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Veterinary Microbiology Jun 2024Rabies, caused by lyssavirus rabies (Rabies lyssavirus, RABV), is a fatal disease among humans and almost all warm-blooded animals. In this study, we found that RABV...
Rabies, caused by lyssavirus rabies (Rabies lyssavirus, RABV), is a fatal disease among humans and almost all warm-blooded animals. In this study, we found that RABV infection induces the up-regulation of receptor transporter protein 4 (RTP4) in mouse brains and different cells of nervous tissue. Over-expression of RTP4 reduces the viral titer of RABV in different neuronal cells. Furthermore, a recombinant RABV expressing RTP4, named rRABV-RTP4, was constructed and displayed a lower viral titer in different neuronal cells due to the expression of RTP4. Moreover, the survival rates of mice infected with rRABV-RTP4 were significantly higher than those of mice infected with parent virus rRABV or control virus rRABV-RTP4(-). In terms of mechanism, RTP4 could bind viral genomic RNA (vRNA) of RABV, and suppress the whole viral genome amplification. In addition, we found that the zinc finger domain (ZFD) of RTP4 exerts the antiviral function by truncation analysis, and an important amino acids site (C95) in the RTP4 3CxxC motif which is essential for its antiviral function was identified by mutation analysis. This study contributes to our understanding of how RTP4 or other RTP proteins play a role in defense against the invasion of RABV or other viruses.
PubMed: 38941768
DOI: 10.1016/j.vetmic.2024.110159 -
Water Research Jun 2024Metals in the drinking water distribution system (DWDS) play an important role on the fate of disinfection by-products (DBPs). They can increase the formation of DBPs... (Review)
Review
Metals in the drinking water distribution system (DWDS) play an important role on the fate of disinfection by-products (DBPs). They can increase the formation of DBPs through several mechanisms, such as enhancing the proportion of reactive halogen species (RHS), catalysing the reaction between natural organic matter (NOM) and RHS through complexation, or by increasing the conversion of NOM into DBP precursors. This review comprehensively summarizes these complex processes, focusing on the most important metals (copper, iron, manganese) in DWDS and their impact on various DBPs. It organizes the dispersed 'metals-DBPs' experimental results into an easily accessible content structure and presents their underlying common or unique mechanisms. Furthermore, the practically valuable application directions of these research findings were analysed, including the toxicity changes of DBPs in DWDS under the influence of metals and the potential enhancement of generalization in DBP model research by the introduction of metals. Overall, this review revealed that the metal environment within DWDS is a crucial factor influencing DBP levels in tap water.
PubMed: 38941679
DOI: 10.1016/j.watres.2024.121991 -
Annual Review of Immunology Jun 2024The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities... (Review)
Review
The COVID-19 pandemic was caused by the recently emerged β-coronavirus SARS-CoV-2. SARS-CoV-2 has had a catastrophic impact, resulting in nearly 7 million fatalities worldwide to date. The innate immune system is the first line of defense against infections, including the detection and response to SARS-CoV-2. Here, we discuss the innate immune mechanisms that sense coronaviruses, with a focus on SARS-CoV-2 infection and how these protective responses can become detrimental in severe cases of COVID-19, contributing to cytokine storm, inflammation, long-COVID, and other complications. We also highlight the complex cross talk among cytokines and the cellular components of the innate immune system, which can aid in viral clearance but also contribute to inflammatory cell death, cytokine storm, and organ damage in severe COVID-19 pathogenesis. Furthermore, we discuss how SARS-CoV-2 evades key protective innate immune mechanisms to enhance its virulence and pathogenicity, as well as how innate immunity can be therapeutically targeted as part of the vaccination and treatment strategy. Overall, we highlight how a comprehensive understanding of innate immune mechanisms has been crucial in the fight against SARS-CoV-2 infections and the development of novel host-directed immunotherapeutic strategies for various diseases.
Topics: Humans; Immunity, Innate; COVID-19; SARS-CoV-2; Cytokine Release Syndrome; Cytokines; Animals; Coronavirus Infections; Immune Evasion
PubMed: 38941608
DOI: 10.1146/annurev-immunol-083122-043545 -
Annual Review of Immunology Jun 2024Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (T) cells are strategically... (Review)
Review
Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (T) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies. Consequently, modulating T cell populations represents an attractive strategy for novel vaccination and therapeutic interventions against tissue-based diseases. Here, we provide an updated overview of T cell heterogeneity and function across tissues and disease states. We discuss mechanisms of T cell-mediated immune protection and their potential contributions to autoimmune disorders. Finally, we examine how T cell responses might be durably boosted or dampened for therapeutic gain.
Topics: Humans; Animals; Immunologic Memory; Memory T Cells; Autoimmune Diseases; Organ Specificity; T-Lymphocyte Subsets; Immunologic Surveillance
PubMed: 38941605
DOI: 10.1146/annurev-immunol-101320-020220 -
The endosymbiont increases resistance to pathogens by enhancing iron sequestration and melanization.MBio Jun 2024Facultative endosymbiotic bacteria, such as and species, are commonly found in association with insects and can dramatically alter their host physiology. Many...
UNLABELLED
Facultative endosymbiotic bacteria, such as and species, are commonly found in association with insects and can dramatically alter their host physiology. Many endosymbionts are defensive and protect their hosts against parasites or pathogens. Despite the widespread nature of defensive insect symbioses and their importance for the ecology and evolution of insects, the mechanisms of symbiont-mediated host protection remain poorly characterized. Here, we utilized the fruit fly and its facultative endosymbiont to characterize the mechanisms underlying symbiont-mediated host protection against bacterial and fungal pathogens. Our results indicate a variable effect of on infection outcome, with endosymbiont-harboring flies being more resistant to , and but more sensitive or as sensitive as endosymbiont-free flies to the infections with species. Further focusing on the protective effect, we identified Transferrin-mediated iron sequestration induced by as being crucial for the defense against and . In the case of , enhanced melanization in -harboring flies plays a major role in protection. Both iron sequestration and melanization induced by require the host immune sensor protease Persephone, suggesting a role of proteases secreted by the symbiont in the activation of host defense reactions. Hence, our work reveals a broader defensive range of than previously appreciated and adds nutritional immunity and melanization to the defensive arsenal of symbionts.
IMPORTANCE
Defensive endosymbiotic bacteria conferring protection to their hosts against parasites and pathogens are widespread in insect populations. However, the mechanisms by which most symbionts confer protection are not fully understood. Here, we studied the mechanisms of protection against bacterial and fungal pathogens mediated by the endosymbiont . We demonstrate that besides the previously described protection against wasps and nematodes, also confers increased resistance to pathogenic bacteria and fungi. We identified -induced iron sequestration and melanization as key defense mechanisms. Our work broadens the known defense spectrum of and reveals a previously unappreciated role of melanization and iron sequestration in endosymbiont-mediated host protection. We propose that the mechanisms we have identified here may be of broader significance and could apply to other endosymbionts, particularly to , and potentially explain their protective properties.
PubMed: 38940615
DOI: 10.1128/mbio.00936-24 -
Applied and Environmental Microbiology Jun 2024Enterotoxigenic (ETEC) is a diverse and poorly characterized pathotype that causes diarrhea in humans and animals. Phages have been proposed for the veterinary...
Enterotoxigenic (ETEC) is a diverse and poorly characterized pathotype that causes diarrhea in humans and animals. Phages have been proposed for the veterinary biocontrol of ETEC, but effective solutions require understanding of porcine ETEC diversity that affects phage infection. Here, we sequenced and analyzed the genomes of the PHAGEBio ETEC collection, gathering 79 diverse ETEC strains isolated from European pigs with post-weaning diarrhea (PWD). We identified the virulence factors characterizing the pathotype and several antibiotic resistance genes on plasmids, while phage resistance genes and other virulence factors were mostly chromosome encoded. We experienced that ETEC strains were highly resistant to phage infection. It was only by enrichment of numerous diverse samples with different media and conditions, using the 41 ETEC strains of our collection as hosts, that we could isolate two lytic phages that could infect a large part of our diverse ETEC collection: vB_EcoP_ETEP21B and vB_EcoS_ETEP102. Based on genome and host range analyses, we discussed the infection strategies of the two phages and identified components of lipopolysaccharides ( LPS) as receptors for the two phages. Our detailed computational structural analysis highlights several loops and pockets in the tail fibers that may allow recognition and binding of ETEC strains, also in the presence of O-antigens. Despite the importance of receptor recognition, the diversity of the ETEC strains remains a significant challenge for isolating ETEC phages and developing sustainable phage-based products to address ETEC-induced PWD.IMPORTANCEEnterotoxigenic (ETEC)-induced post-weaning diarrhea is a severe disease in piglets that leads to weight loss and potentially death, with high economic and animal welfare costs worldwide. Phage-based approaches have been proposed, but available data are insufficient to ensure efficacy. Genome analysis of an extensive collection of ETEC strains revealed that phage defense mechanisms were mostly chromosome encoded, suggesting a lower chance of spread and selection by phage exposure. The difficulty in isolating lytic phages and the molecular and structural analyses of two ETEC phages point toward a multifactorial resistance of ETEC to phage infection and the importance of extensive phage screenings specifically against clinically relevant strains. The PHAGEBio ETEC collection and these two phages are valuable tools for the scientific community to expand our knowledge on the most studied, but still enigmatic, bacterial species-.
PubMed: 38940562
DOI: 10.1128/aem.00807-24 -
MBio Jun 2024Autophagy is an important biological process in host defense against viral infection. However, many viruses have evolved various strategies to disrupt the host antiviral...
UNLABELLED
Autophagy is an important biological process in host defense against viral infection. However, many viruses have evolved various strategies to disrupt the host antiviral system. Porcine reproductive and respiratory syndrome virus (PRRSV) is a typical immunosuppressive virus with a large economic impact on the swine industry. At present, studies on the escape mechanism of PRRSV in the autophagy process, especially through chaperone-mediated autophagy (CMA), are limited. This study confirmed that PRRSV glycoprotein 5 (GP5) could disrupt the formation of the GFAP-LAMP2A complex by inhibiting the MTORC2/PHLPP1/GFAP pathway, promoting the dissociation of the pGFAP-EF1α complex, and blocking the K63-linked polyubiquitination of LAMP2A to inhibit the activity of CMA. Further research demonstrated that CMA plays an anti-PRRSV role by antagonizing nonstructural protein 11 (NSP11)-mediated inhibition of type I interferon (IFN-I) signaling. Taken together, these results indicate that PRRSV GP5 inhibits the antiviral effect of CMA by targeting LAMP2A. This research provides new insight into the escape mechanism of immunosuppressive viruses in CMA.
IMPORTANCE
Viruses have evolved sophisticated mechanisms to manipulate autophagy to evade degradation and immune responses. Porcine reproductive and respiratory syndrome virus (PRRSV) is a typical immunosuppressive virus that causes enormous economic losses in the swine industry. However, the mechanism by which PRRSV manipulates autophagy to defend against host antiviral effects remains unclear. In this study, we found that PRRSV GP5 interacts with LAMP2A and disrupts the formation of the GFAP-LAMP2A complex, thus inhibiting the activity of CMA and subsequently enhancing the inhibitory effect of the NSP11-mediated IFN-I signaling pathway, ultimately facilitating PRRSV replication. Our study revealed a novel mechanism by which PRRSV escapes host antiviral effects through CMA, providing a potential host target, LAMP2A, for developing antiviral drugs and contributing to understanding the escape mechanism of immunosuppressive viruses.
PubMed: 38940560
DOI: 10.1128/mbio.00532-24 -
Bioinformatics (Oxford, England) Jun 2024Electronic health records (EHRs) represent a comprehensive resource of a patient's medical history. EHRs are essential for utilizing advanced technologies such as deep...
MOTIVATION
Electronic health records (EHRs) represent a comprehensive resource of a patient's medical history. EHRs are essential for utilizing advanced technologies such as deep learning (DL), enabling healthcare providers to analyze extensive data, extract valuable insights, and make precise and data-driven clinical decisions. DL methods such as recurrent neural networks (RNN) have been utilized to analyze EHR to model disease progression and predict diagnosis. However, these methods do not address some inherent irregularities in EHR data such as irregular time intervals between clinical visits. Furthermore, most DL models are not interpretable. In this study, we propose two interpretable DL architectures based on RNN, namely time-aware RNN (TA-RNN) and TA-RNN-autoencoder (TA-RNN-AE) to predict patient's clinical outcome in EHR at the next visit and multiple visits ahead, respectively. To mitigate the impact of irregular time intervals, we propose incorporating time embedding of the elapsed times between visits. For interpretability, we propose employing a dual-level attention mechanism that operates between visits and features within each visit.
RESULTS
The results of the experiments conducted on Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Alzheimer's Coordinating Center (NACC) datasets indicated the superior performance of proposed models for predicting Alzheimer's Disease (AD) compared to state-of-the-art and baseline approaches based on F2 and sensitivity. Additionally, TA-RNN showed superior performance on the Medical Information Mart for Intensive Care (MIMIC-III) dataset for mortality prediction. In our ablation study, we observed enhanced predictive performance by incorporating time embedding and attention mechanisms. Finally, investigating attention weights helped identify influential visits and features in predictions.
AVAILABILITY AND IMPLEMENTATION
https://github.com/bozdaglab/TA-RNN.
Topics: Electronic Health Records; Neural Networks, Computer; Humans; Deep Learning; Alzheimer Disease
PubMed: 38940180
DOI: 10.1093/bioinformatics/btae264 -
Frontiers in Bioscience (Landmark... Jun 2024This study investigated the mechanism by which tazarotene-induced gene 1 (TIG1) inhibits melanoma cell growth. The main focus was to analyze downstream genes regulated...
BACKGROUND
This study investigated the mechanism by which tazarotene-induced gene 1 (TIG1) inhibits melanoma cell growth. The main focus was to analyze downstream genes regulated by TIG1 in melanoma cells and its impact on cell growth.
METHODS
The effects of TIG1 expression on cell viability and death were assessed using water-soluble tetrazolium 1 (WST-1) mitochondrial staining and lactate dehydrogenase release assays. RNA sequencing and Western blot analysis were employed to investigate the genes regulated by TIG1 in melanoma cells. Additionally, the correlation between expression and its downstream genes was analyzed in a melanoma tissue array.
RESULTS
TIG1 expression in melanoma cells was associated with decreased cell viability and increased cell death. RNA-sequencing (RNA-seq), quantitative reverse transcription PCR (reverse RT-QPCR), and immunoblots revealed that TIG1 expression induced the expression of Endoplasmic Reticulum (ER) stress response-related genes such as Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 (HERPUD1), Binding immunoglobulin protein (BIP), and DNA damage-inducible transcript 3 (DDIT3). Furthermore, analysis of the melanoma tissue array revealed a positive correlation between expression and the expression of , , and . Additionally, attenuation of the ER stress response in melanoma cells weakened the impact of TIG1 on cell growth.
CONCLUSIONS
TIG1 expression effectively hinders the growth of melanoma cells. TIG1 induces the upregulation of ER stress response-related genes, leading to an increase in caspase-3 activity and subsequent cell death. These findings suggest that the ability of retinoic acid to prevent melanoma formation may be associated with the anticancer effect of TIG1.
Topics: Humans; Endoplasmic Reticulum Stress; Melanoma; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Neoplastic; Cell Death; Apoptosis; Cell Proliferation; Membrane Proteins
PubMed: 38940043
DOI: 10.31083/j.fbl2906233 -
JACC. Advances Jan 2024Post-traumatic stress disorder (PTSD) is associated with increased rates of incident ischemic heart disease (IHD) in women.
BACKGROUND
Post-traumatic stress disorder (PTSD) is associated with increased rates of incident ischemic heart disease (IHD) in women.
OBJECTIVES
The purpose of this study was to determine mechanisms of the PTSD-IHD association in women.
METHODS
In this retrospective longitudinal cohort study, data were obtained from electronic health records of all U.S. women veterans who were enrolled in Veterans Health Administration care from January 1, 2000 to December 31, 2017. Propensity score matching was used to match women with PTSD to women without PTSD on age, number of prior Veterans Health Administration visits, and presence of various traditional and nontraditional cardiovascular risk factors at index visit. Cox regression was used to model time until incident IHD diagnosis (ie, coronary artery disease, angina, or myocardial infarction) as a function of PTSD and potential mediating risk factors. Diagnoses of IHD, PTSD, and risk factors were defined by International Classification of Diseases-9th or -10th Revision, and/or Current Procedural Terminology codes.
RESULTS
PTSD was associated with elevated rates of developing each risk factor. Traditional risk factors (hypertension, hyperlipidemia, smoking, diabetes) accounted for 24.2% of the PTSD-IHD association, psychiatric risk factors (eg, depression, anxiety, substance use disorders) accounted for 33.8% of the association, and all 13 risk factors accounted for 48.5% of the association.
CONCLUSIONS
Traditional IHD risk factors explained a quarter of the PTSD-IHD association in women veterans, and over half of the risk of IHD associated with PTSD remained unexplained even when adjusting for a wide range of risk factors. To be actionable, factors underlying the remaining PTSD-IHD association warrant timely investigation.
PubMed: 38939802
DOI: 10.1016/j.jacadv.2023.100744