Severe coronavirus disease 2019 (COVID-19) is characterized by overproduction of immune mediators, but the role of interferons (IFNs) of the type I (IFN-I) or type III (IFN-III) families remains ...debated. We scrutinized the production of IFNs along the respiratory tract of COVID-19 patients and found that high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity. Production of specific IFN-III, but not IFN-I, members denotes patients with a mild pathology and efficiently drives the transcription of genes that protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In contrast, compared to subjects with other infectious or noninfectious lung pathologies, IFNs are overrepresented in the lower airways of patients with severe COVID-19 that exhibit gene pathways associated with increased apoptosis and decreased proliferation. Our data demonstrate a dynamic production of IFNs in SARS-CoV-2-infected patients and show IFNs play opposing roles at distinct anatomical sites.
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•IFN expression in COVID-19 varies based on location, viral load, age, and severity•IFN-λ1 and IFN-λ3 drive protective ISGs in the upper airways of mildly ill patients•Critical patients express IFN-αβ and IFN-λ2 and have low ISGs and high p53 expression•Epithelial cells efficiently produce protective IFN-λ1, while cDCs express IFN-λ2,3
An in-depth analysis of IFNs in COVID-19 reveals differences in their roles based on anatomical location, viral load, age, and disease severity. In the upper respiratory tract, high levels of IFN-III are protective and result in mild disease in spite of higher SARS-CoV-2 viral burden, while the lower airways of patients with severe COVID-19 demonstrate elevated IFN-I and IFN-III, cell death, and a reduction in IFN-stimulated genes.
Abstract Background The advent of molecular-based methods of identification and characterization of complex microbial populations has led to a new era of microbial discovery. A detailed and ...comprehensive analysis of the microbial ecosystem of the pathologic and healthy prostate tissues has not been yet reported. Objectives To characterize the microbiome possibly associated to the pathologic prostate microenvironment. Design, setting, and participants The microbiome profile of tumor, peri-tumor, and nontumor tissues was assessed on 16 radical prostatectomy-specimens. Outcome measurements and statistical analysis Microbiome analysis was assessed by massive ultradeep pyrosequencing. Bacteria load was expressed as a percentage of the total number of bacteria. The statistical significance of differences among specimen-groups was tested with Friedman's test (Dunn posthoc test) and Wilcoxon rank-sum test. Results and limitations Three phyla, six classes, nine orders, 14 families, and 11 genera were above the set threshold value of 1%, respectively. Significant differences in specific microbial populations among tumor/peri-tumor and nontumor prostate specimens were observed at certain taxonomic levels. Among genera, Propionibacterium spp. were the most abundant. Staphylococcus spp. were more represented in the tumor/peri-tumor tissues ( p < 0.05). The restricted number of specimens represents a potential limitation. Conclusions The prostate contains a plethora of bacteria, which set themselves within the gland with a distribution dependent on the nature of the tissue, thus suggesting a possible pathophysiological correlation between the composition of the local microbial niche and the presence of the tumor itself. Future studies will help to clarify the role of these specific bacteria and their potential to be exploited as new biomarkers. Patient summary The pathological prostate is populated by specific microbial populations, whose distribution varies according to the nature of the tissue. This finding opens interesting perspectives for the identification of novel therapeutic approaches and biomarkers.
The gut microbiota has been causally linked to cancer, yet how intestinal microbes influence progression of extramucosal tumors is poorly understood. Here we provide evidence implying that Prevotella ...heparinolytica promotes the differentiation of Th17 cells colonizing the gut and migrating to the bone marrow (BM) of transgenic Vk*MYC mice, where they favor progression of multiple myeloma (MM). Lack of IL-17 in Vk*MYC mice, or disturbance of their microbiome delayed MM appearance. Similarly, in smoldering MM patients, higher levels of BM IL-17 predicted faster disease progression. IL-17 induced STAT3 phosphorylation in murine plasma cells, and activated eosinophils. Treatment of Vk*MYC mice with antibodies blocking IL-17, IL-17RA, and IL-5 reduced BM accumulation of Th17 cells and eosinophils and delayed disease progression. Thus, in Vk*MYC mice, commensal bacteria appear to unleash a paracrine signaling network between adaptive and innate immunity that accelerates progression to MM, and can be targeted by already available therapies.
The extremely rapid spread of the SARS-CoV-2 has already resulted in more than 1 million reported deaths of coronavirus disease 2019 (COVID-19). The ability of infectious particles to persist on ...environmental surfaces is potentially considered a factor for viral spreading. Therefore, limiting viral diffusion in public environments should be achieved with correct disinfection of objects, tissues, and clothes. This study proves how two widespread disinfection systems, short-wavelength ultraviolet light (UV-C) and ozone (O3), are active in vitro on different commonly used materials. The development of devices equipped with UV-C, or ozone generators, may prevent the virus from spreading in public places.
The molecular basis underlying glioblastoma (GBM) heterogeneity and plasticity is not fully understood. Using transcriptomic data of human patient-derived brain tumor stem cell lines (BTSCs), ...classified based on GBM-intrinsic signatures, we identify the AP-1 transcription factor
as a key regulator of the mesenchymal (MES) subtype. We provide a mechanistic basis to the role of the neurofibromatosis type 1 gene (
), a negative regulator of the RAS/MAPK pathway, in GBM mesenchymal transformation through the modulation of
expression. Depletion of
in
-mutant human BTSCs and
-mutant mouse neural stem cells results in loss of the mesenchymal gene signature and reduction in stem cell properties and in vivo tumorigenic potential. Our data demonstrate that
controls GBM plasticity and aggressiveness in response to
alterations.
The gut microbiota modulates the autoimmune pathogenesis of type 1 diabetes (T1D) via mechanisms that remain largely unknown. The inflammasome components are innate immune sensors that are highly ...influenced by the gut environment and play pivotal roles in maintaining intestinal immune homeostasis. In this study we show that modifications of the gut microbiota induced by oral treatment with Lactobacillaceae-enriched probiotic VSL#3, alone or in combination with retinoic acid (RA), protect NOD mice from T1D by affecting inflammasome at the intestinal level. In particular, we show that VSL#3 treatment inhibits IL-1β expression while enhancing release of protolerogenic components of the inflammasome, such as indoleamine 2,3-dioxygenase (IDO) and IL-33. Those modifications of the intestinal microenvironment in VSL#3-treated NOD mice modulate gut immunity by promoting differentiation of tolerogenic CD103+ DCs and reducing differentiation/expansion of Th1 and Th17 cells in the intestinal mucosa and at the sites of autoimmunity, that is, within the pancreatic lymph nodes (PLN) of VSL#3-treated NOD mice. Our data provide a link between dietary factors, microbiota composition, intestinal inflammation, and immune homeostasis in autoimmune diabetes and could pave the way for new therapeutic approaches aimed at changing the intestinal microenvironment with probiotics to counterregulate autoimmunity and prevent T1D.
While the SARS-CoV-2 pandemic is heavily hitting the world, it is of extreme importance that significant in vitro observations guide the quick set up of clinical trials. In this study, we evidence ...that the anti-SARS-CoV2 activity of a clinically achievable hydroxychloroquine concentration is maximized only when administered before and after the infection of Vero E6 and Caco-2 cells. This suggests that only a combined prophylactic and therapeutic use of hydroxychloroquine may be effective in limiting viral replication in patients.While the SARS-CoV-2 pandemic is heavily hitting the world, it is of extreme importance that significant in vitro observations guide the quick set up of clinical trials. In this study, we evidence that the anti-SARS-CoV2 activity of a clinically achievable hydroxychloroquine concentration is maximized only when administered before and after the infection of Vero E6 and Caco-2 cells. This suggests that only a combined prophylactic and therapeutic use of hydroxychloroquine may be effective in limiting viral replication in patients.
Although highly active antiretroviral therapies (HAART) remarkably increased life expectancy of HIV positive people, the rate of novel HIV-1 infections worldwide still represent a major concern. In ...this context, pre-exposure prophylaxis (PrEP) approaches such as vaginal microbicide gels topically releasing antiretroviral drugs, showed to have a striking impact in limiting HIV-1 spread. Nevertheless, the co-presence of other genital infections, particularly those due to HSV-1 or 2, constitute a serious drawback that strongly limits the efficacy of PrEP approaches. For this reason, combinations of different compounds with mixed antiviral and antiretroviral activity are thoroughly investigated Here we report the synthesis and the biological evaluation of a novel series of rhodanine derivatives, which showed to inhibit both HIV-1 and HSV-1/2 replication at nanomolar concentration, and were found to be active also on acyclovir resistant HSV-2 strains. The compounds showed a considerable reduction of activity in presence of serum due to a high binding to serum albumin, as determined through in vitro ADME evaluations. However, the most promising compound of the series maintained a considerable activity in gel formulation, with an EC50 comparable to that obtained for the reference drug tenofovir. Moreover, the series of compounds showed pharmacokinetic properties suitable for topical formulation, thus suggesting that the novel rhodanine derivatives could represent effective agents to be used as dual anti HIV/HSV microbicides in PrEP approaches.
The integrity of the gut barrier (GB) is fundamental to regulate the crosstalk between the microbiota and the immune system and to prevent inflammation and autoimmunity at the intestinal level but ...also in organs distal from the gut such as the pancreatic islets. In support to this idea, we recently demonstrated that breakage of GB integrity leads to activation of islet-reactive T cells and triggers autoimmune Type 1 Diabetes (T1D). In T1D patients as in the NOD mice, the spontaneous model of autoimmune diabetes, there are alterations of the GB that specifically affect structure and composition of the mucus layer; however, it is yet to be determined whether a causal link between breakage of the GB integrity and occurrence of autoimmune T1D exists.
Here we restored GB integrity in the NOD mice through administration of an anti-inflammatory diet (AID- enriched in soluble fiber inulin and omega 3-PUFA) and tested the effect on T1D pathogenesis.
We found that the AID prevented T1D in NOD mice by restoring GB integrity with increased mucus layer thickness and higher mRNA transcripts of structural (Muc2) and immunoregulatory mucins (Muc1 and Muc3) as well as of tight junction proteins (claudin1). Restoration of GB integrity was linked to reduction of intestinal inflammation (i.e., reduced expression of IL-1β, IL-23 and IL-17 transcripts) and expansion of regulatory T cells (FoxP3
Treg cells and IL-10
Tr1 cells) at the expenses of effector Th1/Th17 cells in the intestine, pancreatic lymph nodes (PLN) and intra-islet lymphocytes (IIL) of AID-fed NOD mice. Importantly, the restoration of GB integrity and immune homeostasis were associated with enhanced concentrations of anti-inflammatory metabolites of the ω3/ω6 polyunsaturated fatty acids (PUFA) and arachidonic pathways and modifications of the microbiome profile with increased relative abundance of mucus-modulating bacterial species such as
and
.
Our data provide evidence that the restoration of GB integrity and intestinal immune homeostasis through administration of a tolerogenic AID that changed the gut microbial and metabolic profiles prevents autoimmune T1D in preclinical models.
(1) Background: Our aim is the evaluation of the neutralizing activity of BNT162b2 mRNA vaccine-induced antibodies in different in vitro cellular models, as this still represents one of the ...surrogates of protection against SARS-CoV-2 viral variants. (2) Methods: The entry mechanisms of SARS-CoV-2 in three cell lines (Vero E6, Vero E6/TMPRSS2 and Calu-3) were evaluated with both pseudoviruses and whole virus particles. The neutralizing capability of sera collected from vaccinated subjects was characterized through cytopathic effects and Real-Time RT PCR. (3) Results: In contrast to Vero E6 and Vero E6/TMPRSS2, Calu-3 allowed the evaluation of both viral entry mechanisms, resembling what occurs during natural infection. The choice of an appropriate cellular model can decisively influence the determination of the neutralizing activity of antibodies against SARS-CoV-2 variants. Indeed, the lack of correlation between neutralizing data in Calu-3 and Vero E6 demonstrated that testing the antibody inhibitory activity by using a single cell model possibly results in an inaccurate characterization. (4) Conclusions: Cellular systems allowing only one of the two viral entry pathways may not fully reflect the neutralizing activity of vaccine-induced antibodies moving increasingly further away from possible correlates of protection from SARS-CoV-2 infection.
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