Wells Syndrome with Multiorgan Involvement Mimicking Hypereosinophilic Syndrome

Eosinophil-associated diseases represent a spectrum of heterogeneous disorders, where blood and cutaneous eosinophilia is the most important feature and eosinophils are the principal cause of cutaneous lesions. These diseases show some similarities in the clinical features but also many distinctive characteristics [Saurat et al., Dermatologia e malattie sessualmente trasmesse, Milano, Masson, 2000]. Wells syndrome is one of these disorders and is an uncommon recurrent inflammatory dermatosis, rarely associated to signs and symptoms of multiple organ involvement [Arch Dermatol 2006;142:1157–1161]. Hypereosinophilic syndrome, in contrast, constitutes a group of idiopathic disorders characterized by blood eosinophilia for at least 6 months, associated with single or multiple organ system dysfunction [Arch Dermatol 2006;142:1157–1161]. Clinically atypical Wells syndrome with multiorgan involvement is reported here. A correct diagnosis is difficult in this case, but clinical and histopathological features are compatible with this diagnosis. The reported condition likely represents a borderline hypereosinophilic disease, in which clinical features of both hypereosinophilic syndrome and Wells syndrome are present

Plant-Derived Epi-Nutraceuticals as Potential Broad-Spectrum Anti-Viral Agents

Although the COVID-19 pandemic appears to be diminishing, the emergence of SARS-CoV-2 variants represents a threat to humans due to their inherent transmissibility, immunological evasion, virulence, and invulnerability to existing therapies. The COVID-19 pandemic affected more than 500 million people and caused over 6 million deaths. Vaccines are essential, but in circumstances in which vaccination is not accessible or in individuals with compromised immune systems, drugs can provide additional protection. Targeting host signaling pathways is recommended due to their genomic stability and resistance barriers. Moreover, targeting host factors allows us to develop compounds that are effective against different viral variants as well as against newly emerging virus strains. In recent years, the globe has experienced climate change, which may contribute to the emergence and spread of infectious diseases through a variety of factors. Warmer temperatures and changing precipitation patterns can increase the geographic range of disease-carrying vectors, increasing the risk of diseases spreading to new areas. Climate change may also affect vector behavior, leading to a longer breeding season and more breeding sites for disease vectors. Climate change may also disrupt ecosystems, bringing humans closer to wildlife that transmits zoonotic diseases. All the above factors may accelerate the emergence of new viral epidemics. Plant-derived products, which have been used in traditional medicine for treating pathological conditions, offer structurally novel therapeutic compounds, including those with anti-viral activity. In addition, plant-derived bioactive substances might serve as the ideal basis for developing sustainable/efficient/cost-effective anti-viral alternatives. Interest in herbal antiviral products has increased. More than 50% of approved drugs originate from herbal sources. Plant-derived compounds offer diverse structures and bioactive molecules that are candidates for new drug development. Combining these therapies with conventional drugs could improve patient outcomes. Epigenetics modifications in the genome can affect gene expression without altering DNA sequences. Host cells can use epigenetic gene regulation as a mechanism to silence incoming viral DNA molecules, while viruses recruit cellular epitranscriptomic (covalent modifications of RNAs) modifiers to increase the translational efficiency and transcript stability of viral transcripts to enhance viral gene expression and replication. Moreover, viruses manipulate host cells' epigenetic machinery to ensure productive viral infections. Environmental factors, such as natural products, may influence epigenetic modifications. In this review, we explore the potential of plant-derived substances as epigenetic modifiers for broad-spectrum anti-viral activity, reviewing their modulation processes and anti-viral effects on DNA and RNA viruses, as well as addressing future research objectives in this rapidly emerging field

Longitudinal Evolution of the Pseudomonas-Derived Cephalosporinase (PDC) Structure and Activity in a CysticFibrosis Patient Treated with b-Lactams

Traditional studies on the evolution of antibiotic resistance development use approaches that can range from laboratory-based experimental studies, to epidemiological surveillance, to sequencing of clinical isolates. However, evolutionary trajectories also depend on the environment in which selection takes place, compelling the need to more deeply investigate the impact of environmental complexities and their dynamics over time. Herein, we explored the within-patient adaptive long-term evolution of a Pseudomonas aeruginosa hypermutator lineage in the airways of a cystic fibrosis (CF) patient by performing a chronological tracking of mutations that occurred in different subpopulations; our results demonstrated parallel evolution events in the chromosomally encoded class C β-lactamase (blaPDC). These multiple mutations within blaPDC shaped diverse coexisting alleles, whose frequency dynamics responded to the changing antibiotic selective pressures for more than 26 years of chronic infection. Importantly, the combination of the cumulative mutations in blaPDC provided structural and functional protein changes that resulted in a continuous enhancement of its catalytic efficiency and high level of cephalosporin resistance. This evolution was linked to the persistent treatment with ceftazidime, which we demonstrated selected for variants with robust catalytic activity against this expanded-spectrum cephalosporin. A “gain of function” of collateral resistance toward ceftolozane, a more recently introduced cephalosporin that was not prescribed to this patient, was also observed, and the biochemical basis of this cross-resistance phenomenon was elucidated. This work unveils the evolutionary trajectories paved by bacteria toward a multidrug-resistant phenotype, driven by decades of antibiotic treatment in the natural CF environmental setting. IMPORTANCE Antibiotics are becoming increasingly ineffective to treat bacterial infections. It has been consequently predicted that infectious diseases will become the biggest challenge to human health in the near future. Pseudomonas aeruginosa is considered a paradigm in antimicrobial resistance as it exploits intrinsic and acquired resistance mechanisms to resist virtually all antibiotics known. AmpC β-lactamase is the main mechanism driving resistance in this notorious pathogen to β-lactams, one of the most widely used classes of antibiotics for cystic fibrosis infections. Here, we focus on the β-lactamase gene as a model resistance determinant and unveil the trajectory P. aeruginosa undertakes on the path toward a multidrug-resistant phenotype during the course of two and a half decades of chronic infection in the airways of a cystic fibrosis patient. Integrating genetic and biochemical studies in the natural environment where evolution occurs, we provide a unique perspective on this challenging landscape, addressing fundamental molecular mechanisms of resistance.Fil: Colque, Claudia A. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentina.Fil: Albarracín Orio, Andrea G. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentina.Fil: Hedemann, Laura G. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentina.Fil: Feliziani, Sofía. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentina.Fil: Moyano, Alejandro J. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentina.Fil: Smania, Andrea M. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Química Biológica; Argentina.Fil: Colque, Claudia A. Universidad Nacional de Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC-CONICET); Argentina.Fil: Albarracín Orio, Andrea G. Universidad Nacional de Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC-CONICET); Argentina.Fil: Hedemann, Laura G. Universidad Nacional de Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC-CONICET); Argentina.Fil: Feliziani, Sofía. Universidad Nacional de Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC-CONICET); Argentina.Fil: Moyano, Alejandro J. Universidad Nacional de Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC-CONICET); Argentina.Fil: Smania, Andrea M. Universidad Nacional de Córdoba. Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC-CONICET); Argentina.Fil: Tomatis, Pablo E. Universidad Nacional de Rosario. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.Fil: Dotta, Gina. Universidad Nacional de Rosario. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.Fil: Vila, Alejandro J. Universidad Nacional de Rosario. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.Fil: Tomatis, Pablo E. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.Fil: Moreno, Diego M. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.Fil: Vila, Alejandro J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.Fil: Albarracín Orio, Andrea G. Universidad Católica de Córdoba. Facultad de Ciencias Agropecuarias. (IRNASUS-CONICET); Argentina.Fil: Moreno, Diego M. Universidad Nacional de Rosario. Instituto de Química de Rosario (IQUIR-CONICET); Argentina.Fil: Hickman Rachel A. Department of Clinical Microbiology; Denmark.Fil: Sommer, Lea M. Department of Clinical Microbiology; Denmark.Fil: Johansen, Helle K. Department of Clinical Microbiology; Denmark.Fil: Hickman Rachel A. Technical University of Denmark, Lyngb. Novo Nordisk Foundation Centre for Biosustainability; Denmark.Fil: Sommer, Lea M. Technical University of Denmark, Lyngb. Novo Nordisk Foundation Centre for Biosustainability; Denmark.Fil: Johansen, Helle K. Technical University of Denmark, Lyngb. Novo Nordisk Foundation Centre for Biosustainability; Denmark.Fil: Bonomo, Robert A. Case Western Reserve University. Departments of Molecular Biology and Microbiology, Medicine, Biochemistry, Pharmacology, and Proteomics and Bioinformatics; United States.Fil: Bonomo, Robert A. Senior Clinical Scientist Investigator. Louis Stokes Cleveland Department of Veterans Affairs; United States.Fil: Johansen, Helle K. University of Copenhagen. Department of Clinical Medicine; Denmark

Mucoidy, Quorum Sensing, Mismatch Repair and Antibiotic Resistance in Pseudomonas aeruginosa from Cystic Fibrosis Chronic Airways Infections

Survival of Pseudomonas aeruginosa in cystic fibrosis (CF) chronic infections is based on a genetic adaptation process consisting of mutations in specific genes, which can produce advantageous phenotypic switches and ensure its persistence in the lung. Among these, mutations inactivating the regulators MucA (alginate biosynthesis), LasR (quorum sensing) and MexZ (multidrug-efflux pump MexXY) are the most frequently observed, with those inactivating the DNA mismatch repair system (MRS) being also highly prevalent in P. aeruginosa CF isolates, leading to hypermutator phenotypes that could contribute to this adaptive mutagenesis by virtue of an increased mutation rate. Here, we characterized the mutations found in the mucA, lasR, mexZ and MRS genes in P. aeruginosa isolates obtained from Argentinean CF patients, and analyzed the potential association of mucA, lasR and mexZ mutagenesis with MRS-deficiency and antibiotic resistance. Thus, 38 isolates from 26 chronically infected CF patients were characterized for their phenotypic traits, PFGE genotypic patterns, mutations in the mucA, lasR, mexZ, mutS and mutL gene coding sequences and antibiotic resistance profiles. The most frequently mutated gene was mexZ (79%), followed by mucA (63%) and lasR (39%) as well as a high prevalence (42%) of hypermutators being observed due to loss-of-function mutations in mutL (60%) followed by mutS (40%). Interestingly, mutational spectra were particular to each gene, suggesting that several mechanisms are responsible for mutations during chronic infection. However, no link could be established between hypermutability and mutagenesis in mucA, lasR and mexZ, indicating that MRS-deficiency was not involved in the acquisition of these mutations. Finally, although inactivation of mucA, lasR and mexZ has been previously shown to confer resistance/tolerance to antibiotics, only mutations in MRS genes could be related to an antibiotic resistance increase. These results help to unravel the mutational dynamics that lead to the adaptation of P. aeruginosa to the CF lung

Microevolution of Neisseria lactamica during nasopharyngeal colonisation induced by controlled human infection.

Neisseria lactamica is a harmless coloniser of the infant respiratory tract, and has a mutually-excluding relationship with the pathogen Neisseria meningitidis. Here we report controlled human infection with genomically-defined N. lactamica and subsequent bacterial microevolution during 26 weeks of colonisation. We find that most mutations that occur during nasopharyngeal carriage are transient indels within repetitive tracts of putative phase-variable loci associated with host-microbe interactions (pgl and lgt) and iron acquisition (fetA promotor and hpuA). Recurrent polymorphisms occurred in genes associated with energy metabolism (nuoN, rssA) and the CRISPR-associated cas1. A gene encoding a large hypothetical protein was often mutated in 27% of the subjects. In volunteers who were naturally co-colonised with meningococci, recombination altered allelic identity in N. lactamica to resemble meningococcal alleles, including loci associated with metabolism, outer membrane proteins and immune response activators. Our results suggest that phase variable genes are often mutated during carriage-associated microevolution