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Frontiers in Microbiology 2024species are pathogenic fungi known to cause pneumonia in immunocompromised mammals. They are obligate to their host, replicate extracellularly in lung alveoli and...
INTRODUCTION
species are pathogenic fungi known to cause pneumonia in immunocompromised mammals. They are obligate to their host, replicate extracellularly in lung alveoli and thrive in the copper-enriched environment of mammalian lungs. In this study, we investigated the proteome of , a model organism that infects mice, in the context of its copper sensing and tolerance.
METHODS AND RESULTS
The query for copper-associated annotations in FungiDB followed by a manual curation identified only 21 genes in , significantly fewer compared to other clinically relevant fungal pathogens or phylogenetically similar free-living fungi. We then employed instrumental analyses, including Size-Exclusion Chromatography Inductively Coupled Plasma Mass Spectrometry (SEC-ICP-MS), Immobilized Metal Affinity Chromatography (IMAC), and Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS), to isolate and identify copper-binding proteins from freshly extracted organisms, revealing 29 distinct cuproproteins. The RNA sequencing (RNA-seq) analysis of exposed to various CuSO concentrations at three temporal intervals (0.5, 2, and 5 h) indicated that significant gene expression changes occurred only under the highest CuSO concentration probed (100 μM) and the longest exposure duration (5 h). This stimulus led to the upregulation of 43 genes and downregulation of 27 genes compared to untreated controls. Quantitative PCR (qPCR) confirmed the expression of four out of eight selected upregulated genes, including three assumed transcription factors (PNEG_01236, PNEG_01675, and PNEG_01730) and a putative copper transporter (PNEG_02609). Notably, the three applied methodologies - homology-based annotation, SEC-ICP-MS/IMAC/LC-MS/MS, and RNA-seq - yielded largely distinct findings, with only four genes (PNEG_02587, PNEG_03319, PNEG_02584, and PNEG_02989) identified by both instrumental methods.
DISCUSSION
The insights contribute to the broader knowledge of copper homeostasis and provide novel facets of host-pathogen interactions for extracellular pathogens. We suggest that future studies of pathogenicity and copper stress survival should consider the entire spectrum of identified genes.
PubMed: 38812685
DOI: 10.3389/fmicb.2024.1383737 -
Diagnostics (Basel, Switzerland) Apr 2024A 54-year-old woman presented to an outpatient clinic with a recurrence of triple-negative breast cancer and multiple bone metastases. The patient had a large mass...
A 54-year-old woman presented to an outpatient clinic with a recurrence of triple-negative breast cancer and multiple bone metastases. The patient had a large mass lesion of 10 cm on the sternum. She received the immune checkpoint inhibitors pembrolizumab and taxane. Initially, the patient responded excellently to treatment, but stopped pembrolizumab for grade IV skin toxicity with multiple ulcerative wounds over the bilateral leg and trunk. The lesions abated following administration of antibiotics and oral prednisolone for two months. After that, she was referred to the radiation oncology department for further treatment. She received radiotherapy for the sternum mass but stopped radiation at 42Gy/21 fractions for severe dyspnea and fever. Blood sampling found leukocytosis with neutrophil predominance. Chest radiography showed bilateral lung infiltration. Pulmonary CT scan yielded bilateral lung patchy consolidation compatible with radiation isodose-line. Bronchial lavage showed positive Pneumocystis jiroveci PCR. Dyspnea improved after titrating methylprednisolone within two days. The patient recovered well with TMP-SMX and glucocorticoids after the initiation of therapy.
PubMed: 38667495
DOI: 10.3390/diagnostics14080850 -
The Journal of Rheumatology Nov 2023This study aimed to explore the experiences of dermatologists and rheumatologists in the early recognition of psoriatic arthritis (PsA) and to identify potential...
OBJECTIVE
This study aimed to explore the experiences of dermatologists and rheumatologists in the early recognition of psoriatic arthritis (PsA) and to identify potential improvements to the current shared-care model.
METHODS
A 24-question survey addressing referral strategies was constructed by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) project steering committee and sent to all members (n = 927). Questions addressed the use of screening tools, frequency of PsA in patients with psoriasis, therapeutic decision making, and suggestions for earlier PsA recognition and current unmet needs.
RESULTS
There were 149 respondents (16.1% response rate), which included 113 rheumatologists from 37 countries and 26 dermatologists from 16 countries. Of the dermatologists, 81% use PsA-specific screening instruments. Conversely, rheumatologists reported that only 26.8% of patients referred to them from all sources had been assessed with screening tools. Although dermatologists reported that a mean of 67% of suspected PsA cases were confirmed, rheumatologists reported a mean of 47.9% of confirmed cases. Both specialties reported similar views regarding optimization of the diagnostic process and indicated that the best approach involved combining patient-reported (ie, screening tools) and physician-confirmed findings. Moreover, both specialties identified the education of primary care physicians (PCPs) and dermatologists as the greatest priority to improve PsA screening.
CONCLUSION
The survey indicated the current unmet needs in the early recognition of PsA. Important areas to address include improving the use of screening instruments, increasing the education of community-based dermatologists and PCPs, and using a combination of patient-reported and physician-confirmed findings in the screening approach.
Topics: Humans; Arthritis, Psoriatic; Severity of Illness Index; Psoriasis; Rheumatologists; Surveys and Questionnaires; Pneumonia, Pneumocystis
PubMed: 37582554
DOI: 10.3899/jrheum.2023-0424 -
Clinical Microbiology and Infection :... May 2024Fungal infections are common in HIV-infected individuals and significantly contribute to mortality. However, a substantial number of cases are undiagnosed before death. (Review)
Review
BACKGROUND
Fungal infections are common in HIV-infected individuals and significantly contribute to mortality. However, a substantial number of cases are undiagnosed before death.
OBJECTIVE
To determine the frequency of fungal pathogens in autopsy studies of people who died with HIV in Africa.
METHODS
We conducted a scoping review of autopsy studies conducted in Africa.
DATA SOURCES
PubMed, Scopus, Web of Science, Embase, Google Scholar, and African Journal Online.
STUDY ELIGIBILITY CRITERIA
The review encompasses studies published from inception to September 2023, and no language restrictions were imposed during the search process. We included studies that reported histopathological or microbiological evidence for the diagnosis of fungal infections and other pathogens.
DATA SYNTHESIS
Data were summarized using descriptive statistics and no meta-analysis was performed.
RESULTS
We examined 30 articles reporting studies conducted between 1991 and 2019, encompassing a total of 13 066 HIV-infected decedents across ten African countries. In five studies, the autopsy type was not specified. Among those studies with specified autopsy types, 20 involved complete diagnostic autopsies, whereas 5 were categorized as partial or minimally invasive autopsies. There were 2333 pathogens identified, with 946 (40.5%) being mycobacteria, 856 (36.7%) fungal, 231 (3.8%) viral, 208 (8.9%) parasitic, and 92 (3.9%) bacterial. Of the 856 fungal pathogens identified, 654 (28.0%) were Cryptococcus species, 167 (7.2%) Pneumocystis jirovecii, 16 (0.69%) Histoplasma species, 15 (0.64%) Aspergillus species, and 4 (0.17%) Candida species. Other major non-fungal pathogens identified were cytomegalovirus 172 (7.37%) and Toxoplasma gondii 173 (7.42%).
CONCLUSIONS
Invasive fungal infections occur in over one-third of people who succumb to HIV in Africa. In addition to cryptococcosis and Pneumocystis jirovecii pneumonia, integrating other priority fungal pathogen detection and management strategies into the broader framework of HIV care in Africa is recommended. This involves increasing awareness regarding the impact of fungal infections in advanced HIV disease and strengthening diagnostic and treatment capacity.
Topics: Humans; Autopsy; Africa; HIV Infections; Mycoses; Fungi; AIDS-Related Opportunistic Infections
PubMed: 38145865
DOI: 10.1016/j.cmi.2023.12.016 -
Pediatric Blood & Cancer Jan 2024Initially developed as immunosuppressive agents, mammalian target of rapamycin (mTOR) inhibitors are currently used widely in the management of vascular malformations... (Review)
Review
BACKGROUND AND OBJECTIVES
Initially developed as immunosuppressive agents, mammalian target of rapamycin (mTOR) inhibitors are currently used widely in the management of vascular malformations and tumors. The incidence of infectious complications in the vascular anomalies (VA) population is not well defined. The goal of this systematic review was to better define the types and severity of reported infectious complications in patients with VAs treated with mTOR inhibition.
METHODS
This was a systematic review conducted following PRISMA guidelines evaluating all research articles focused on infectious complications in patients with VAs treated with sirolimus or everolimus. Thirty articles including 1182 total patients and 316 infections (in 291 unique patients) were ultimately included.
RESULTS
The majority of infections were viral upper respiratory (n = 137, 54%), followed by pneumonia (n = 53, 20%), and cutaneous infections (n = 20, 8%). There were six total infection-related fatalities, which all occurred in patients younger than 2 years. Two cases of Pneumocystis jirovecii pneumonia (PJP) were reported. These were infants with kaposiform hemangioendothelioma (KHE) who were also treated with steroids and did not receive PJP prophylaxis. Almost one-third (n = 96, 32%) of infectious complications were graded 3-4 according to Common Terminology Criteria for Adverse Events (CTCAE) criteria. Details of patient age, subtype of VA, and timing of infection were lacking from many reports.
CONCLUSIONS
Most infectious complications reported in patients with VA on mTOR inhibitors were viral respiratory infections and non-severe. Bacteremia, infectious fatalities, and PJP are exceedingly rare. Future studies are needed to clarify the spectrum of infectious risks in VA patients and to provide guidance for infection prevention.
Topics: Infant; Humans; Sirolimus; Immunosuppressive Agents; Everolimus; Pneumonia, Pneumocystis; Vascular Malformations; TOR Serine-Threonine Kinases
PubMed: 37933207
DOI: 10.1002/pbc.30758 -
Journal of Fungi (Basel, Switzerland) Nov 2023A systematic literature search on in 276 pet, farm, zoo, and wild mammal species resulted in 124 publications originating from 38 countries that were analyzed...
A systematic literature search on in 276 pet, farm, zoo, and wild mammal species resulted in 124 publications originating from 38 countries that were analyzed descriptively and statistically, for which inclusion and exclusion criteria were exactly defined. The range of recorded prevalence was broad, yet in half of the citations a prevalence of ≤25% was documented. Prevalence was significantly dependent on the method used for detection, with PCR revealing the highest percentages. Pet animals showed the lowest median prevalence, followed by farm, wild, and zoo animals. In contrast, pet and farm animals showed higher proportions of high-grade infection levels compared to zoo and wild mammals. Only in individual cases, all of them associated with severe pneumonia, was an underlying immunosuppression confirmed. Acquired immunosuppression caused by other diseases was frequently discussed, but its significance, especially in highly immunosuppressive cases, needs to be clarified. This meta-analysis supported a potential influence of the social and environmental factors of the host on transmission in wildlife, which must be further elucidated, as well as the genetic diversity of the fungus.
PubMed: 37998885
DOI: 10.3390/jof9111081 -
Chest Jun 2024
Topics: Humans; Pneumonia, Pneumocystis
PubMed: 38852956
DOI: 10.1016/j.chest.2024.02.038 -
Seminars in Arthritis and Rheumatism Dec 2023Invasive fungal infections (IFIs) are life-threatening opportunistic infections in patients with connective tissue disease CTD) that cause significant morbidity and... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Invasive fungal infections (IFIs) are life-threatening opportunistic infections in patients with connective tissue disease CTD) that cause significant morbidity and mortality. We attempted to determine the potential risk factors associated with IFIs in CTD.
METHODS
We systematically searched PubMed, Embase, and the Cochrane Library databases for relevant articles published from the database inception to February 1, 2023.
RESULTS
Twenty-six studies were included in this systematic review and meta-analysis. Risk factors identified for IFIs were diabetes (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.00 to 2.64), pulmonary diseases (OR 3.43; 95% CI 2.49 to 4.73), interstitial lung disease (ILD; OR, 4.06; 95% CI, 2.22 to 7.41), renal disease (OR, 4.41; 95% CI, 1.84 to 10.59), glucocorticoid (GC) use (OR, 4.15; 95% CI, 2.74 to 6.28), especially moderate to high-dose GC, azathioprine (AZA) use (OR, 1.50; 95% CI, 1.12 to 2.01), calcineurin inhibitor (CNI) use (OR, 2.49; 95% CI, 1.59 to 3.91), mycophenolate mofetil (MMF) use (OR, 2.83; 95% CI, 1.59 to 5.03), cyclophosphamide (CYC) use (OR, 3.35; 95% CI, 2.47 to 4.54), biologics use (OR, 3.43; 95% CI, 2.36 to 4.98), and lymphopenia (OR, 4.26; 95% CI, 2.08 to 8.73). Hydroxychloroquine (HCQ) use reduced risk of IFIs (OR, 0.67; 95% CI, 0.54 to 0.84). Furthermore, 17 of the 26 studies only reported risk factors for Pneumocystis jiroveci pneumonia (PJP) in patients with CTD. Pulmonary disease; ILD; and the use of GC, CNIs, CYC, methotrexate (MTX), MMF and biologics, and lymphopenia increased the risk of PJP, whereas the use of HCQ reduced its risk.
CONCLUSION
Diabetes, pulmonary disease, ILD, renal disease, use of GC (especially at moderate to high dose) and immunosuppressive drugs, and lymphopenia were found to be associated with significant risk for IFIs (especially PJP) in patients with CTD. Furthermore, the use of HCQ may reduce the risk of IFIs in patients with CTD.
Topics: Humans; Connective Tissue Diseases; Cyclophosphamide; Lung Diseases, Interstitial; Mycophenolic Acid; Glucocorticoids; Risk Factors; Diabetes Mellitus; Lymphopenia; Biological Products; Invasive Fungal Infections
PubMed: 37633041
DOI: 10.1016/j.semarthrit.2023.152257 -
The Lancet. Microbe Apr 2024In October, 2022, WHO published the first fungal priority pathogen list, which categorised 19 fungal entities into three priority groups (critical, high, and medium),... (Review)
Review
In October, 2022, WHO published the first fungal priority pathogen list, which categorised 19 fungal entities into three priority groups (critical, high, and medium), for prioritisation of research efforts. The final ranking was determined via multiple criteria decision analysis, considering both research and development needs and perceived public health importance. In this Personal View, we discuss the positioning of the fungal pathogens, namely, Mucorales, Candida spp, Histoplasma spp, Coccidioides and Paracoccidioides spp, Fusarium spp, eumycetoma causative agents, Talaromyces marneffei, and Pneumocystis jirovecii, while expressing concerns about potential disparities between the WHO fungal priority pathogen list ranking and the actual disease burden associated with these pathogens. Finally, we propose a revised prioritisation list that also considers the regional disparities in the burden of fungal diseases.
PubMed: 38608682
DOI: 10.1016/S2666-5247(24)00042-9 -
Antimicrobial Agents and Chemotherapy Dec 2023Rezafungin is a chemically and metabolically stable echinocandin with a longer half-life than other echinocandins, allowing for a once-weekly intravenous infusion versus...
Rezafungin is a chemically and metabolically stable echinocandin with a longer half-life than other echinocandins, allowing for a once-weekly intravenous infusion versus a daily infusion. Rezafungin is approved in the US for the treatment of candidemia and/or invasive candidiasis and is in development for the prevention of invasive fungal disease caused by , , and spp. in immunosuppressed patients. A population pharmacokinetic (PPK) model was developed using data from five Phase 1, one Phase 2, and one Phase 3 study. The model found to best describe the available data was a three-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V23), intercompartmental clearance 1, and intercompartmental clearance 2. The variability model included correlated interindividual variability in CL, V1, and V23 and a proportional residual variability model. The following statistically significant covariates were identified: albumin concentrations on V23; body surface area (BSA) on CL, V1, and V23; and disease state on CL and V1. Disease states were defined as patients from the Phase 2 and Phase 3 studies and hepatically impaired subjects. Covariates of BSA, disease state, or albumin, included in the final model, were not associated with clinically meaningful changes in PK, nor were any other patient factors, indicating that a common dose regimen is adequate for all adult patients. Target attainment simulations were performed to estimate the probability of achieving PK/pharmacodynamic targets across the range of minimum inhibitory concentration values for six species of .
Topics: Adult; Humans; Candidemia; Antifungal Agents; Echinocandins; Candidiasis, Invasive; Candida; Albumins
PubMed: 38014945
DOI: 10.1128/aac.00916-23