High resistance barrier and prophylactic protection in preclinical models of SARS-CoV-2 with two siRNA combination
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ABSTRACT:
PROVIDER: PRJNA1159326 | ENA |
REPOSITORIES: ENA
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Project description:RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral RNA. We identified potent lipophilic small-interfering RNA (siRNA) conjugates targeting highly conserved regions of the SARS-CoV-2 outside of the spike-encoding region capable of achieving ≥3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single-siRNA approach. Viral resistance to single siRNA treatment occurred due to emergence of point mutations at critical positions required for siRNA-mediated target binding and cleavage, which led to a loss of siRNA efficacy. With a two-siRNA combination, emergence of mutations within the siRNA binding site was abolished. When delivered intranasally, two-siRNA combination protected Syrian hamsters from weight loss and lung pathology by viral infection upon prophylactic administration but not following onset of infection. Together, the data support potential utility of RNAi as a prophylactic approach with high resistance barrier to counteract SARS-CoV-2 emergent variants and complement vaccination. Most importantly, given that the siRNAs can be rapidly developed from a new pathogen sequence, this strategy has implications as a new type of preventive medicines that may protect against future coronavirus pandemics.
2024-12-04 | GSE276876 | GEO
Project description:Inhalation of ACE2-expressing lung spheroid cell exosomes provides prophylactic protection against SARS-CoV-2
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Project description:Continued emergence of SARS-CoV-2 variants of concern that are capable of escaping vaccine-induced immunity pose the urgency for developing new COVID-19 therapeutics. An essential mechanism for SARS-CoV-2 infection begins with the viral spike protein binding to the human ACE2. Consequently, inhibiting this interaction is a highly promising therapeutic strategy against COVID-19. Herein, we demonstrate that ACE2-expressing human lung spheroid cells (LSC)-derived exosomes (LSC-Exo) could function as a prophylactic agent to bind and neutralize SARS-CoV-2 and protect the host against SARS-CoV-2 infection. Inhalation of LSC-Exo facilitates their deposition and biodistribution throughout the whole lung in a female mouse model. We show that LSC-Exo blocks the interaction of SARS-CoV-2 with host cells in vitro and in vivo by neutralizing the virus. LSC-Exo treatment protected hamsters from SARS-CoV-2-induced disease and reduced viral loads. Furthermore, LSC-Exo intercept the entry of multiple SARS-CoV-2 variant pseudoviruses in female mice and show comparable or equal potency against the wild-type strain, demonstrating that LSC-Exo may act as broad-spectrum protectant against existing and emerging virus variants.
2024-01-13 | GSE249987 | GEO
Project description:Gene expression in histologically normal epithelium from breast cancer patients and cancer-free prophylactic mastectomy patients share a similar profile Introduction: We hypothesized that gene expression in histologically normal epithelium (NlEpi) would differ in breast cancer patients (HN) compared to usual-risk controls undergoing reduction mammoplasty (RM), and that gene expression in NlEpi from cancer-free prophylactic mastectomies from high-risk women (PM), would resemble HN gene expression. Methods: We analyzed gene expression in 73 NlEpi samples microdissected from frozen tissue. In 42 cases, we used Affymetrix HU133A microarrays to compare gene expression in 18 RM vs 18 age-matched HN (9 ER+, 9 ER-) and 6 PM. Data were validated with qPCR in 31 independent NlEpi samples (8 RM, 17 HN, 6 PM). Results: 98 probesets (86 genes) were differentially expressed between RM and HN samples. Perfoming supervised hierarchical analysis with these 98 probesets, PM and HN samples clustered together, away from RM samples. qPCR validation of independent samples was high (84%) and uniform in RM vs HN, and lower (58%), but more heterogeneous, in RM vs PM. The 86 genes were implicated in many processes including transcription and the MAPK pathway. Conclusion: Gene expression differs between NlEpi of cancer cases and controls. The cancer cases' profile can be discerned in high-risk NlEpi. This suggests that the profile is not an effect of the tumor, but may mark increased risk and reveal breast cancer's earliest genomic changes. We determined that 98 probesets significantly differed between reduction mammoplasty and histologically normal epithelium from breast cancer patients. We also found that the histologically normal epithelium from prophylactic mastectomy patients' gene expression was more similar to histologically normal epithelium from breast cancer patients' than to reduction mammoplasty patients' gene expression. These results demonstrate that gene expression differs between NlEpi of cancer cases and controls. The cancer casesâ?? profile can be discerned in high-risk NlEpi. This suggests that the profile is not an effect of the tumor, but may mark increased risk and reveal breast cancer's earliest genomic changes. 42 total laser capture microdissected histologically normal breast tissue samples were analyzed with Affymetrix HU133A microarrays. 36 samples were age-matched between reduction mammoplasty (n=18) and histologically normal epithelial samples from breast cancer patients (n=18; 9ER+, 9ER-). 6 histologically normal epithelial samples from prophylactic mastectomy patients were then compared to data generated from the original 36 sample comparison. Sample numbers correspond to individual patient samples.
2010-06-08 | E-GEOD-20437 | biostudies-arrayexpress
Project description:Deficiency in IL-36R antagonist caused by loss of function mutations in IL-36RN leads to DITRA (1), a rare inflammatory human disease that belongs to a subgroup of Generalized Pustular Psoriasis (GPP). Herein, we report a novel functional genetic mouse model of DITRA with enhanced IL-36R signaling analogous to one observed in DITRA patients which supports and provides new insight in our understanding of IL-36 family of molecules in regulating barrier integrity across multiple tissues. Humanized DITRA-like mice displayed increased skin inflammation in preclinical model of psoriasis, and in vivo blockade of IL-36R pathway using anti-human IL-36R antibody ameliorated IMQ-induced skin pathology at both prophylactic and therapeutic treatments. Deeper characterization of the humanized DITRA-like mice revealed that deregulated IL-36R signaling promoted tissue pathology during intestinal injury and led to impairment in mucosal restoration in the repair phase of chronic DSS-induced colitis. Blockade of IL-36R pathway significantly ameliorated DSS-induced intestinal inflammation and rescued the inability of DITRA-like mice to recover from mucosal damage in vivo. Thus, our results indicate a central role for IL-36 in regulating the pro-inflammatory responses in the skin and epithelial barrier function in the intestine suggesting a new therapeutic potential for IL-36R axis in psoriasis and at the later stages of intestinal pathology.
2020-12-18 | GSE161406 | GEO
Project description:We demonstrated that lung spheroid cell derived exosomes (LSC-Exo) carry the parental cell’s ACE2 that are able to target lung, intercept SARS-CoV-2 entry, confer protection against SARS-CoV-2 infection. This LSC-Exo prophylaxis paradigm would not be limited by viral evolution, showing great potential for emerged SARS-CoV-2 variants, including those that are yet to emerge.
2024-01-13 | PXD047542 | Pride
Project description:Protection of the mucosal barrier by dual IgM and IgG bacterial coating in the absence of IgA
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Project description:The epidermal barrier protects the body against mechanical injury, infection and dehydration. The respective contribution of type I and type II keratins which form the major cytoskeleton in epidermal keratinocytes in barrier formation and stress protection is incompletely understood. Here, we reveal a novel mechanism by which keratins control anti-oxidant responses through barrier-dependent and cell-autonomous mechanisms. Mice lacking the entire type I (KtyI) or type II (KtyII) keratin gene clusters suffer from distinct prenatal barrier defects. Comparative transcriptome profiling identifies essential cornified envelope components and reveals strong upregulation of the bZIP transcription factor Nrf2 in situ. Isolated keratinocytes from both strains of mice show elevated mitochondrial oxygen consumption and Nrf2 activity, decreased upon keratin re-expression. We propose a model in which keratins control mitochondria-derived oxidative stress via Nrf2 activation. Our findings reveal major contributions of keratins to chronic inflammation and autoimmune disorders. Total RNA obtained from E18.5 embryo back skin from typeI and II keratin knockout compared with respective wild type.
2016-03-26 | E-GEOD-79590 | biostudies-arrayexpress
Project description:The blood-brain barrier (BBB) is an evolutionary conserved tissue interface that possesses potent chemical protection properties functioning to strictly modulate the central nervous system (CNS) microenvironment. These same properties, including tight cellular junctions and efflux transporters, also limit access of CNS-active pharmaceuticals. For this reason, understanding the molecular mechanisms that regulate BBB chemical protection is of great biomedical interest. The BBB of Drosophila consists of two surface glia layers that completely surround the brain. This tissue interface contains both “tight” cellular junctions (termed septate junctions) and drug efflux transporters; thus, the Drosophila BBB can potentially serve as a model for understanding complex regulation of BBB physiology. In this study, we show reciprocal compensatory responses following disruption of critical BBB genes: deletion of the septate junction regulator Moody causes increased drug efflux and up-regulation of the P-glycoprotein ortholog Mdr65; conversely, disruption of Mdr65 expression causes increased septate junction tightness and up-regulation of Moody. We reveal these homeostatic interactions with physiologic observations, gene expression data, and anatomical images of the BBB surface. Whole brain microarray data point to responses that are consistent with our physiologic observations and these responses are likely localized to the BBB. To our knowledge, this is the first observation of a reciprocal compensatory interaction at a tissue barrier. Furthermore, this study paves the way for future studies elucidating the direct pathways that link GPCR signaling and drug transporter regulation at the BBB. The main comparisons are between WT_new, C17 (Moody null), and PMdr65 (Mdr65 null). Since WT_new were processed on a different day than C17 and PMdr65, we also included another WT sample (WT_old) to control for genes that change depending on batch effects. Since the mutants are also in a different genetic background than WT, we also included a control that is in a similar background (UAS_control).
2013-12-31 | E-GEOD-46550 | biostudies-arrayexpress
Project description:Disruption of blood-brain barrier (BBB) integrity is a hallmark of several neurological disorders. Here we show that the BBB is dynamically and differentially affected during the preclinical, progression and remission phase of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We isolated vascular fragments, representing the BBB, from spinal cords of imatinib and PBS treated mice at the preclinical, progression and remission phase of MOG-EAE as well as from non-immunized, naive mice.
2020-12-25 | GSE150562 | GEO