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MSphere Oct 2020and are significant human pathogens, causing infections at multiple body sites, including across the skin. Both are organisms that cause human diseases and secrete...
and are significant human pathogens, causing infections at multiple body sites, including across the skin. Both are organisms that cause human diseases and secrete superantigens, including toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxins (SEs), and streptococcal pyrogenic exotoxins (SPEs). On the skin, human keratinocytes represent the first cell type to encounter these superantigens. We employed transcriptome sequencing (RNA-seq) to evaluate the human primary keratinocyte response to both TSST-1 and staphylococcal enterotoxin B (SEB) in triplicate analyses. Both superantigens caused large numbers of genes to be up- and downregulated. The genes that exhibited 2-fold differential gene expression compared to vehicle-treated cells, whether up- or downregulated, totaled 5,773 for TSST-1 and 4,320 for SEB. Of these, 4,482 were significantly upregulated by exposure of keratinocytes to TSST-1, whereas 1,291 were downregulated. For SEB, expression levels of 3,785 genes were upregulated, whereas those of 535 were downregulated. There was the expected high overlap in both upregulation (3,412 genes) and downregulation (400 genes). Significantly upregulated genes included those associated with chemokine production, with the possibility of stimulation of inflammation. We also tested an immortalized human keratinocyte line, from a different donor, for chemokine response to four superantigens. TSST-1 and SEB caused production of interleukin-8 (IL-8), MIP-3α, and IL-33. SPEA and SPEC were evaluated for stimulation of expression of IL-8 as a representative chemokine; both stimulated production of IL-8. and are common human pathogens, causing infections that include the skin. Both pathogens produce a family of secreted toxins called superantigens, which have been shown to be important in human diseases. The first cell types encountered by superantigens on skin are keratinocytes. Our studies demonstrated, that the human keratinocyte pathway, among other pathways, responds to superantigens with production of chemokines, setting off inflammation. This inflammatory response may be harmful, facilitating opening of the skin barrier.
Topics: Cell Line, Transformed; Cells, Cultured; Cytokines; Enterotoxins; Gene Expression Profiling; Humans; Inflammation; Keratinocytes; RNA-Seq; Staphylococcus aureus; Streptococcus pyogenes; Superantigens
PubMed: 33028686
DOI: 10.1128/mSphere.00803-20 -
BioRxiv : the Preprint Server For... Apr 2023Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods...
Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [F]FDG, yet lack specificity to the causative pathogen () and so do not directly correlate with pathogen viability. Here we show that a close mimic that is also positron-emitting of the non-mammalian disaccharide trehalose - 2-[F]fluoro-2-deoxytrehalose ([F]FDT) - can act as a mechanism-based enzyme reporter in vivo. Use of [F]FDT in the imaging of in diverse models of disease, including non-human primates, successfully co-opts -specific processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment. A pyrogen-free, direct enzyme-catalyzed process for its radiochemical synthesis allows the ready production of [F]FDT from the most globally-abundant organic F-containing molecule, [F]FDG. The full, pre-clinical validation of both production method and [F]FDT now creates a new, bacterium-specific, clinical diagnostic candidate. We anticipate that this distributable technology to generate clinical-grade [F]FDT directly from the widely-available clinical reagent [F]FDG, without need for either bespoke radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer.
PubMed: 37333343
DOI: 10.1101/2023.04.03.535218 -
Biotechnologia 2022Liposomes (LSs) are promising nanoparticles with unique properties such as controlled nanosize, large surface area, increased reactivity, and ability to undergo... (Review)
Review
Liposomes (LSs) are promising nanoparticles with unique properties such as controlled nanosize, large surface area, increased reactivity, and ability to undergo modification. Worldwide, licensed liposomal forms of antibiotics, hormones, antioxidants, cytostatics, ophthalmic drugs, etc., are available on the pharmaceutical market. This review focuses on the adjuvant properties of LSs in the production of vaccines (VACs). LS-VACs have the following advantages: antigens with low immunogenicity can become highly immunogenic; LSs can include both hydrophilic and hydrophobic antigens; LSs allow to achieve a prolonged specific action of antibodies; and LSs reduce the toxicity and pyrogenicity of encapsulated antigens and adjuvants. The immune response is influenced by the composition of the liposomal membrane, physicochemical characteristics of lipids, antigen localization in LSs, interaction of LSs with complement, and a number of proteins, which leads to opsonization. The major requirements for adjuvants are their ability to enhance the immune response, biodegradability, and elimination from the organism, and LSs fully meet these requirements. The effectiveness and safety of LSs as carriers in the antigen delivery system have been proven by the long-term clinical use of licensed vaccines against hepatitis A, influenza, herpes zoster, malaria, and COVID-19.
PubMed: 36685697
DOI: 10.5114/bta.2022.120709 -
International Dental Journal Jun 2023A significant increase in the incidence of scarlet fever, mainly in Europe, has been noted during the COVID-19 postpandemic period. Scarlet fever is caused by a... (Review)
Review
A significant increase in the incidence of scarlet fever, mainly in Europe, has been noted during the COVID-19 postpandemic period. Scarlet fever is caused by a pyrogenic exotoxin-producing streptococcus-Streptococcus pyogenes-responsible for more than 500,000 deaths annually worldwide. Superantigens (SAgs) secreted by this Group A streptococcus (GAS) usually overstimulate the human immune system, causing an amplified hypersensitivity reaction leading to initial symptoms such as sore throat, high fever, and a sandpaper-like skin rash. There could be concurrent oral manifestations known as "strawberry tongue" or "raspberry tongue," which may be first noted by oral health professionals. The early diagnosis and treatment of this disease is critical to obviate the development of local and systemic sequelae such as acute rheumatic fever, endocarditis, and glomerulonephritis. Antibiotics should be prescribed early to mitigate its duration, sequelae, and community spread. Dental practitioners should be aware of the early symptoms of scarlet fever for infection detection, emergency patient management, and appropriate referral. This concise review outlines the prevalence, pathogenicity, oral and systemic manifestations, as well as the dental implications of scarlet fever.
Topics: Humans; Scarlet Fever; Dentists; COVID-19; Professional Role; Streptococcus pyogenes; Recurrence
PubMed: 37062653
DOI: 10.1016/j.identj.2023.03.009 -
The Journal of Clinical Investigation Oct 2023BACKGROUNDThe biology of Plasmodium vivax is markedly different from that of P. falciparum; how this shapes the immune response to infection remains unclear. To address...
BACKGROUNDThe biology of Plasmodium vivax is markedly different from that of P. falciparum; how this shapes the immune response to infection remains unclear. To address this shortfall, we inoculated human volunteers with a clonal field isolate of P. vivax and tracked their response through infection and convalescence.METHODSParticipants were injected intravenously with blood-stage parasites and infection dynamics were tracked in real time by quantitative PCR. Whole blood samples were used for high dimensional protein analysis, RNA sequencing, and cytometry by time of flight, and temporal changes in the host response to P. vivax were quantified by linear regression. Comparative analyses with P. falciparum were then undertaken using analogous data sets derived from prior controlled human malaria infection studies.RESULTSP. vivax rapidly induced a type I inflammatory response that coincided with hallmark features of clinical malaria. This acute-phase response shared remarkable overlap with that induced by P. falciparum but was significantly elevated (at RNA and protein levels), leading to an increased incidence of pyrexia. In contrast, T cell activation and terminal differentiation were significantly increased in volunteers infected with P. falciparum. Heterogeneous CD4+ T cells were found to dominate this adaptive response and phenotypic analysis revealed unexpected features normally associated with cytotoxicity and autoinflammatory disease.CONCLUSIONP. vivax triggers increased systemic interferon signaling (cf P. falciparum), which likely explains its reduced pyrogenic threshold. In contrast, P. falciparum drives T cell activation far in excess of P. vivax, which may partially explain why falciparum malaria more frequently causes severe disease.TRIAL REGISTRATIONClinicalTrials.gov NCT03797989.FUNDINGThe European Union's Horizon 2020 Research and Innovation programme, the Wellcome Trust, and the Royal Society.
Topics: Humans; Plasmodium vivax; Plasmodium falciparum; Malaria, Vivax; Malaria, Falciparum; Malaria; Lymphocyte Activation
PubMed: 37616070
DOI: 10.1172/JCI152463 -
European Journal of Microbiology &... Sep 2018The fever-inducing effect of lipopolysaccharides (LPS) is well known, and human blood is extremely responsive to this pyrogen. Recently, the safety of LPS-containing... (Review)
Review
The fever-inducing effect of lipopolysaccharides (LPS) is well known, and human blood is extremely responsive to this pyrogen. Recently, the safety of LPS-containing food supplements and probiotic drugs as immune-stimulants has been questioned, although these products are orally taken and do not reach the bloodstream undigested. The concerns are understandable, as endotoxaemia is a pathological condition, but the oral uptake of probiotic products containing LPS or Gram-negative bacteria does not pose a health risk, based on the available scientific evidence, as is reviewed here. The available methods developed to detect LPS and other pyrogens are mostly used for quality control of parentally applied therapeuticals. Their outcome varies considerably when applied to food supplements, as demonstrated in a simple comparative experiment. Products containing different strains can result in vastly different results on their LPS content, depending on the method of testing. This is an inherent complication to pyrogen testing, which hampers the communication that the LPS content of food supplements is not a safety concern.
PubMed: 30345085
DOI: 10.1556/1886.2018.00017 -
ALTEX 2021The use of in vitro assays to inform decision-making requires robust and reproducible results across studies, laboratories, and time. Experiments using positive control...
The use of in vitro assays to inform decision-making requires robust and reproducible results across studies, laboratories, and time. Experiments using positive control materials are an integral component of an assay procedure to demonstrate the extent to which the measurement system is performing as expected. This paper reviews ten characteristics that should be considered when selecting a positive control material for an in vitro assay: 1) the biological mechanism of action, 2) ease of preparation, 3) chemical purity, 4) verifiable physical properties, 5) stability, 6) ability to generate responses spanning the dynamic range of the assay, 7) technical or biological interference, 8) commercial availability, 9) user toxicity, and 10) disposability. Examples and a case study of the monocyte activation test are provided to demonstrate the application of these characteristics for identification and selection of potential positive control materials. Because specific positive control materials are often written into testing standards for in vitro assays, selection of the positive control material based on these characteristics can aid in ensuring the long-term relevance and usability of these standards.
Topics: Biological Assay; Laboratories; Research Design
PubMed: 33637998
DOI: 10.14573/altex.2102111 -
Clinical Neurology and Neurosurgery Jun 2022To describe the clinical characteristics and outcomes of CVT in patients with history of recent COVID-19 infection or vaccination. (Review)
Review
OBJECTIVE
To describe the clinical characteristics and outcomes of CVT in patients with history of recent COVID-19 infection or vaccination.
METHODS
We reviewed demographic, clinical, and radiographic characteristics of non-pyrogenic, non-traumatic CVT cases at our multi-center institution between March 2020 and December 2021. Patients were grouped according to their history of recent COVID-19 infection or vaccination into group-I (+COVID-19 association) and group-II (-COVID-19 association).
RESULTS
Fifty-one patients with CVT were included, of which 14 (27.4%) had a positive COVID-19 association: 10 with infection and 4 with mRNA-COVID-vaccine. Nine patients in group-I had COVID-19 infection or vaccine within 30 days of CVT diagnosis, including 3 patients with active infection at the time of CVT diagnosis. Half of the patients in group-I (n = 7,50.0%) and 32.4% (n = 12) of group-II were male, and mean age was 52.6 years in group-I and 51.4 years in group-II. Fever at presentation was noted in one patient who had active COVID infection (I=1 (7.1%), II= 0 (0%)). Higher rates of comorbidities were observed in group-II: hypertension (I= 2 (14.3%), II= 13 (35.1%)), deep venous thrombosis(I=1(7.1%), II= 10 (27.0%)), pulmonary emboli (I=1(7.1%), II= 8(21.6%)), or stroke(I=0(0%), II= 6(16.4%)). Three patients had thrombocytopenia at the time of CVT diagnosis (5.4%) and most patients (n = 37, 72.5%) were treated medically with anticoagulation. Complication rate during hospitalization was 17.6% (n = 6), and no mortality was noted.
CONCLUSION
Twenty-seven percent of CVT patients were associated with COVID-19 infection or vaccination, and the majority presented within 30 days of infection/vaccination.
Topics: COVID-19; Female; Humans; Intracranial Thrombosis; Male; Middle Aged; Multicenter Studies as Topic; Pandemics; Vaccines; Venous Thrombosis
PubMed: 35462303
DOI: 10.1016/j.clineuro.2022.107256 -
Nature Microbiology Sep 2022Forest soil microbiomes have crucial roles in carbon storage, biogeochemical cycling and rhizosphere processes. Wildfire season length, and the frequency and size of...
Forest soil microbiomes have crucial roles in carbon storage, biogeochemical cycling and rhizosphere processes. Wildfire season length, and the frequency and size of severe fires have increased owing to climate change. Fires affect ecosystem recovery and modify soil microbiomes and microbially mediated biogeochemical processes. To study wildfire-dependent changes in soil microbiomes, we characterized functional shifts in the soil microbiota (bacteria, fungi and viruses) across burn severity gradients (low, moderate and high severity) 1 yr post fire in coniferous forests in Colorado and Wyoming, USA. We found severity-dependent increases of Actinobacteria encoding genes for heat resistance, fast growth, and pyrogenic carbon utilization that might enhance post-fire survival. We report that increased burn severity led to the loss of ectomycorrhizal fungi and less tolerant microbial taxa. Viruses remained active in post-fire soils and probably influenced carbon cycling and biogeochemistry via turnover of biomass and ecosystem-relevant auxiliary metabolic genes. Our genome-resolved analyses link post-fire soil microbial taxonomy to functions and reveal the complexity of post-fire soil microbiome activity.
Topics: Carbon; Forests; Microbiota; Soil; Wildfires
PubMed: 36008619
DOI: 10.1038/s41564-022-01203-y