Metabolic homeostasis in fungal infections from the perspective of pathogens, immune cells, and whole-body systems.

SUMMARYThe ability to overcome metabolic stress is a major determinant of outcomes during infections. Pathogens face nutrient and oxygen deprivation in host niches and during their encounter with immune cells. Immune cells require metabolic adaptations for producing antimicrobial compounds and mounting antifungal inflammation. Infection also triggers systemic changes in organ metabolism and energy expenditure that range from an enhanced metabolism to produce energy for a robust immune response to reduced metabolism as infection progresses, which coincides with immune and organ dysfunction. Competition for energy and nutrients between hosts and pathogens means that successful survival and recovery from an infection require a balance between elimination of the pathogen by the immune systems (resistance), and doing so with minimal damage to host tissues and organs (tolerance). Here, we discuss our current knowledge of pathogen, immune cell and systemic metabolism in fungal infections, and the impact of metabolic disorders, such as obesity and diabetes. We put forward the idea that, while our knowledge of the use of metabolic regulation for fungal proliferation and antifungal immune responses (i.e., resistance) has been growing over the years, we also need to study the metabolic mechanisms that control tolerance of fungal pathogens. A comprehensive understanding of how to balance resistance and tolerance by metabolic interventions may provide insights into therapeutic strategies that could be used adjunctly with antifungal drugs to improve patient outcomes.

Voriconazole in the treatment of invasive aspergillosis of orbit.

Background: The aim of the study was to evaluate the outcomes of voriconazole in terms of functional recovery and response on imaging in the management of invasive aspergillosis of orbit. Methods: This was a prospective non-comparative interventional study. Diagnosed cases of invasive orbital aspergillosis were studied in a tertiary care hospital. Intravenous voriconazole followed by oral treatment was given. Sinus debridement was done, where needed. The response to treatment was assessed clinically and on radiology. Results: A total of 10 diagnosed cases of invasive orbital aspergillosis were studied. Nine cases (90%) occurred in immunocompetent patients. Predisposing sinus infection was seen in 8 patients (80%). The most common presenting complaint was the protrusion of eye. On voriconazole treatment, there was a statistically significant improvement in vision and extraocular movements from first week onwards (p = 0.01 and p = 0.02, respectively) and reduction in proptosis from second week onwards (p = 0.003). Imaging was done at three months follow-up which revealed a good response to treatment in 90% of patients. All patients tolerated the drug well except one who had transient hepatic dysfunction. The mean follow-up was 5.8 months (range: 3-12 months). There was no recurrence of disease till the last follow-up. Conclusion: Invasive orbital aspergillosis commonly presents as sino-orbital disease, mostly in immunocompetent adult patients. Voriconazole is a safe and effective drug with good short-term clinical outcome.

Association between the pre-transplantation serum ferritin level and outcomes of hematopoietic stem cell transplantation: A systematic review and meta-analysis.

Background: Iron overload, as indicated by evaluated serum ferritin (SF) level, occurs commonly in patients with hematological diseases. To evaluate the association between pre-transplant SF level and outcomes of hematopoietic stem cell transplantation (HSCT), we performed this systematic review and meta-analysis. Methods: PubMed, Embase, Web of Science and the Cochrane Library electronic database were searched from inception to August 2023, and 56 studies with 14149 patients were found to be eligible. Results: An elevated pre-transplantation SF level was associated with inferior overall survival (hazard ratio [HR],1.77; 95 % confidence interval [CI],1.61-1.96) and disease-free survival (HR, 1.86; 95 % CI, 1.58-2.19), and increased risk of non-relapse mortality (HR, 1.73; 95 % CI, 1.49-2.02), and relapse (HR, 1.46; 95 % CI, 1.29-1.65). However, no meaningful association was observed between SF levels and acute graft-versus-host disease (GVHD) (risk ratio [RR], 1.09; 95 % CI, 0.96-1.24), or chronic GVHD (RR, 0.95; 95 % CI, 0.79-1.16). Furthermore, an elevated pre-transplantation SF level was associated with a higher risk of fungal infection (RR, 1.56; 95 % CI, 1.16-2.10), but not with bacterial infection (RR, 1.09; 95 % CI, 0.80-1.50). Moreover, an elevated pre-transplantation SF level was related to a higher risk of death due to relapse/disease progression (RR, 1.72; 95 % CI, 1.33-2.23) and infection (RR, 2.21; 95 % CI, 1.55-3.15), but not death due to GVHD (RR, 1.18; 95 % CI, 0.79-1.77). Conclusions: A higher pre-transplantation SF level was significantly associated with a higher risk of relapse/disease progression and infections, which contributed to worse survival in patients undergoing HSCT. In particular, a higher SF level was related to a higher risk of fungal infection, indicating that patients with a higher pre-transplantation SF level require more attention regarding the risk of fungal infection after HSCT.

Antigenic peptide-tobacco mosaic virus conjugates as a fungal vaccine candidate.

Fungal infections are becoming an increasingly serious challenge in clinic due to the increase in drug resistance and the lack of anti-fungal drugs. Vaccination is a useful approach to prevent fungal infections. However, the balance between effectiveness and side effects presents a challenge in vaccine development. In this work, we designed a plant virus-based conjugate vaccine. The non-infectiveness and innate immunogenicity of plant viruses make this vaccine both safe and effective. By conjugating a fungal antigenic peptide to the tobacco mosaic virus (TMV), the resultant vaccine improved the uptake efficiency of antigenic peptides by antigen-presenting cells and enhanced the ability to target lymph nodes. The results of in vivo vaccination in mice showed a significant increase of antigen-specific IgG antibody levels induced by the TMV conjugate vaccine. This work suggests that TMV conjugate vaccines may become a potential vaccine candidate for preventing fungal infections.

The Zoonotic Potential of Fungal Pathogens: Another Dimension of the One Health Approach.

Zoonotic diseases are caused by viruses, bacteria, fungi and parasites and they comprise about 75% of all emerging infectious diseases. These can be transmitted via the direct (scratches on skin or animal bites) or indirect mode (through environmental shedding of infectious agent by the infected animal) of transmission. Environmental changes, whether in the form of urbanization, industrialization or destruction of wildlife habitats, lead to more human invasion in wildlife areas, subsequently leading to an increased passage of animals towards human dwellings and more exposure to animals, making humans susceptible to these infections. Climate change is another major factor. Global warming and the evolving thermotolerance of fungi, adapting more to human body temperature than their saprophytic nature, is leading to the emergence of humans as new hosts for fungi. The domestication of animals, rising populations, enhanced tourism, migratory populations, intrusions into wildlife, etc., are other known factors. Zoonotic fungal infections have long been neglected and are now gaining due attention. In this review, we briefly discuss the various aspects currently known for zoonotic fungal infections and bring forth the importance of this particular issue to be addressed in a timely manner.

Management and outcomes of histoplasmosis in youth with inflammatory bowel disease in an endemic area.

OBJECTIVE: Patients with inflammatory bowel disease (IBD) prescribed immunosuppressive therapies including antitumor necrosis factor (aTNF) therapies are at increased risk of histoplasmosis. We aim to evaluate the presentation, management, and outcomes of youth with IBD and concurrent histoplasmosis. METHODS: Single center, retrospective review of youth with IBD diagnosed with histoplasmosis from January 12, 2007 to January 1, 2022. Management and outcomes were followed for up to 2 years after diagnosis. RESULTS: Nineteen patients (10 male, median age 16 years, range 8-22) with IBD were diagnosed with histoplasmosis: disseminated (N = 15/19; 79%), pulmonary (N = 3/19; 16%), lymph node (N = 1/19; 5%). At the time of histoplasmosis diagnosis, patients were predominantly receiving aTNF therapy (N = 17/19; 89%, median duration 21.9 months (interquartile range 8.5-52.0). Thirteen (13/19, 68%) patients required hospitalization and 2/19 (11%) required intensive care. All achieved antigen clearance with no recurrences. At the time of histoplasmosis diagnosis, aTNF was stopped in 15/17 (88%) patients and the following IBD therapies were initiated: 5-aminosalicylates (N = 4/19; 21%), 6-mercaptopurine (N = 3/19; 16%), enteral therapy (N = 2/19; 11%), and vedolizumab (N = 2/19; 11%); 6 of 19 (32%) received no IBD therapy and 2 of 19 (11%) patients continued aTNF. During follow-up, 6 of 19 (32%) patients had an emergency department (ED) visit and/or hospitalization for symptoms attributed to active IBD, all of whom had discontinued aTNF; one patient required colectomy. CONCLUSIONS: Severe histoplasmosis infection in youth with IBD was rare. IBD treatment was modified by reducing immunosuppression. Histoplasmosis outcomes were favorable, but multiple patients required hospitalization or ED visits for IBD symptoms. The optimal approach to managing IBD during histoplasmosis treatment is challenging and requires further study.

Impact of Simultaneous Nutrient Priming and Biopriming on Soybean Seed Quality and Health.

In soybean production, numerous strategies are utilized to enhance seed quality and mitigate the effects of biotic and abiotic stressors. Zn-based nutrient priming has been shown to be effective for field crops, and biopriming is a strategy that is becoming increasingly important for sustainable agriculture. On the other hand, there is a lack of information about the effect of comprehensive nutrient priming and biopriming techniques on soybean seed quality and viability and seed health. This study was performed to assess the benefits of nutrient priming with Zn, biopriming with Bacillus megaterium and Bradyrhizobium japonicum (single and co-inoculation), and combination of nutrient priming and biopriming on the seed quality and viability, as well as seed infection caused by Alternaria spp. and Fusarium spp. Three different laboratory tests were employed: germination test, accelerated aging test, and seed health test. The results revealed that all tested priming treatments have a beneficial effect on seed germination, initial plant growth, and reduction of seed infection in normal and aged seeds. Additionally, comprehensive priming with Zn, Bacillus megaterium, and Bradyrhizobium japonicum reduced the occurrence of Alternaria spp. (-84% and -75%) and Fusarium spp. (-91% and -88%) on soybean seeds in the germination and accelerated aging tests, respectively, as compared to the control, which proved to be the most effective treatment in both optimal and stressful conditions.

Rhino-orbital-cerebral mucormycosis with Klebsiella and MRSA co-infection in a diabetic patient: a case report.

Introduction and importance: Rhino-orbital-cerebral mucormycosis is an opportunistic infection caused by fungus species Rhizopus and Mucor. Early recognition and aggressive management is crucial for favorable outcomes. A delay in diagnosis and treatment is fatal. Case presentation: A 32-year-old female presented with high-grade fever, right-sided facial deviation associated with facial swelling, and inability to move her left eye for 10 days. Biopsy from the left nasal cavity showed fibrinoid material, edema, and sheets of neutrophilic infiltrate while KOH preparation of nasal scrapping showed aseptate hyphae with obtuse-angled branching. Amphotericin B, oral posaconazole, and antibiotics were started with exploration and debridement of the affected tissue. The patient recovered well and was discharged. Discussion: Immunocompromised people are primarily affected by mucormycosis, a serious fungal illness. Inhaling fungal spores, especially those of the Rhizopus and Mucor species, is the usual cause. Rhinocerebral mucormycosis (ROCM), the most common type, increased during COVID-19 pandemic, frequently as a result of hyperglycemia brought on by steroids. Angioinvasion and tissue necrosis are pathogenesis-related processes that are made worse by diabetes and the overuse of glucocorticoids. Histopathology, culture, and imaging are used in the diagnosis. Surgery and antifungal drugs like Amphotericin B are used in treatment. Early intervention and interdisciplinary care, including hyperbaric oxygen therapy, are critical for survival. Results deteriorate with postponed therapy, underscoring the urgency of prompt action. Conclusion: Mucormycosis should be kept in mind while formulating differential diagnosis of infective pathology in immunocompromised patients. Early diagnosis and treatment are important in improving patient prognosis in rhino-orbital-cerebral mucormycosis.

Central Nervous System Fungal Diseases in Children with Malignancies: A 16-Year Study from the Infection Working Group of the Hellenic Society of Pediatric Hematology Oncology.

We analyzed data on pediatric invasive fungal diseases of the central nervous system (CNS-IFDs) reported by five of a total of eight Pediatric Hematology-Oncology Departments in Greece for 16 years (2007-2022). A total of twelve patients (11 boys, median age: 9.5 years, range: 2-16) were reported suffering from CNS-IFDs. The underlying malignancy was acute lymphoblastic leukemia in 9/12 and acute myeloid leukemia, Ewing sarcoma, and rhabdomyosarcoma in one each. Eleven patients presented with CNS-related symptoms (i.e., seizures, headache, cerebral palsy, ataxia, hallucination, seizures, blurred vision, amaurosis). All patients had pathological MRI findings. Multifocal fungal disease was observed in 6/12 patients. Nine proven and three probable CNS-IFD cases were diagnosed. Causative pathogens in proven cases were Aspergillus spp. and Candida albicans (n = 2 each), Mucor spp., Rhizopus arrhizus, Absidia spp., Fusarium oxysporum and Cryptococcus neoformans (n = 1 each). Causative pathogens in probable cases were Aspergillus spp. (n = 2) and Candida spp. (n = 1). All patients received appropriate antifungal therapy (median duration: 69.5 days, range 19-364). Two patients underwent additional surgical treatment. Six patients were admitted to the Intensive Care Unit due to complications. Three patients (25%) died, two due to IFD and one due to an underlying disease. Early recognition and prompt intervention of CNS-IFDs may rescue the patients and improve overall survival.

Navigating the fungal battlefield: cysteine-rich antifungal proteins and peptides from Eurotiales.

Fungi are ubiquitous in the environment and play a key role in the decomposition and recycling of nutrients. On the one hand, their special properties are a great asset for the agricultural and industrial sector, as they are used as source of nutrients, producers of enzymes, pigments, flavorings, and biocontrol agents, and in food processing, bio-remediation and plant growth promotion. On the other hand, they pose a serious challenge to our lives and the environment, as they are responsible for fungal infections in plants, animals and humans. Although host immunity opposes invading pathogens, certain factors favor the manifestation of fungal diseases. The prevalence of fungal infections is on the rise, and there is an alarming increase in the resistance of fungal pathogens to approved drugs. The limited number of antimycotics, the obstacles encountered in the development of new drugs due to the poor tolerability of antifungal agents in patients, the limited number of unique antifungal targets, and the low species specificity contribute to the gradual depletion of the antifungal pipeline and newly discovered antifungal drugs are rare. Promising candidates as next-generation therapeutics are antimicrobial proteins and peptides (AMPs) produced by numerous prokaryotic and eukaryotic organisms belonging to all kingdom classes. Importantly, filamentous fungi from the order Eurotiales have been shown to be a rich source of AMPs with specific antifungal activity. A growing number of published studies reflects the efforts made in the search for new antifungal proteins and peptides (AFPs), their efficacy, species specificity and applicability. In this review, we discuss important aspects related to fungi, their impact on our life and issues involved in treating fungal infections in plants, animals and humans. We specifically highlight the potential of AFPs from Eurotiales as promising alternative antifungal therapeutics. This article provides insight into the structural features, mode of action, and progress made toward their potential application in a clinical and agricultural setting. It also identifies the challenges that must be overcome in order to develop AFPs into therapeutics.

Post COVID-19 mucormycosis in critical care settings: A prospective cohort study in a tertiary care center in Egypt.

BACKGROUND: The emergence of mucormycosis as a life-threatening fungal infection after the coronavirus disease of 2019 (COVID-19) is a major concern and challenge, but there is limited information on the risk factors for mortality in patients. METHODS: We conducted a prospective cohort study from May 2021 to April 2022 to determine the in-hospital outcomes of post-COVID-19 mucormycosis during the intensive care unit (ICU) stay. The sample of the study was collected as consecutive sampling using all accessible patients in the study period. The Statistical Package for Social Sciences (SPSS), version 25 (IBM, Chicago, Illinois, USA) was used for statistical analysis. RESULTS: Among 150 patients with post-COVID-19 mucormycosis, the majority had a primary sinus infection (86.0 %), while 11.3 % had both sinus and ocular infections, and 2.7 % had sinus and cutaneous infections. Around 21 % (n = 31) of patients deceased after staying in the ICU for a median (range) of 45.0 (10.0-145.0) days. The majority of the patients who deceased had pneumonia patches on computed tomography (CT) (90.3 %) while none of the patients who were discharged had pneumonia patches (p < 0.001). The deceased group had higher rates of pulmonary embolism (93.5 %) compared to the surviving groups (21.8 %). In a multivariate Cox regression analysis, the risk of death was higher in older patients above 60 years old (hazard ratio (95 %CI): 6.7 (1.73-15.81)), increase among patient with history of steroid administration (hazard ratio (95 %CI): 5.70 (1.23-10.91)), who had facial cutaneous infection with mucormycosis (hazard ratio (95 %CI): 8.76 (1.78-25.18)), patients with uncontrolled diabetes (hazard ratio (95 %CI): 10.76 (1.78, 65.18)), and total leukocytic count (TLC>10 ×103 mcL) (hazard ratio (95 %CI): 10.03 (3.29-30.61)). CONCLUSIONS: Identifying high-risk patients especially old diabetic patients with corticosteroid administration and detecting their deterioration quickly is crucial in reducing post-COVID-19 mucormycosis mortality rates, and these factors must be considered when developing treatment and quarantine strategies.

Chromoblastomycosis: A Single Centre Clinical Laboratory Experience of Seven Years (2016-2022) and Literature Review From Pakistan.

BACKGROUND: Chromoblastomycosis (CBM) is a chronic infection of skin and subcutaneous tissue. CBM cases have been reported in local literature from Pakistan with heterogenous demographic, diagnostic and therapeutic information. The objective of this study is to share the experience of CBM from a large tertiary care hospital laboratory in Pakistan. METHOD: This was a retrospective observational study. Histopathology and microbiology data of suspected CBM between 2016 and 2022 was retrieved. Patients' demographics, site of involvement, histopathological findings and positive microbiology cultures were assessed. Literature search on Google Scholar, PubMed and PakMediNet was done between 1990 and 2023 with multiple terms. RESULT: A total of 16 CBM cases were identified; 14 were histopathology positive and two were both histopathology and culture positive. The median age was 21 years, and 11 patients were male. The predominant site was lower extremities followed by the face. Severe acanthosis, hyperkeratosis and granuloma with sclerotic bodies were observed in all histopathology slides. Alternaria spp. and Phialophora spp. were isolated from two culture-positive cases. A total of nine cases of CBM were reported from Pakistan in PubMed non-indexed journal. CONCLUSION: CBM is not a commonly thought of disease when evaluating skin lesions in Pakistan. A high index of suspicion when assessing patients who may have a history of trauma, exposure to soil and suggestive lesions is reasonable. An integrated approach between clinicians, histopathologist and microbiologist is required to do early identification and therapeutic interventions.

A Rare Case of Simultaneous Histoplasmosis and Coccidioidomycosis.

Histoplasma and Coccidioides are fungi that can cause serious infections in immunocompromised patients. Histoplasma is primarily endemic to the central and eastern United States, while Coccidioides is primarily endemic to the southwestern United States. Here, we present a case of simultaneous histoplasmosis and coccidioidomycosis. A 69-year-old female with a past medical history of rheumatoid arthritis and polymyalgia rheumatica on immunosuppression presented to the emergency department (ED) with fevers, malaise, and confusion. She initially developed these symptoms a month prior while visiting her son in Tennessee. During this time, she lived in his basement where mold exposure was confirmed. Her symptoms gradually improved but recurred, prompting her to come to the ED. In the ED, her vital signs were as follows: temperature of 36.5˚C, heart rate of 88, respiratory rate of 16, blood pressure of 158/88, and oxygen saturation of 94% on room air. She was alert and oriented without focal neurologic deficits. Heart sounds were regular rate and rhythm, lungs were clear to auscultation bilaterally and abdomen was soft, non-tender, and non-distended. No skin rashes were observed either. Laboratory work revealed an elevated C-reactive protein (CRP), thrombocytopenia, and transaminitis. Chest X-ray showed patchy airspace disease in the left lower lobe, and she underwent a lumbar puncture which was negative for meningitis. Due to her travel to Tennessee, a urine Histoplasma antigen test was ordered which resulted positive, along with a beta-1,3-D-glucan level >500 picograms per milliliter (pg/mL), indicating disseminated histoplasmosis. Coccidioides antibodies also resulted positive, pointing to concurrent coccidioidomycosis. The patient was subsequently started on intravenous amphotericin B. Over the following days, the patient's transaminitis and thrombocytopenia improved, and she was ultimately discharged on oral itraconazole with outpatient infectious disease follow-up. Although the patient's exposure to mold was likely the source of her histoplasmosis, the source of her coccidioidomycosis is less clear given its endemicity. Even rarer is the coinciding infections, and to the best of our knowledge, this is one of the very few known cases. Immunocompromised patients who present with infectious symptoms should have a low threshold for a fungal infection workup, as prompt treatment is crucial to limiting the morbidity and mortality of these infections. Furthermore, geographic location should not narrow one's workup to endemic fungi only, as evidenced by this patient's simultaneous infections.

Histological and transcriptomic insights into the interaction between grapevine and Colletotrichum viniferum.

Introduction: Grape is of high economic value. Colletotrichum viniferum, a pathogen causing grape ripe rot and leaf spot, threatens grape production and quality. Methods: This study investigates the interplay between C. viniferum by Cytological study and transcriptome sequencing. Results: Different grapevine germplasms, V. vinifera cv. Thompson Seedless (TS), V. labrusca accession Beaumont (B) and V. piasezkii Liuba-8 (LB-8) were classified as highly sensitive, moderate resistant and resistant to C. viniferum, respectively. Cytological study analysis reveals distinct differences between susceptible and resistant grapes post-inoculation, including faster pathogen development, longer germination tubes, normal appressoria of C. viniferum and absence of white secretions in the susceptible host grapevine. To understand the pathogenic mechanisms of C. viniferum, transcriptome sequencing was performed on the susceptible grapevine "TS" identifying 236 differentially expressed C. viniferum genes. These included 56 effectors, 36 carbohydrate genes, 5 P450 genes, and 10 genes involved in secondary metabolism. Fungal effectors are known as pivotal pathogenic factors that modulate plant immunity and affect disease development. Agrobacterium-mediated transient transformation in Nicotiana benthamiana screened 10 effectors (CvA13877, CvA01508, CvA05621, CvA00229, CvA07043, CvA05569, CvA12648, CvA02698, CvA14071 and CvA10999) that inhibited INF1 (infestans 1, P. infestans PAMP elicitor) induced cell death and 2 effectors (CvA02641 and CvA11478) that induced cell death. Additionally, transcriptome analysis of "TS" in response to C. viniferum identified differentially expressed grape genes related to plant hormone signaling (TGA, PR1, ETR, and ERF1/2), resveratrol biosynthesis genes (STS), phenylpropanoid biosynthesis genes (PAL and COMT), photosynthetic antenna proteins (Lhca and Lhcb), transcription factors (WRKY, NAC, MYB, ERF, GATA, bHLH and SBP), ROS (reactive oxygen species) clearance genes (CAT, GSH, POD and SOD), and disease-related genes (LRR, RPS2 and GST). Discussion: This study highlights the potential functional diversity of C. viniferum effectors. Our findings lay a foundation for further research of infection mechanisms in Colletotrichum and identification of disease response targets in grape.

Epidemiology and prognostic factors of mucormycosis in France (2012-2022): a cross-sectional study nested in a prospective surveillance programme.

Background: Mucormycosis is a deadly invasive fungal infection recently included in the WHO priority pathogen list. Here we sought to describe epidemiological trends of mucormycosis in France, and to evaluate factors associated with mortality. Methods: From 2012 to 2022, we implemented a nationwide prospective surveillance programme for mucormycosis in France, focusing on epidemiology, species, seasonal variations. Factors associated with 3-month mortality were studied by univariable and multivariable logistic regression. Findings: Among 550 cases of mucormycosis, the main underlying conditions were haematological malignancy (HM, 65.1%, 358/550), trauma (8%, 44/550), diabetes (7.5%, 41/550) and solid-organ transplants (6.5%, 36/550). Site of infection was pulmonary in 52.4% (288/550), rhinocerebral in 14.5% (80/550), and cutaneo-articular in 17.1% (94/550). Main species identified were Rhizopus arrhizus (21%, 67/316), Rhizopus microsporus (13.6%, 43/316), Lichtheimia corymbifera and Mucor circinelloides (13.3%, 42/316 each), Rhizomucor pusillus (12%, 38/316), and Lichtheimia ramosa (10.8%, 34/316). We found associations between underlying condition, site of infection, and infecting species, including a previously undescribed triad of trauma, cutaneo-articular localisations, and L. ramosa/M. circinelloides. Diagnostic contribution of Polymerase Chain Reaction (PCR) increased from 16% (4/25) in 2012 to 91% (61/67) in 2022, with more than 50% of diagnoses relying solely on PCR in 2022. We also found seasonal variations with relatively more cases in autumn. Ninety-day mortality was 55.8% (276/495). Independent prognostic factors were age, diagnosis in Intensive Care Unit (ICU), and HM while diagnosis after 2015 (i.e. large implementation of PCR) and surgery were associated with reduced mortality. Interpretation: This study reveals major mucormycosis epidemiological changes in France, with a large predominance of HM patients, and a parallel between PCR multicentre implementation and improved prognosis. We also evidence new associations between species, localisations and risk factors, as well as seasonal variations. Funding: Recurrent financial support from Santé Publique France and Institut Pasteur.

Genome-level therapeutic targets identification and chimeric Vaccine designing against the Blastomyces dermatitidis.

Blastomyces dermatitidis is a thermally dimorphic fungus that can cause serious and sometimes fatal infections, including blastomycosis. After spore inhalation, a pulmonary infection develops, which can be asymptomatic and have lethal effects, such as acute respiratory distress syndrome. Its most common extra-pulmonary sites are the central nervous system, bones, skin, and genito-urinary systems. Currently, no vaccine has been approved by the FDA to prevent this infection. In the study, a peptide-based vaccine was developed against blastomycosis by using subtractive proteomics and reverse vaccinology approaches. It focuses on mining the whole genome of B. dermatitidis, identifying potential therapeutic targets, and pinpointing potential epitopes for both B- and T-cells that are immunogenic, non-allergenic, non-toxic, and highly antigenic. Multi-epitope constructs were generated by incorporating appropriate linker sequences. A linker (EAAAK) was also added to incorporate an adjuvant sequence to increase immunological potential. The addition of adjuvants and linkers ultimately resulted in the formation of a vaccine construct in which the number of amino acids was 243 and the molecular weight was 26.18 kDa. The designed antigenic and non-allergenic vaccine constructs showed suitable physicochemical properties. The vaccine's structures were predicted, and further analysis verified their interactions with the human TLR-4 receptor through protein-protein docking. Additionally, MD simulation showed a potent interaction between prioritized vaccine-receptor complexes. Immune simulation predicted that the final vaccine injections resulted in significant immune responses for the T- and B-cell immune responses. Moreover, in silico cloning ensured a high expression possibility of the lead vaccine in the E. coli (K12) vector. This study offers an initiative for the development of effective vaccines against B. dermatitidis; however, it is necessary to validate the designed vaccine's immunogenicity experimentally.

A review of the roles of pathogens in Alzheimer's disease.

Alzheimer's disease (AD) is one of the leading causes of dementia and is characterized by memory loss, mental and behavioral abnormalities, and impaired ability to perform daily activities. Even as a global disease that threatens human health, effective treatments to slow the progression of AD have not been found, despite intensive research and significant investment. In recent years, the role of infections in the etiology of AD has sparked intense debate. Pathogens invade the central nervous system through a damaged blood-brain barrier or nerve trunk and disrupt the neuronal structure and function as well as homeostasis of the brain microenvironment through a series of molecular biological events. In this review, we summarize the various pathogens involved in AD pathology, discuss potential interactions between pathogens and AD, and provide an overview of the promising future of anti-pathogenic therapies for AD.

DIAGNOSIS AND PREVENTION OF INVASIVE FUNGAL INFECTIONS IN THE IMMUNOCOMPROMISED HOST.

TOPIC IMPORTANCE: The prevalence of invasive fungal infections (IFI) has risen in the past three decades, attributed to advancements in immune-modulatory therapies employed in transplantation, rheumatology, and oncology. REVIEW FINDINGS: Organisms that cause IFI evade the host's natural defenses or at opportunities of immunologic weakness. Infections occur from inhalation of potentially pathogenic organisms, translocation of commensal organisms, or reactivation of latent infection. Organisms that cause IFI in immunocompromised populations include Candida spp., Cryptococcus spp., environmental molds, and endemic fungi. Diagnosis of these infections is challenging due to slow organism growth and fastidious culture requirements. Moreover, fungal biomarkers tend to be non-specific and can be negatively impacted by prophylactic antifungals. Antibody-based tests are not sensitive in immunocompromised hosts making antigen-based testing necessary. Prevention of IFI is guided by pathogen avoidance, removal or minimization of immune-suppressing factors, and pharmacologic prophylaxis in select hosts. SUMMARY: Understanding the complex interplay between the immune system and opportunistic fungal pathogens plays a key role in early diagnosis and prevention.