Innate Defense Research Articles

Infection-induced trained immunity: a twist in paradigm of innate host defense and generation of immunological memory.

In contrast to adaptive immunity, which relies on memory T and B cells for long-term pathogen-specific responses, trained immunity involves the enhancement of innate immune responses through cellular reprogramming. Experimental evidence from animal models and human studies supports the concept of trained immunity and its potential therapeutic applications in the development of personalized medicine. However, there remains a huge gap in understanding the mechanisms, identifying specific microbial triggers responsible for the induction of trained immunity. This underscores the importance of investigating the potential role of trained immunity in redefining host defense and highlights future research directions. This minireview will provide a comprehensive summary of the new paradigm of trained immunity or innate memory pathways. It will shed light on infection-induced pathways through non-specific stimulation within macrophages and natural killer cells, which will be further elaborated in multiple disease perspectives caused by infectious agents such as bacteria, fungi, and viruses. The article further elaborates on the biochemical and cellular basis of trained immunity and its impact on disease status during recurrent exposures. The review concludes with a perspective segment discussing potential therapeutic benefits, limitations, and future challenges in this area of study. The review also sheds light upon potential risks involved in the induction of trained immunity.

Selective Biofilm Inhibition through Mucin-Inspired Engineering of Silk Glycopolymers.

Mucins are key components of innate immune defense and possess remarkable abilities to manage pathogenic microbes while supporting beneficial ones and maintaining microbial homeostasis at mucosal surfaces. Their unique properties have garnered significant interest in developing mucin-inspired materials as novel therapeutic strategies for selectively controlling pathogens without disrupting the overall microbial ecology. However, natural mucin production is challenging to scale, driving the need for simpler materials that reproduce mucin's bioactivity. In this work, we generated silk-based glycopolymers with different monosaccharides (GalNAc, GlcNAc, NeuNAc, GlcN, and GalN) and different grafting densities. Using the oral cavity as a model system, we treated in vitro cultures of pathogenic Streptococcus mutans and commensal Streptococcus sanguinis with our glycopolymers, finding that silk-tethered GalNAc uniquely prevented biofilm formation without affecting overall bacterial growth of either species. This relatively simple material reproduced mucin's virulence-neutralizing effects while maintaining biocompatibility. These mucin-inspired materials represent a valuable tool for preventing infection-related harm and offer a strategy for the domestication of pathogens in other environments.

Weapons in Space: Technology, Politics, and the Rise and Fall of the Strategic Defense Initiative

Weapons in Space: Technology, Politics, and the Rise and Fall of the Strategic Defense Initiative

Verbal Abuse, Depersonalization, and the Innate Alarm and Defensive Systems: A Single Case Illustration of Treatment with Deep Brain Reorienting

AbstractThis study aimed to a) discuss the neurobiological mechanisms of depersonalization as arising from activation at the brainstem level and b) assess the effectiveness of deep brain reorienting psychotherapy (DBR) with a patient presenting with depersonalization-derealization disorder (DDD). In the first part of the paper, we discuss verbal abuse as a severe form of relational trauma and how it can be connected to depersonalization. It is argued that suddenly aversive experiences engage the brainstem locus coeruleus in widespread noradrenergic activation of the thalamus and cortex such that the balance of functioning within the cortex becomes disturbed and a subjective experience of chronic depersonalization results. In the second part, the single-case study aims to provide initial evidence of how the patient experienced and responded to DBR therapy. Pre- and post-treatment measures consisted of instruments to measure depersonalization, social anxiety symptoms and quality of life. After 43 DBR sessions, the participant's depersonalization and comorbid symptoms decreased significantly. Patients with DDD may benefit from DBR. Future research is required to address generalizability to a larger population.

Understanding the spleen response of Russian sturgeon (Acipenser gueldenstaedtii) dealing with chronic heat stress and Aeromonas hydrophila challenge

Sturgeon aquaculture has grown in recent years, driven by increasing global demand for its highly valued products. Russian sturgeon (Acipenser gueldenstaedtii), recognised as one of the most valuable species for caviar production, is farmed in several warm-temperate regions. However, the substantial temperature increase due to global warming represents a challenge for developing sturgeon aquaculture. Previously we demonstrated that Russian sturgeon under chronic heat stress (CHS) exhibited a liver metabolic reprogramming to meet energy demands, weakening their innate defences and leading to increased mortality and economic losses. Here, we used RNA-seq technology to analyse regulated genes in the spleen of Russian sturgeons exposed to CHS and challenged with Aeromonas hydrophila. The assembly gave 253,415 unigenes, with 13.7 % having at least one reliable functional annotation. We found that CHS caused mild splenitis and upregulated genes related to protein folding, heat shock response, apoptosis and autophagy while downregulated genes associated with the cell cycle. The cell cycle arrest was maintained upon A. hydrophila challenge in heat-stressed fish, potentially inducing cell senescence. Surprisingly, immunoglobulin heavy and light chains were upregulated in the spleen of stressed sturgeons but not in those maintained at tolerable temperatures; however, no changes in IgM serum levels were observed in any condition. Our findings indicate that long-term exposure to non-tolerable temperatures induced a heat shock response and activated apoptosis and autophagy processes in the spleen. These mechanisms may enable the control of tissue damage and facilitate the recycling of cell components in a condition where the nutrient supply by the liver might be insufficient. Stressed sturgeons challenged with A. hydrophila maintain these mechanisms, which could culminate in cellular senescence.

Herpes simplex virus-1 targets the 2′-3'cGAMP importer SLC19A1 as an antiviral countermeasure

The extracellular addition of the STING agonist, 2-3cGAMP, induces an antiviral state that inhibits HSV-1 replication in a cell type dependent manner via the transportation of the cyclic-dinucleotide through the folate antiporter SLC19A1. To establish a successful infection, herpes simplex virus-1 (HSV-1), a ubiquitous virus with high seropositivity in the human population, must undermine a multitude of host innate and intrinsic immune defense mechanisms, including key players of the STimulator of INterferon Genes (STING) pathway. Herein, we report that HSV-1 infection results in the reduction of SLC19A1 transcription, translation, and importantly, the rapid removal of SLC19A1 from the cell surface of infected cells. Our data indicate SLC19A1 functions as a newly identified antiviral mediator for extracellular 2′-3'cGAMP which is undermined by HSV-1 protein ICP27. This work presents novel and important findings about how HSV-1 manipulates the host's immune environment for viral replication and discovers details about an important antiviral mechanism.

Melittin - the main component of bee venom: a promising therapeutic agent for neuroprotection through keap1/Nrf2/HO-1 pathway activation

The Nuclear factor erythroid 2–related factor (Nrf2)/ Heme oxygenase-1 (HO-1) pathway, known for its significant role in regulating innate antioxidant defense mechanisms, is increasingly being recognized for its potential in neuroprotection studies. Derived from bee venom, melittin's neuroprotective effects have raised interest. This study confirmed that melittin specificity upregulated the weakened Nrf2/HO-1 signaling in mice brain. Interestingly, we also revealed melittin’s efficient tactic, as it was suggested to first restore redox balance and then gradually stabilized other regulations of the mouse hippocampus. Using a neuro-stress-induced scopolamine model, chromatography and mass spectrometry analysis revealed that melittin crossed the compromised blood–brain barrier and accumulated in the hippocampus, which provided the chance to interact directly to weakened neurons. A wide range of improvements of melittin action were observed from various tests from behavior Morris water maze, Y maze test to immune florescent staining, western blots. As we need to find out what is the focus of melittin action, we conducted a careful observation in mice which showed that: the first signs of changes, in the hippocampus, within 5 h after melittin administration were the restoration of the Nrf2/HO-1 system and suppression of oxidative stress. After this event, from 7 to 12.5 h after administration, a diversity of conditions was all ameliorated: inflammation, apoptosis, neurotrophic factors, cholinergic function, and tissue ATP level. This chain reaction underscores that melittin focus was on redox balance's role, which revived multiple neuronal functions. Evidence of enhancement in the mouse hippocampus led to further exploration with hippocampal cell line HT22 model. Immunofluorescence analysis showed melittin-induced Nrf2 translocation to the nucleus, which would initiating the translation of antioxidant genes like HO-1. Pathway inhibitors pinpointed melittin's direct influence on the Nrf2/HO-1 pathway. 3D docking models and pull-down assays suggested melittin's direct interaction with Keap1, the regulator of the Nrf2/HO-1 pathway. Overall, this study not only highlighted melittin specifically effect on Nrf2/HO-1, thus rebalancing cellular redox, and also showed that this is an effective multi-faceted therapeutic strategy against neurodegeneration.

BCL2 regulates antibacterial autophagy in the intestinal epithelium

Autophagy is a key innate immune defense mechanism in intestinal epithelial cells. Bacterial invasion of epithelial cells activates antibacterial autophagy through a process that requires the innate immune adaptor protein MYD88, yet how MYD88 signaling connects to the autophagy machinery is unknown. Here, we show that the mouse intestinal pathogen Salmonella enterica Serovar Typhimurium (Salmonella Typhimurium) triggers MYD88 signaling that regulates binding of the anti-autophagy factor B cell lymphoma 2 (BCL2) to the essential autophagy protein Beclin1 (BECN1) in small intestinal enterocytes, a key epithelial cell lineage. Salmonella infection activated the kinase c-Jun N-terminal protein kinase 1 (JNK1) downstream of MYD88. JNK1 induced enterocyte BCL2 phosphorylation, promoting dissociation of the inhibitory BCL2-BECN1 complex and releasing BECN1 to initiate autophagy. Mice with BCL2 phosphorylation site mutations that prevent BCL2-BECN1 dissociation showed increased Salmonella invasion of enterocytes and dissemination to extraintestinal sites. These findings reveal that BCL2 links MYD88 signaling to enterocyte autophagy initiation, providing mechanistic insight into how invading bacteria trigger autophagy in the intestinal epithelium.

Calnexin interacts with B-cell receptor-associated protein 31 (Bap31) to mediate coelomocyte phagocytosis and Vibrio splendidus clearance in Apostichopus japonicus

Calnexin serves as a lectin chaperone located on the endoplasmic reticulum membrane and functions in glycoprotein folding and synthesis quality control, as well as in Ca2+ storage. Calnexin is extensively documented to participate in host immunity in the endoplasmic reticulum. However, the functions and fundamental mechanisms of calnexin in the invertebrate innate defence remain largely unknown. In this research, the complete cDNA sequence for calnexin from Apostichopus japonicus (Ajcalnexin) was cloned, revealing a 1779 bp open reading frame that codes for 592 amino acids, 113 bp 5′-Untranslated Region (UTR), and 3251 bp 3′-UTR. Upon Vibrio splendidus infection, both AjCalnexin mRNA and protein levels were significantly increased in coelomocytes. Knocking down Ajcalnexin with specific siRNAs significantly decreased coelomocyte phagocytosis, reducing the intracellular load of V. splendidus. By contrast, overexpression of AjCalnexin using recombinant AjCalnexin protein (rAjCalnexin) had the opposite effect. Moreover, B-cell receptor-associated protein 31 of A. japonicus (AjBap31) was identified as an interacting partner of AjCalnexin, which positively regulates AjBap31 expression. Silencing Ajbap31 also decreased coelomocyte phagocytosis and inhibited the intracellular load of V. splendidus. Furthermore, phagocytosis levels and intracellular loads of V. splendidus in the coelomocytes of sea cucumbers treated with rAjCalnexin and siAjBap31 were significantly lower than those in rAjCalnexin- and siNC-treated sea cucumbers. Collectively, we provide the first functional evidence that the AjCalnexin-AjBap31 axis plays a crucial role in host immune defence by mediating coelomocyte phagocytosis in A. japonicus during V. splendidus infection. These findings enhance understanding of the regulatory mechanism of phagocytosis in echinoderms and offer theoretical insights for preventing and controlling skin ulcer syndrome in sea cucumbers.

Identification of Novel Genomic Variants in COVID-19 Patients Using Whole-Exome Sequencing: Exploring the Plausible Targets of Functional Genomics.

Covid-19 caused by SARS-CoV-2 virus has emerged as an immense burden and an unparalleled global health challenge in recorded human history. The clinical characteristics and risk factors of COVID-19 exhibit considerable variability, leading to a spectrum of clinical severity. Moreover, the likelihood of exposure to the virus may differ based on comorbidity status as comorbid illnesses have mechanisms that can considerably increase mortality by reducing the body's ability to withstand injury. The mammalian target of rapamycin (mTOR) pathway is essential for orchestrating innate immune cell defense, including cytokine production and is dysregulated in severe Coronavirus Disease 2019 (COVID-19) individuals. Through genome-wide, association studies, numerous genetic variants in the human host have been identified that have a significant impact on the immune response to SARS-CoV-2. To identify potentially significant genetic variants in Covid-19 patients that could affect the risk, severity, and clinical outcome of the infection, this study has used whole-exome sequencing (WES) on the 16 COVID-19 patients with varying comorbidities and severity of the disease including fatal outcomes. Among them, 8 patients made a full recovery and were discharged, while 8 patients unfortunately did not survive due to the severity of the illness and majority of them were males. The study identified 10,204 variants in the patients. From 1120 variants, which were chosen for novel variant analysis using mutation, function prediction tools to identify deleterious variants that could affect normal gene function, 116 variants of 57 genes were found to be deleterious. These variants were further classified as likely pathogenic and variants of uncertain significance. The data showed that among the likely pathogenic variants five genes were identified in connection to immune response whereas two were related to respiratory system. The common variants associated with the covid-19 phenotype showed the top 10 significant genes identified in this study such as ERCC2, FBXO5, HTR3D, FAIM, DNAH17, MTOR, IGHMBP2, ZNF530, QSER1, and FOXRED2 with variant rs1057079 of the MTOR gene representing the highest odds ratio (1.7, p = 8.7e-04). The mammalian target of rapamycin (mTOR) pathway variant rs1057079 was reported with high odds ratio, may orchestrate innate immune cell defense, including cytokine production, and is dysregulated. This study concluded that the mTOR signaling gene variant (rs1057079) is associated with different degrees of covid-19 severity and is essential for orchestrating innate immune cell defense including cytokine production. Inhibiting mTOR and its corresponding deleterious immune responses with medicinal approaches may provide a novel avenue for treating severe COVID-19 illness. Besides the PPI network exhibited a significantly high local clustering coefficient of 0.424 (p = 0.000536), suggesting the presence of tightly knit functional modules. These findings enhance our comprehension of the intricate interactions between genetic factors and COVID-19 disease.

A novel C-type lectin, perlucin, from the small abalone, Haliotis diversicolor involved in the innate immune defense against Vibrio harveyi infection

C-type lectins (CTLs), a member of pattern recognition receptors, play an important role in the innate immunity by recognizing invading microorganisms. In this study, a novel perlucin gene (designated as HdPer 3), a typical CTLs was cloned and characterized from the small abalone Haliotis diversicolor. The open reading frame of HdPer 3 was 471 bp, encoding a protein of 156 amino acids that included a single carbohydrate-recognition domain. HdPer 3 was widely expressed in all tested tissues and developmental stage. HdPer 3 expression was significantly up-regulated after Vibrio harveyi infection, suggesting that HdPer 3 was activated in response to bacterial infection. The encapsulation ability of hemocytes could be significantly enhanced by the recombinant protein HdPer 3 (rHdPer 3). To understand the regulation mechanism of the HdPer 3, HdPer 3 was silenced in vivo by RNAi. Knocking down HdPer 3 decreased the hemocytes phagocytosis. Meanwhile, knocking down HdPer 3 can reduce the expression of 2 phagocytosis-related genes (Rab and Dynamin), TNF-α, and 2 MAPK pathway-related genes (MAPK-X1 and Ras) after V. harveyi infection. Moreover, HdPer 3 interference could increase the bacterial load in the hemolymph and the mortality of abalones after V. harveyi infection. All these results suggested that HdPer 3 played a crucial role in the defense against V. harveyi infection by recognizing bacterial pathogens and activating the expression of immune-related genes.

Antiviral defense in aged Caenorhabditis elegans declines due to loss of DRH-1/RIG-I deSUMOylation via ULP-4/SENP7.

Innate host defense mechanisms require posttranslational modifications (PTM) to protect against viral infection. Age-associated immunosenescence results in increased pathogenesis and mortality in the elderly, but the contribution of altered PTM regulation to immunosenescence is unknown. SUMOylation is a rapid and reversible post-translational modification that has been implicated in age-associated disease and plays conflicting roles in viral replication and antiviral defenses in mammals. We have discovered in Caenorhabditis elegans that induction of antiviral defense is regulated through SUMOylation of DRH-1, the ortholog of the DEAD/H-box helicase and cytosolic pattern recognition receptor RIG-I, and that this regulation breaks down during aging. We find the SUMO isopeptidase ULP-4 is essential for deSUMOylation of DRH-1 and activation of the intracellular pathogen response (IPR) after exposure to Orsay virus (OV), a natural enteric C. elegans pathogen. ULP-4 promotes stabilization of DRH-1, which translocates to the mitochondria to activate the IPR in young animals exposed to virus. Loss of either drh-1 or ulp-4 compromises antiviral defense resulting in a failure to clear the virus and signs of intestinal pathogenesis. During aging, expression of ulp-4 decreases, which results in increased proteosomal degradation of DRH-1 and loss of the IPR. Mutating the DRH-1 SUMOylated lysines resulted in the constitutive activation of the IPR in young animals and partially rescued the age-associated lost inducibility of the IPR. Our work establishes that aging results in dysregulated SUMOylation and loss of DRH-1, which compromises antiviral defense and creates a physiological shift to favor chronic pathological infection in older animals.

Analysis of the presence of natural killer cell subpopulations in preterm human milk: A first approach

Several immune cell populations are transferred to the newborn through breast milk, including natural killer (NK) cells, which are critical for innate defense and regulation of the immune response, especially in preterm infants. The aim of this study was to analyze the presence of NK cell subpopulations in different types of preterm breast milk. The study quantified the presence of NK cell subpopulations by flow cytometry using the relative expression of CD56 and CD16 markers in colostrum, transitional and mature milk samples from preterm mothers. Flow cytometry analysis revealed the presence of five NK cell subpopulations, but unlike those reported in peripheral blood, CD56dimCD16+ and CD56-CD16+ populations are predominantly present in preterm milk, only the CD56brightCD16dim population is increased in mature milk. Analysis of NK cell subpopulations in preterm milk revealed a pattern of NK cell presence in preterm breast milk with predominantly cytotoxic phenotypes in relation to CD16 marker expression.

PROSPECTS FOR THE INTEGRATION OF UKRAINE'S NATIONAL SECURITY MECHANISMS WITH THE COLLECTIVE SECURITY SYSTEMS OF THE EU AND NATO

This article examines the prospects for integrating Ukraine's national security mechanisms with the collective security systems of the European Union and NATO. The study addresses the current challenges and opportunities arising from Ukraine's efforts to align its national security policy with the standards and requirements of international security organizations. The analysis underscores the significance of this integration in the context of ongoing geopolitical tensions and the necessity for enhanced cooperation in safeguarding national and regional security. Utilizing a qualitative research methodology, the article employs a comprehensive literature review, analyzing existing frameworks, policies, and strategic documents relevant to Ukraine's security landscape. Comparative analysis is also applied to assess the effectiveness of Ukraine's security initiatives against those of EU and NATO member states, identifying best practices that can be adapted to the Ukrainian context. The findings reveal critical areas of cooperation, including military interoperability, intelligence sharing, and joint training exercises, which are essential for strengthening Ukraine's defense capabilities. The article further explores the legal, institutional, and operational frameworks necessary for harmonizing Ukraine's security strategies with those of its partners, emphasizing the importance of aligning legislative measures and defense policies with EU and NATO standards. In conclusion, the article advocates for a strategic approach to integration that prioritizes resilience and adaptability within Ukraine's national security mechanisms. By enhancing collaboration with EU and NATO, Ukraine can bolster its security architecture, thereby contributing to regional stability and collective defense initiatives. The recommendations presented aim to guide policymakers in implementing effective strategies for fostering greater alignment with international security frameworks, ensuring a robust response to evolving threats in the region. Through these measures, Ukraine can not only advance its national security objectives but also play a pivotal role in the broader European security landscape.

Security-Diplomacy Nexus: Nature of Bilateral Cooperation in Kenya - India Military Diplomatic Relations Since 1963

Bilateral and multilateral agreements have been one of the mechanisms through which growth and development have taken place. The newly created independent states of the Cold War period presented a major paradigm shift in international cooperation to include military diplomacy. Kenya and India being among these newly created states have had their cooperation where by the two countries have used their good diplomatic relations to bolster one another's military capabilities. The current study sought to put into perspective the conduct of bilateral relations between Kenya and India. The objective of this study was to examine the nature of bilateral cooperation in enhancing Kenya-India military-diplomatic relations since 1963. The study was anchored on power theory. The study adopted a descriptive research design. The study was carried out in Nairobi County, Kenya with a specific focus on the Ministry of Foreign Affairs, Defence Ministry, and Indian High Commission. The target population was 2500. The sample size for the study was determined using Yamane's (1967) formula to calculate the sample size, which was 250 Qualitative data obtained from interviews were analysed using narrative reports using thematic techniques. Quantitative data from the questionnaires was edited, coded, and entered into a computer spreadsheet in a standard format to allow descriptive statistics analysis. Statistical Packages for Social Sciences (SPSS) edition 24 and Microsoft Office Excel 2013 were used for the quantitative data. The findings of the study revealed that the nature of Kenya-India military diplomatic relations manifested in various forms including through High-profile visits by Kenyan and Indian officials to both states as a way of strengthening bilateral relations. Technological transfer was another way through which these two nations shaped their diplomatic relationship, particularly in information and communication technology (ICT). Additionally, Defense trade and trade agreements, Security Partnerships, Counterterrorism activities, Maritime Safety, and Peacekeeping missions were common areas of cooperation between Kenya and India. The study concludes that bilateral cooperation between Kenya and India has been instrumental in enhancing their military-diplomatic relations since 1963. The study recommends that, to better understand the nature of bilateral cooperation, Kenya and India should establish a permanent joint military commission to oversee and coordinate defense initiatives.

PiRNA Defense Against Endogenous Retroviruses.

Infection by retroviruses and the mobilization of transposable elements cause DNA damage that can be catastrophic for a cell. If the cell survives, the mutations generated by retrotransposition may confer a selective advantage, although, more commonly, the effect of new integrants is neutral or detrimental. If retrotransposition occurs in gametes or in the early embryo, it introduces genetic modifications that can be transmitted to the progeny and may become fixed in the germline of that species. PIWI-interacting RNAs (piRNAs) are single-stranded, 21-35 nucleotide RNAs generated by the PIWI clade of Argonaute proteins that maintain the integrity of the animal germline by silencing transposons. The sequence specific manner by which piRNAs and germline-encoded PIWI proteins repress transposons is reminiscent of CRISPR, which retains memory for invading pathogen sequences. piRNAs are processed preferentially from the unspliced transcripts of piRNA clusters. Via complementary base pairing, mature antisense piRNAs guide the PIWI clade of Argonaute proteins to transposon RNAs for degradation. Moreover, these piRNA-loaded PIWI proteins are imported into the nucleus to modulate the co-transcriptional repression of transposons by initiating histone and DNA methylation. How retroviruses that invade germ cells are first recognized as foreign by the piRNA machinery, as well as how endogenous piRNA clusters targeting the sequences of invasive genetic elements are acquired, is not known. Currently, koalas (Phascolarctos cinereus) are going through an epidemic due to the horizontal and vertical transmission of the KoRV-A gammaretrovirus. This provides an unprecedented opportunity to study how an exogenous retrovirus becomes fixed in the genome of its host, and how piRNAs targeting this retrovirus are generated in germ cells of the infected animal. Initial experiments have shown that the unspliced transcript from KoRV-A proviruses in koala testes, but not the spliced KoRV-A transcript, is directly processed into sense-strand piRNAs. The cleavage of unspliced sense-strand transcripts is thought to serve as an initial innate defense until antisense piRNAs are generated and an adaptive KoRV-A-specific genome immune response is established. Further research is expected to determine how the piRNA machinery recognizes a new foreign genetic invader, how it distinguishes between spliced and unspliced transcripts, and how a mature genome immune response is established, with both sense and antisense piRNAs and the methylation of histones and DNA at the provirus promoter.

Tetracycline and Oxacillin Act Synergistically on Biofilms and Display Increased Efficacy In Vivo Against Staphylococcus aureus.

Oxacillin (bactericidal) and tetracycline (bacteriostatic) are clinically relevant antibiotics that are routinely prescribed to treat Staphylococcus aureus infections but not conventionally used in combination. There is an urgent need for treatment regimens that can act upon biofilms during infection, associated with chronic infections on indwelling devices, as well as acute planktonic (systemic) infection. Here we show that in an in vitro model oxacillin and tetracycline act synergistically against S. aureus UAMS-1 biofilms, reducing the concentration of both antibiotics necessary to eradicatean established biofilm. Using an in vivo zebrafish larval infection model with S. aureus NewHG, they display improved bacterial clearance compared to each drug alone and can counteract a loss of host phagocytes, an important innate defence against S. aureus. In these cases, the bacteriostatic nature of tetracycline enhances rather than dampens the bactericidal action of oxacillin, although an exact mechanism remains to be elucidated. We suggest a dual therapy could be of clinical use against biofilm-forming S. aureus and has a potential use in patients with a compromised immune system.

IFITM1 is a host restriction factor that inhibits porcine epidemic diarrhea virus infection.

Porcine epidemic diarrhea virus (PEDV) infection and transmission pose a serious threat to the global swine industry. The search for a new host factor with anti-PEDV effect may be an effective potential target for the development of novel antiviral drugs. Interferon-induced transmembrane proteins (IFITMs) play a crucial role in the innate immune response triggered by viral infection, and it has been suggested that IFITMs can block the early stages of viral replication, but the mechanism of action is currently unclear. The current study sheds light on the role of IFITM1 in PEDV infection. Specifically, overexpression of IFITM1 suppresses PEDV proliferation in IPEC-J2 cells, while knockdown of IFITM1 has the opposite effect. Collectively, these findings underscore IFITM1's inhibitory role in PEDV infection, with critical implications for the residues and structural motifs within its CTD. The study demonstrates that IFITM1, an interferon-induced transmembrane protein, plays a critical role in the antiviral response against Porcine Epidemic Diarrhea Virus (PEDV). Notably: Overexpression of IFITM1 suppresses PEDV proliferation.IFITM1 co-localizes with PEDV virions in the cytoplasm surrounding the nucleus.Immunocolloidal gold electron microscopy reveals IFITM proteins embedded on the surface of PEDV virions.IFITM1 directly interacts with the N protein of PEDV.C-terminal domain mutations in IFITM1 compromise its inhibitory function against PEDV, with specific amino acid residues playing a pronounced role.These findings enhance our understanding of innate immunity and antiviral defense mechanisms, with potential implications for therapeutic strategies against PEDV infection. The study establishes IFITM1 as a key player in the antiviral response against PEDV. Its inhibitory function, co-localization with virions, and interaction with the N protein provide valuable insights. Notably, the CTD mutations of IFITM1 have a fundamental impact on its modulatory action. These findings contribute to our understanding of innate immunity and antiviral defense mechanisms, with potential implications for therapeutic strategies against PEDV infection.

Beyond Pharmacology: The Biological Mechanisms of Remote Ischemic Conditioning in Cerebrovascular Disease.

Cerebrovascular diseases (CVDs), comprising predominantly ischemic stroke and chronic cerebral hypoperfusion (CCH), are a significant threat to global health, often leading to disability and mortality. Remote ischemic conditioning (RIC) has emerged as a promising, non-pharmacological strategy to combat CVDs by leveraging the body's innate defense mechanisms. This review delves into the neuroprotective mechanisms of RIC, categorizing its effects during the acute and chronic phases of stroke recovery. It also explores the synergistic potential of RIC when combined with other therapeutic strategies, such as pharmacological treatments and physical exercise. Additionally, this review discusses the pathways through which peripheral transmission can confer central neuroprotection. This review concludes by addressing the challenges regarding and future directions for RIC, emphasizing the need for standardized protocols, biomarker identification, and expanded clinical trials to fully realize its therapeutic potential.

Genetic variations in Interferon-Induced with Helicase C Domain 1: Impact on COVID-19 risk and severity in the Moroccan population

BackgroundThe clinical spectrum of COVID-19 varies considerably, ranging from asymptomatic cases to severe disease and even death. This variability can partly be attributed to genetic differences in genes associated with inflammation and immune responses. Among these genes, Interferon Induced with Helicase C Domain 1 (IFIH1), which codes for a cytoplasmic sensor, plays a crucial role in detecting SARS-CoV-2 viral RNA and initiating the antiviral interferon (IFN) response, thereby constituting a key element of innate immune defense. AimThis study aims to examine the association between genetic variants in the IFIH1 gene and susceptibility to, as well as the severity of, COVID-19 in the Moroccan population. Materials and MethodsWe conducted a case-control study involving 299 COVID-19 positive patients (149 severe, 150 benign) and 145 uninfected-SARS-CoV-2 controls. We determined the genotypes of two functional variants, rs1990760 (Ala946Thr) and rs3747517 (His843Arg), in the IFIH1 gene using predesigned TaqMan real-time allelic discrimination assay. ResultsOur results indicated that the TT genotype of rs1990760 was associated with increased susceptibility to SARS-CoV-2 under a recessive model (odds ratio [OR] = 2.22, 95 % confidence interval [CI] 1.28–3.84, P=0.003). Conversely, the CT genotype appeared to confer protection against SARS-CoV-2 infection (OR=0.58, 95 % CI 0.38–0.91, P=0.016) and COVID-19 severity (OR=0.56, 95 % CI 0.34–0.91, P=0.019). No significant association was found between rs3747517 and the risk of hospitalization or infection susceptibility. ConclusionThese findings underscore the significance of genetic variability in the IFIH1 gene in shaping individual responses to SARS-CoV-2 in the Moroccan population.