scholarly journals RILEVANZA DEL SESSO NELLA MALATTIA DA COVID-19: QUANDO UN CROMOSOMA IN PIÙ FA LA DIFFERENZA!

2021 ◽  
Author(s):  
Lidia Larizza
Keyword(s):  
Immune Response ◽  
Intensive Care ◽  
Intensive Care Units ◽  
X Chromosome ◽  
Meta Analysis ◽  
Epigenetic Mechanism ◽  
Type I ◽  
Loss Of Function ◽  
Dutch Study

Meta-analysis of epidemiological world-wide reports of SARS-CoV-2 patients requiring mechanical ventilation in intensive care units highlighted the male sex as a risk factor for severe, often fatal evolution of COVID-19 disease, as signaled by previous coronavirus infections. X chromosome inactivation (XCI), an epigenetic mechanism used by female somatic cells to equalize the dosage of X-linked genes between the sexes and the female advantage with mosaicism of the numerous immune-related genes and the increased expression of those escaping XCI determined a growing recognition of the unique biology of the X chromosome to account for females more robust immune response. In the wake of studies aimed at establishing the contribution of immune-regulatory X-linked genes to sex-specific differences of COVID-19 disease, the expression of TLR7, a gene of innate immune response encoding a member of Toll-like family receptors sensing the SARS-CoV-2 endosomal RNA, has been quantified in human female plasmacytoid dendritic cells which are high producers of interferons, acting as powerful viral inhibitors. The study confirmed that TLR7 escapes XCI promoting higher TLR7 mRNA and higher interferon mRNA at the single-cell level. The relevance of TLR7 signaling has been highlighted by a Dutch study exploring the presence of genetic variants among young men with severe COVID-19 which identified pathogenic TLR7 variants in two pairs of brothers (mean age 26 years) without medical history admitted to intensive care units due to SARS-CoV-2 acute respiratory syndrome, one of whom deceased due to septic shock. Whole exome sequencing of the patients identified “loss of function variants” of the X-chromosomal TLR7 and functional studies on their peripheral blood mononucleate cells after in vitro stimulation with a TLR7 agonist showed significant reduction of TLR7-specific mRNA and decreased mRNA expression of various interferon type I genes as compared to family members and controls. While rare mutations in TLR7 are unlikely to be a major drive of severe COVID-19 disease, their identification begins to unravel the molecular underpinning of COVID-19 infection highlighting TLR7 receptor as a critical node in recognizing SARS-CoV-2 and initiating an early immune response to clear the virus and prevent the development of COVID-19.

High content screening and computational prediction reveal viral genes that suppress innate immune response

2021 ◽  
Author(s):  
Tai L Ng ◽  
Erika J Olson ◽  
Tae Yeon Yoo ◽  
H. Sloane Weiss ◽  
Yukiye Koide ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Nuclear Transport ◽  
Computational Prediction ◽  
Viral Proteins ◽  
Innate Immune ◽  
Type I ◽  
Viral Genes ◽  
Genes Encoding

Suppression of the host innate immune response is a critical aspect of viral replication. Upon infection, viruses may introduce one or more proteins that inhibit key immune pathways, such as the type I interferon pathway. However, the ability to predict and evaluate viral protein bioactivity on targeted pathways remains challenging and is typically done on a single virus/gene basis. Here, we present a medium-throughput high-content cell-based assay to reveal the immunosuppressive effects of viral proteins. To test the predictive power of our approach, we developed a library of 800 genes encoding known, predicted, and uncharacterized human viral genes. We find that previously known immune suppressors from numerous viral families such as Picornaviridae and Flaviviridae recorded positive responses. These include a number of viral proteases for which we further confirmed that innate immune suppression depends on protease activity. A class of predicted inhibitors encoded by Rhabdoviridae viruses was demonstrated to block nuclear transport, and several previously uncharacterized proteins from uncultivated viruses were shown to inhibit nuclear transport of the transcription factors NF-kB and IRF3. We propose that this pathway-based assay, together with early sequencing, gene synthesis, and viral infection studies, could partly serve as the basis for rapid in vitro characterization of novel viral proteins.

scholarly journals Estimating the Case Fatality Risk of COVID-19 using Cases from Outside China

2020 ◽  
Author(s):  
Nick Wilson ◽  
Amanda Kvalsvig ◽  
Lucy Telfar Barnard ◽  
Michael G Baker
Keyword(s):  
Intensive Care ◽  
Intensive Care Units ◽  
Meta Analysis ◽  
Case Fatality ◽  
Large Uncertainty ◽  
Icu Patients ◽  
Fatality Risk ◽  
Case Fatality Risk ◽  
Respiratory Conditions

AbstractThere is large uncertainty around the case fatality risk (CFR) for COVID-19 in China. Therefore, we considered symptomatic cases outside of China (countries/settings with 20+ cases) and the proportion who are in intensive care units (4.0%, 14/349 on 13 February 2020). Given what is known about CFRs for ICU patients with severe respiratory conditions from a meta-analysis, we estimated a CFR of 1.37% (95%CI: 0.57% to 3.22%) for COVID- 19 cases outside of China.

scholarly journals Overview on the Prevalence of Fungal Infections, Immune Response, and Microbiome Role in COVID-19 Patients

2021 ◽  
Vol 7 (9) ◽  
pp. 720
Author(s):  
Maryam Roudbary ◽  
Sunil Kumar ◽  
Awanish Kumar ◽  
Lucia Černáková ◽  
Fatemeh Nikoomanesh ◽  
...  
Keyword(s):  
Immune Response ◽  
Intensive Care ◽  
Intensive Care Units ◽  
Fungal Infections ◽  
Fungal Species ◽  
Fungal Diseases ◽  
Severe Illness ◽  
Rising Incidence ◽  
Cryptococcus Spp

Patients with severe COVID-19, such as individuals in intensive care units (ICU), are exceptionally susceptible to bacterial and fungal infections. The most prevalent fungal infections are aspergillosis and candidemia. Nonetheless, other fungal species (for instance, Histoplasma spp., Rhizopus spp., Mucor spp., Cryptococcus spp.) have recently been increasingly linked to opportunistic fungal diseases in COVID-19 patients. These fungal co-infections are described with rising incidence, severe illness, and death that is associated with host immune response. Awareness of the high risks of the occurrence of fungal co-infections is crucial to downgrade any arrear in diagnosis and treatment to support the prevention of severe illness and death directly related to these infections. This review analyses the fungal infections, treatments, outcome, and immune response, considering the possible role of the microbiome in these patients. The search was performed in Medline (PubMed), using the words “fungal infections COVID-19”, between 2020–2021.

scholarly journals Handwash versus hand-rub practices for preventing nosocomial infection in hospital intensive care units: A systematic review and meta-analysis

2020 ◽  
pp. 82-90
Author(s):  
S Bello ◽  
EA Bamgboye ◽  
DT Ajayi ◽  
EN Ossai ◽  
EC Aniwada ◽  
...  
Keyword(s):  
Systematic Review ◽  
Intensive Care ◽  
Adverse Events ◽  
Nosocomial Infection ◽  
Intensive Care Units ◽  
Meta Analysis ◽  
Healthcare Providers ◽  
Length Of Hospital Stay ◽  
Clinical Effectiveness ◽  
Infection Rates

Background: Compliance with handwashing in busy healthcare facilities, such as intensive care units (ICUs), is suboptimal and alcohol hand-rub preparations have been suggested to improve compliance. There is no evidence on the comparative effectiveness between handwash and hand-rub strategies. This systematic review was to assess the effectiveness of handwash versus hand-rub strategies for preventing nosocomial infection in ICUs. Methods Studies conducted in ICUs and indexed in PubMed comparing the clinical effectiveness and adverse events between handwash and hand-rub groups were included in a systematic review. The primary outcome was nosocomial infection rates. Secondary outcomes included microbial counts on healthcare providers’ hands, mortality rates, patient/hospital cost of treatment of healthcare-associated infections (HCAIs), length of ICU/hospital stays, and adverse events. Studies were independently screened and data extracted by at least two authors. Meta-analyses of risk ratios (RR), incidence rate ratios (IRR), odds ratios (OR) and mean differences (MD), were conducted using the RevMan 5.3 software. Results: Seven studies published between 1992-2009 and involving a total of 11,663 patients were included. Five studies (10,981 patients) contributed data to the ICU acquired nosocomial infection rates. The pooled IRR was 0.71 (95% CI 0.61, 0.82; I2 = 94%). On sensitivity analysis, pooled IRR was 0.39 (95% CI 0.32, 0.48; 4 studies; 8,247 patients; I2 = 0%) in favour of hand rub. The pooled OR for mortality was 0.95 (95% CI 0.78, 1.61; 4 studies; 3,475 patients; I2 = 39%). The pooled MD for length of hospital stay was -0.74 (95% CI -2.83, 1.34; 3 studies; 741 patients; I2 = 0%). The pooled OR for an undesirable skin effect was 0.37 (95% CI 0.23, 0.60; 3 studies;1504 patients; I2 = 0%) in favour of hand rub. Overall quality of evidence was low. Conclusion: Hand rub appeared more effective when compared to handwash in ICUs.

scholarly journals A Trifecta of New Insights into Ovine Footrot for Infection Drivers, Immune Response and Host Pathogen Interactions.

2021 ◽  
Author(s):  
Adam M. Blanchard ◽  
Ceri E. Staley ◽  
Laurence Shaw ◽  
Sean R Wattegedera ◽  
Christina-Marie Baumbach ◽  
...  
Keyword(s):  
Immune Response ◽  
Type I Collagen ◽  
Global Analysis ◽  
Bacterial Species ◽  
Skin Barrier ◽  
Control Measures ◽  
Skin Barrier Function ◽  
Type I ◽  
Bacterial Populations

Footrot is a polymicrobial infectious disease in sheep causing severe lameness, leading to one of the industry’s biggest welfare problems. The complex aetiology of footrot makes in-situ or in-vitro investigations difficult. Computational methods offer a solution to understanding the bacteria involved, how they may interact with the host and ultimately providing a way to identify targets for future hypotheses driven investigative work. Here we present the first combined global analysis of the bacterial community transcripts together with the host immune response in healthy and diseased ovine feet during a natural polymicrobial infection state using metatranscriptomics. The intra tissue and surface bacterial populations and the most abundant bacterial transcriptome were analysed, demonstrating footrot affected skin has a reduced diversity and increased abundances of, not only the causative bacteria Dichelobacter nodosus , but other species such as Mycoplasma fermentans and Porphyromonas asaccharolytica . Host transcriptomics reveals a suppression of biological processes relating to skin barrier function, vascular functions, and immunosurveillance in unhealthy interdigital skin, supported by histological findings that type I collagen (associated with scar tissue formation) is significantly increased in footrot affected interdigital skin comparted to outwardly healthy skin. Finally, we provide some interesting indications of host and pathogen interactions associated with virulence genes and the host spliceosome which could lead to the identification of future therapeutic targets. Impact Statement Lameness in sheep is a global welfare and economic concern and footrot is the leading cause of lameness, affecting up to 70% of flocks in the U.K. Current methods for control of this disease are labour intensive and account for approximately 65% of antibiotic use in sheep farming, whilst preventative vaccines suffer from poor efficacy due to antigen competition. Our limited understanding of cofounders, such as strain variation and polymicrobial nature of infection mean new efficacious, affordable and scalable control measures are not receiving much attention. Here we examine the surface and intracellular bacterial populations and propose potential interactions with the host. Identification of these key bacterial species involved in the initiation and progression of disease and the host immune mechanisms could help form the basis of new therapies.

A transcriptional and post-transcriptional dysregulation of Dishevelled 1 and 2 underlies the Wnt signaling impairment in type I Gaucher disease experimental models

2019 ◽  
Vol 29 (2) ◽  
pp. 274-285 ◽  
Author(s):  
Roberto Costa ◽  
Stefania Bellesso ◽  
Susanna Lualdi ◽  
Rosa Manzoli ◽  
Valeria Pistorio ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Gaucher Disease ◽  
Wnt Pathway ◽  
Experimental Models ◽  
Type I ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Bone Differentiation

Abstract Bone differentiation defects have been recently tied to Wnt signaling alterations occurring in vitro and in vivo Gaucher disease (GD) models. In this work, we provide evidence that the Wnt signaling multi-domain intracellular transducers Dishevelled 1 and 2 (DVL1 and DVL2) may be potential upstream targets of impaired beta glucosidase (GBA1) activity by showing their misexpression in different type 1 GD in vitro models. We also show that in Gba mutant fish a miR-221 upregulation is associated with reduced dvl2 expression levels and that in type I Gaucher patients single-nucleotide variants in the DVL2 3′ untranslated region are related to variable canonical Wnt pathway activity. Thus, we strengthen the recently outlined relation between bone differentiation defects and Wnt/β-catenin dysregulation in type I GD and further propose novel mechanistic insights of the Wnt pathway impairment caused by glucocerebrosidase loss of function.

scholarly journals Angiostatic activity of the antitumor cytokine interleukin-21

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4940-4947 ◽  
Author(s):  
Karolien Castermans ◽  
Sebastien P. Tabruyn ◽  
Rong Zeng ◽  
Judy R. van Beijnum ◽  
Cheryl Eppolito ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Angiogenesis ◽  
Chorioallantoic Membrane ◽  
Antitumor Immune Response ◽  
In Vivo Studies ◽  
Type I ◽  
Stat3 Phosphorylation ◽  
Interleukin 21

Abstract Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ongoing. IL-21 belongs to the type I cytokine family of which other members, ie, IL-2, IL-15, and IL-4, have been shown to exert activities on vascular endothelial cells (ECs). We hypothesized that IL-21, in addition to inducing the antitumor immune response, also inhibits tumor angiogenesis. In vitro experiments showed a decrease of proliferation and sprouting of activated ECs after IL-21 treatment. We found that the IL-21 receptor is expressed on vascular ECs. Furthermore, in vivo studies in the chorioallantoic membrane of the chick embryo and in mouse tumors demonstrated that IL-21 treatment disturbs vessel architecture and negatively affects vessel outgrowth. Our results also confirm the earlier suggested angiostatic potential of IL-2 in vitro and in vivo. The angiostatic effect of IL-21 is confirmed by the decrease in expression of angiogenesis-related genes. Interestingly, IL-21 treatment of ECs leads to a decrease of Stat3 phosphorylation. Our research shows that IL-21 is a very powerful antitumor compound that combines the induction of an effective antitumor immune response with inhibition of tumor angiogenesis.

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