toxic and cause drug-drug interactions. Topical therapy is more patient compliant being devoid of such adverse effects but it suffers from another setback of improper nail penetration. Amorolfine and ciclopirox nail lacquers are popular market products. Since decades, efforts have been made to enhance topical delivery for efficiently treating ony-chomycosis. Mechanical, physical and chemical methods have been em-ployed. Despite all the attempts made, the nail delivery issues are far from be-ing solved. Recently, the focus has shifted to novel drug delivery systems like nanoparticles, microemulsions, polymeric films and nail lacquers for en-hanced drug permeation and localized therapy. The research around the world is exploring their potential as effective treatment options. This review intends to further explore the novel delivery strategies to treat a persistent fungal in-fection like onychomycosis.

Targeted screening for primary immunodeficiency disorders in the neonatal period and early infancy

Primary immunodeficiency diseases (PID) comprise a group of more than 300 diseases that affect development and /or function of the immune system. The aim of this study was diagnosis of PID among a suspected group of neonates and infants within the first six months of life as well as identifying the warning signs of PID characteristic to this period. Fifty neonates presenting with warning signs of PID were enrolled in the study. The study revealed that twenty six patients (52%) were diagnosed with Primary Immunodeficiency, T cell/combined immunodeficiency were noted as the most common PID class (88.5%) with fourteen T-B-SCID patients (70%) and six T-B+ SCID patients (30%), phagocytic disorders were estimated to be 7.7% while 3.8% were unclassified immunodeficiency. The mean age of presentation for PID group was 1.42±1.38 months with a diagnostic lag of 3.08±1.78 months. Consanguinity was positive in 76.9% of the PID group. Lower respiratory tract infections, persistent fungal infections and lymphopenia were the most significant warning signs for diagnosing PID with a p value of (0.01). Combined, lower respiratory tract infections, fungal infections and lymphopenia were 12.3 times more likely to be associated with PID. Focused screening in high risk neonates proved to be a valuable tool for diagnosis of PID disorders.

Anti–PD-1 Antibody Treatment Promotes Clearance of Persistent Cryptococcal Lung Infection in Mice

Activation of immunomodulatory pathways in response to invasive fungi can impair clearance and promote persistent infections. The programmed cell death protein-1 (PD-1) signaling pathway inhibits immune effector responses against tumors, and immune checkpoint inhibitors that block this pathway are being increasingly used as cancer therapy. The objective of this study was to investigate whether this pathway contributes to persistent fungal infection and to determine whether anti-PD-1 Ab treatment improves fungal clearance. Studies were performed using C57BL/6 mice infected with a moderately virulent strain of Cryptococcus neoformans (52D), which resulted in prolonged elevations in fungal burden and histopathologic evidence of chronic lung inflammation. Persistent infection was associated with increased and sustained expression of PD-1 on lung lymphocytes, including a mixed population of CD4+ T cells. In parallel, expression of the PD-1 ligands, PD-1 ligands 1 and 2, was similarly upregulated on specific subsets of resident and recruited lung dendritic cells and macrophages. Treatment of persistently infected mice for 4 wk by repetitive administration of neutralizing anti-PD-1 Ab significantly improved pulmonary fungal clearance. Treatment was well tolerated without evidence of morbidity. Immunophenotyping revealed that anti-PD-1 Ab treatment did not alter immune effector cell numbers or myeloid cell activation. Treatment did reduce gene expression of IL-5 and IL-10 by lung leukocytes and promoted sustained upregulation of OX40 by Th1 and Th17 cells. Collectively, this study demonstrates that PD-1 signaling promotes persistent cryptococcal lung infection and identifies this pathway as a potential target for novel immune-based treatments of chronic fungal disease.

Gain-of-function STAT1 mutations are associated with intracranial aneurysms

Chronic mucocutaneous candidiasis, characterized by persistent or recurrent fungal infections, represents the clinical hallmark in gain-of-function (GOF) signal transducer and activator of transcription 1 (STAT1) mutation carriers. Several cases of intracranial aneurysms have been reported in patients with GOF STAT1 mutation but the paucity of reported cases likely suggested this association still as serendipity. In order to endorse this association, we link the development of intracranial aneurysms with STAT1 GOF mutation by presenting the two different cases of a patient and her mother, and demonstrate upregulated phosphorylated STAT4 and IL-12 receptor β1 upon stimulation in patient's blood cells. We also detected increased transforming growth factor (TGF)-β type 2 receptor expression, particularly in CD14+ cells, and a slightly higher phosphorylation rate of SMAD3. In addition, the mother of the patient developed disseminated bacille Calmette-Guérin disease after vaccination, speculating that GOF STAT1 mutations may confer a predisposition to weakly virulent mycobacteria.

Using a tracheal stent for conservative management of speaking valve-associated tracheo-oesophageal fistula.

Surgical voice rehabilitation is an essential dimension of treatment following total laryngectomy. The gold standard is tracheo-oesophageal puncture and speaking valve placement. Whilst offering excellent phonation in many patients, there is a well-documented risk of valve associated fistula formation, the incidence of which varies from 1 to 21% 1. Risk factors for delayed valve associated tracheo-oesophageal fistula include post chemo-radiotherapy (salvage laryngectomy), oesophageal stricture, persistent fungal infection and poor patient compliance in managing their speaking valve2. This article is protected by copyright. All rights reserved.

Short Cationic Antimicrobial Peptides Display Superior Antifungal Activities toward Candidiasis and Onychomycosis in Comparison with Terbinafine and Amorolfine.

Novel antifungals are in high demand due to the challenges associated with resistant, persistent, and systemic fungal infections. Synthetic mimics of antimicrobial peptides are emerging as a promising class of compounds for antifungal treatment. In the current study, five synthetic cationic antimicrobial tripeptides were evaluated as antifungal therapeutics against 24 pathogenic strains of fungi. Three of the peptides displayed strong general antifungal properties at low micromolar inhibitory concentrations. The most promising peptide, compound 5, was selected and evaluated as an antifungal remedy for Candida albicans candidiasis in a human skin model and for the treatment of Trichophyton rubrum induced onychomycosis in an infected human nail model. Compound 5 was shown to display antifungal properties and a rapid mode of action superior to those of both the commercial comparators Loceryl and Lamisil. Compound 5 was also active against a clinical isolate of Candida albicans with acquired fluconazole resistance.