The COVID-19 pandemic had a profound impact on global health. This study focuses on an in-depth analysis of the structural proteins (Spike (S), Nucleocapsid (N), Membrane (M), and Envelope (E) protein) of SARS-CoV-2 and its variants, aiming to develop a multiepitope vaccine construct that targets the virus independently of its variants. The analysis began by examining genetic variations in viral proteins relative to the reference strain Wuhan-Hu2, particularly in the S, M, N, and E proteins. T-cell epitope predictions for MHC Class-I and Class-II binding were conducted, shedding light on potential cytotoxic and helper T lymphocyte recognition. Identification of linear B-cell epitopes laid the groundwork for antibody-based humoral immune responses. The safety and efficacy of these epitopes were assessed for antigenicity, allergenicity, toxicity, immunogenicity, and conservancy. Population coverage analysis indicated promising global effectiveness of the designed vaccine construct. By incorporating 28 epitopes, we validated that was designed vaccine construct for stability through structural analysis. Molecular dynamics simulations and docking studies revealed its robust interaction with Toll-like receptor 4 (TLR4). Immune simulation studies suggested that the vaccine construct could induce a potent immune response by enhancing antibody titers, B-cell proliferation, memory cell development, and activation of T cells and natural killer cells upon administration. This comprehensive approach offers a promising multiepitope vaccine against SARS-CoV-2, with the potential for broad global coverage and strong immunogenicity. Further experimental validation holds the prospect of introducing a novel candidate vaccine to aid in the ongoing battle against the COVID-19 pandemic.

Triple-negative breast cancer (TNBC) is difficult to treat due to the lack of clear therapeutic targets. Paclitaxel (PTX) is commonly used to treat TNBC, but drug resistance limits its effectiveness. Myeloid differentiation protein 2 (MD2) and serum amyloid A1 (SAA1) are involved in various diseases, including infections, inflammatory diseases, and cancer. We investigated their role in PTX resistance to identify potential anti-TNBC drugs. In this study, we investigated the changes of SAA1 in TNBC tissues and its role in PTX-induced TNBC cells. Our study revealed SAA1 expressed in the human TNBC subtype and TNBC cells. PTX and CIS induce SAA1 in TNBC cells, and PTX induces inflammatory response via SAA1 in TNBC cells. MD2 blockade increased the sensitivity of TNBC cells to PTX, which was related to the expression of SAA1 during PTX-caused damage of TNBC cells. In further research, SAA1 binds to MD2, promotes the combination of TLR4/MD2 and TLR4/MyD88, activates the NF-κB signaling pathway, and creates the inflammatory microenvironment for cancer cells. Our study reports for the first time that the PTX/SAA1/MD2 axis exists in the PTX-resistance process, which could be a potential treatment target of PTX-resistance.

Recent emergence of zoonotic monkeypox virus (Mpox) in human has triggered the virologists to develop plausible preventive measures. Hitherto, our understanding on the mechanism of immunopathogenesis of Mpox infection is elusive. However, available experimental evidences suggest induction of inflammation as the main cause of pathogenesis. Toll-like receptors (TLRs) are critical in initiating and modulating the host immune response to pathogens. Inflammatory responses observed in various poxvirus infections have, in fact, been shown to be mediated through TLR activation. Therefore, by in silico approaches, this study seeks to identify the Mpox antigen(s) (MAg) that are most likely to interact with human cell-surface TLRs. The Mpox proteomics data available in UniProt database contain 174 protein sequences, among which 105 immunoreactive proteins were modeled for 3D structure and examined for comparative protein-protein interactions with the TLRs through molecular docking and molecular dynamics simulation. F14, an 8.28 kDa infective protein of Mpox, was found to exhibit strong binding affinity (ΔG=-12.5 Kcal mol-1) to TLR1/2 dimer to form a compact thermodynamically stable protein complex. Interestingly, a significant level of conformational change was also observed in both F14 and TLR6 while forming F14-TLR1/2 complex. Based on these data we propose F14 as a putative ligand of human TLR1/2 to initiate proinflammatory signaling in the Mpox-infected host.

Infection with the Zika virus (ZIKV) poses a threat to human health. An improved understanding of the host Toll-like receptor response, disease onset, and viral clearance in vivo and in vitro may lead to the development of therapeutic or prophylactic interventions against viral infections. Currently, no clinically approved ZIKV vaccine is available, highlighting the need for its development. In this study, we discuss the progress in the Zika vaccine, including advances in the use of Toll-like receptor agonists as vaccine adjuvants to enhance vaccine efficacy.

Small ruminant lentiviruses (SRLV) cause multisystemic chronic inflammatory disease and significant economic losses in sheep and goats worldwide. However, no vaccines or therapies are currently available. In this study, a recombinant Sendai virus (SeV) vector encoding the SRLV gag-P25 gene (rSeV-GFP-P25) from the EV1 strain was generated using In-FUSION cloning and rescued using the SeV reverse genetic system. Transgene expression and stimulation of innate immunity and interferon-stimulated genes (ovine A3Z1, OBST2 and SAMHD1) were evaluated in ovine skin fibroblasts (OSF) transduced with SeV-GFP and rSeV-GFP-P25. Additionally, to characterize the effect of the SRLV restriction in transduced OSF, the SRLV DNA load was quantified at different times post-transduction and post-infection with strain EV1. Using immunohistochemistry and image analysis, transgene expression and tissue distribution of recombinant P25 were studied in two lambs inoculated intranasally, one with rSeV-GFP-P25 and the other with SeV-GFP. rSeV-GFP-P25 induced efficient and transient transgene expression in vitro and in vivo. Furthermore, OSF transduced with rSeV-GFP-P25 presented upregulation of TLR2, TLR3, TLR6, TLR7, RIG-I, MyD88 and IFN-β, whereas SeV-GFP did not induce TLR6 or IFN-β upregulation. Among the interferon-stimulated genes, OBST2 was significantly upregulated after transduction with rSeV-GFP-P25 compared with the empty vector. SRLV restriction gradually increased and persisted after transduction with SeV-GFP and rSeV-GFP-P25, with OSF transduced three times showing cumulative restriction. Forty-eight hours post-inoculation in vivo, marked P25 expression was observed in ciliated epithelial cells and submucosal macrophages/dendritic cells of the nasal mucosa. This study reinforces the important role of the innate immune response in controlling SRLV infection and suggests that rSeV-GFP-P25 is a potential vaccine candidate against SRLV.

The hepatitis A virus (HAV) and rotavirus are mainly transmitted through fecal-oral and person-to-person contact, and cause severe gastrointestinal complications and liver disease. This work used reverse vaccinology and immunoinformatic methods to create a novel bivalent vaccine against rotavirus and HAV. The amino acid sequences of HAV-rotavirus proteins (VP1 and VP8∗) were retrieved from the GenBank database. Various computational approaches were employed to predict highly conserved regions and the most immunogenic B-cell and T-cell epitopes of VP8 and VP1 of rotavirus and HAV proteins in both humans and BALB/c. Moreover, the predicted fusion protein was analyzed regarding primary and secondary structures and homology validation. In this study, we used two highly conserved peptide sequences of VP8 and VP1 of rotavirus and HAV that induce T and B cell immunogenicity. According to T-cell epitope prediction, this area comprises 2713 antigenic peptides for HLA class II and 30 HLA class I antigenic peptides, both of which are virtually entirely conserved in the Iranian population. In this study, validation as well as analysis of the secondary and three-dimensional structure of the VP8∗-rotavirus + AAY + HAV-VP1 fusion protein, with the aim of designing a multi-epitope vaccine with different receptors. TLR 3, 4 high immunogenic binding ability with immunological properties and interaction between multi-epitope target and TLR were predicted, and it is expected that the target fusion protein has stable antigenic potency and compatible half-life. The above is suggested as a universal vaccination program.

Eastern equine encephalitis virus (EEEV) is a lethal Alphavirus transmitted by Culiseta melanura mosquitoes that primarily cycles between birds. Although rare, infections in humans and horses are associated with high mortality rates and severe neurological effects. Climate change appears to be increasing the spread of this virus. This study aims to provide a comprehensive analysis of EEEV, including its transmission dynamics, pathogenesis, induced host immune response, and long-term impacts on survivors. It also highlights the virus's unique immune evasion strategies that complicate disease management and contribute to severe clinical outcomes, such as encephalitis with fever, convulsions, and coma. Survivors often face chronic cognitive, motor, and psychosocial impairments. Despite these significant public health risks, gaps remain in understanding the molecular mechanisms underlying immune evasion and the long-term neurological sequelae in survivors. By collating current knowledge, this review underscores the urgent need for the development of targeted vaccines and therapeutic interventions to mitigate the growing threat of EEEV, particularly in the context of climate change-driven geographical expansion.

The Marburg virus (MARV), a member of the Filoviridae family, is a highly lethal pathogen that causes Marburg virus disease (MVD), a severe hemorrhagic fever with high fatality rates.Despite recurrent outbreaks, no licensed vaccine is currently available. This review explores MARV's genomic architecture, structural proteins, and recent advancements in vaccine development. It highlights the crucial role of MARV's seven monocistronic genes in viral replication and pathogenesis, with a focus on structural proteins such as nucleoprotein (NP), glycoprotein (GP), and viral proteins VP35, VP40, and VP24. These proteins are essential for viral entry, immune evasion, and replication. The review further examines various vaccine platforms, including multi-epitope vaccines, DNA-based vaccines, viral vector vaccines, virus-like particles (VLPs), and mRNA vaccines. Cutting-edge immunoinformatics approaches are discussed for identifying conserved epitopes critical for broad-spectrum protection. The immunological responses induced by these vaccine candidates, particularly their efficacy in preclinical trials, are analyzed, showcasing promising results in generating both humoral and cellular immunity. Moreover, the review addresses challenges and future directions in MARV vaccine development, emphasizing the need for enhanced immunogenicity, safety, and global accessibility. The integration of omics technologies (genomics, transcriptomics, proteomics) with immunoinformatics is presented as a transformative approach for next-generation vaccine design. Innovative platforms such as mRNA and VLP-based vaccines offer rapid and effective development opportunities. In this study, underscores the urgent need for a licensed MARV vaccine to prevent future outbreaks and strengthen global preparedness. By synthesizing the latest research and technological advancements, it provides a strategic roadmap for developing safe, effective, and broadly protective vaccines. The fight against MARV is a global priority, requiring coordinated efforts from researchers, policymakers, and public health organizations.

Although the peak of the COVID-19 pandemic has passed, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a significant global threat and remains a public health concern. Given the ongoing risk and the substantial loss of life caused by the virus, continuous research into vaccine development is essential. This study employs immunoinformatics approaches to identify T-cell and B-cell epitopes for designing a multi-epitope peptide vaccine candidate targeting the Omicron variant. The proposed vaccine construct comprises 1435 amino acids, including eight linear B lymphocyte, seven cytotoxic T lymphocyte, and five helper T lymphocyte epitopes, along with appropriate adjuvants and linkers. The evaluation of the vaccine revealed high antigenicity, non-allergenicity, non-toxicity, and favorable physicochemical properties. To further assess its efficacy, molecular docking studies were performed to investigate interactions between the vaccine and key immune components, including Toll-like receptors and major histocompatibility complex molecules. Stability of these interactions was confirmed using molecular dynamics simulations in triplicate, conducted over 100 ns using GROMACS 2023 to compute key metrics, such as root mean square deviation, root mean square fluctuation, solvent-accessible surface area, and radius of gyration. The results demonstrate that the multi-epitope vaccine has the potential to elicit strong immune responses against the Omicron variant, providing a promising foundation for further experimental validation and clinical development in COVID-19 vaccine research.

Cardiovascular disease (CVD) is the leading cause of morbidity globally, with chronic inflammation as a key modifiable risk factor. Toll-like receptors (TLRs), pivotal components of the innate immune system, including TLR-3, -7, -8, and -9 within endosomes, trigger intracellular cascades, leading to inflammatory cytokine production by various cell types, contributing to systemic inflammation and atherosclerosis. Recent research highlights the role of endosomal TLRs in recognizing self-derived nucleic acids during sterile inflammation, implicated in autoimmune conditions like myocarditis.

This review explores the impact of endosomal TLRs on viral infections, autoimmunity, and inflammatory responses, shedding light on their intricate involvement in cardiovascular health and disease by examining literature on TLR-mediated mechanisms and their roles in CVD pathophysiology.

Removal of endosomal TLRs mitigates myocardial damage and immune reactions, applicable in myocardial injury. Targeting TLRs with agonists enhances innate immunity against fatal viruses, lowering viral loads and mortality. Prophylactic TLR agonist administration upregulates TLRs, protecting against fatal viruses and improving survival. TLRs play a complex role in CVDs like atherosclerosis and myocarditis, with therapeutic potential in modulating TLR reactions for cardiovascular health.

Acute respiratory infections (ARIs) caused by viruses such as SARS-CoV-2, influenza viruses, and respiratory syncytial virus (RSV), pose significant global health challenges, particularly for the elderly and immunocompromised individuals. Substantial evidence indicates that acute viral infections can manipulate the host's epigenome through mechanisms like DNA methylation and histone modifications as part of the immune response. These epigenetic alterations can persist beyond the acute phase, influencing long-term immunity and susceptibility to subsequent infections. Post-infection modulation of the host epigenome may help distinguish infected from uninfected individuals and predict disease severity. Understanding these interactions is crucial for developing effective treatments and preventive strategies for viral ARIs. This review highlights the critical role of epigenetic modifications following viral ARIs in regulating the host's innate immune defense mechanisms. We discuss the implications of these modifications for diagnosing, preventing, and treating viral infections, contributing to the advancement of precision medicine. Recent studies have identified specific epigenetic changes, such as hypermethylation of interferon-stimulated genes in severe COVID-19 cases, which could serve as biomarkers for early detection and disease progression. Additionally, epigenetic therapies, including inhibitors of DNA methyltransferases and histone deacetylases, show promise in modulating the immune response and improving patient outcomes. Overall, this review provides valuable insights into the epigenetic landscape of viral ARIs, extending beyond traditional genetic perspectives. These insights are essential for advancing diagnostic techniques and developing innovative treatments to address the growing threat of emerging viruses causing ARIs globally.

The initial interaction between COVID-19 and the human body involves the receptor-binding domain (RBD) of the viral spike protein with the angiotensin-converting enzyme 2 (ACE2) receptor. Likewise, the spike protein can engage with immune-related proteins, such as toll-like receptors (TLRs) and pulmonary surfactant proteins A (SP-A) and D (SP-D), thereby triggering immune responses. In this study, we utilize computational methods to investigate the interactions between the spike protein and TLRs (specifically TLR2 and TLR4), as well as (SP-A) and (SP-D). The study is conducted on four variants of concern (VOC) to differentiate and identify common virus behaviours. An assessment of the structural stability of various variants indicates slight changes attributed to mutations, yet overall structural integrity remains preserved. Our findings reveal the spike protein's ability to bind with TLR4 and TLR2, prompting immune activation. In addition, our in-silico results reveal almost similar docking scores and therefore affinity for both ACE2-spike and TLR4-spike complexes. We demonstrate that even minor changes due to mutations in all variants, surfactant A and D proteins can function as inhibitors against the spike in all variants, hindering the ACE2-RBD interaction.Communicated by Ramaswamy H. Sarma.

The tripartite-motif protein 56 (TRIM56) is a RING-type E3 ubiquitin ligase whose functions were recently beginning to be unveiled. While the physiological role(s) of TRIM56 remains unclear, emerging evidence suggests this protein participates in host innate defense mechanisms that guard against viral infections. Interestingly, TRIM56 has been shown to pose a barrier to viruses of distinct families by utilizing its different domains. Apart from exerting direct, restrictive effects on viral propagation, TRIM56 is implicated in regulating innate immune signaling pathways that orchestrate type I interferon response or autophagy, through which it indirectly impacts viral fitness. Remarkably, depending on viral infection settings, TRIM56 either operates in a canonical, E3 ligase-dependent fashion or adopts an enzymatically independent, non-canonical mechanism to bolster innate immune signaling. Moreover, the recent revelation that TRIM56 is an RNA-binding protein sheds new light on its antiviral mechanisms against RNA viruses. This review summarizes recent advances in the emerging roles of TRIM56 in innate antiviral immunity. We focus on its direct virus-restricting effects and its influence on innate immune signaling through two critical pathways: the endolysosome-initiated, double-stranded RNA-sensing TLR3-TRIF pathway and the cytosolic DNA-sensing, cGAS-STING pathway. We discuss the underpinning mechanisms of action and the questions that remain. Further studies understanding the complexity of TRIM56 involvement in innate immunity will add to critical knowledge that could be leveraged for developing antiviral therapeutics.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative primarily affecting motor neurons, leading to disability and neuronal death, and ATP-Binding Cassette (ABC) transporter due to their role in drug efflux and modulation of various cellular pathways contributes to the pathogenesis of ALS. In this article, we extensively investigated various molecular and mechanistic pathways linking ALS transporter to the pathogenesis of ALS; this involves inflammatory pathways such as Mitogen-Activated Protein Kinase (MAPK), Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt), Toll-Like Receptor (TLR), Glycogen Synthase Kinase 3β (GSK-3β), Nuclear Factor Kappa-B (NF-κB), and Cyclooxygenase (COX). Oxidative pathways such as Astrocytes, Glutamate, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Sirtuin 1 (SIRT-1), Forkhead box protein O (FOXO), Extracellular signal-regulated kinase (ERK). Additionally, we delve into the role of autophagic pathways like TAR DNA-binding protein 43 (TDP-43), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and lastly, the apoptotic pathways. Furthermore, by understanding these intricate interactions, we aim to develop novel therapeutic strategies targeting ABC transporters, improving drug delivery, and ultimately offering a promising avenue for treating ALS.

Chronic stress can significantly promote breast cancer progression. When exposed to chronic stress, exosomes released from neural and neuroendocrine cells in the central nervous system are enhanced and modified. However, whether tumor-derived exosomes (TDEs) are influenced by chronic stress and participate in chronic stress-mediated distant metastasis remains unclear. Here, it is shown that chronic stress remarkably facilitates the secretion of TDEs and modifies the contents of exosomes by activating the adrenergic β receptor in 4T1 tumor-bearing mice. Exosomes injection and blockade experiments indicate that exosomes play a crucial role in chronic stress-mediated lung metastasis of breast cancer. Chronic stress-induced TDEs are internalized by pulmonary neutrophils and strengthen neutrophil recruitment via the CXCL2 autocrine. In addition, the level of SP1 in TDEs increases, which favors the secretion of IL-1β by neutrophils through the activation of the TLR4-NFκβ pathway, ultimately aggravating lung metastasis of breast cancer. Collectively, this study provides a novel mechanism by which neutrophils within a pre-metastatic niche acquire their inflamed phenotype and establishes an important link among neuroendocrine changes, exosomes, immunity, and metastasis.

Arboviruses are a significant threat to global public health, with outbreaks occurring worldwide. Toll-like receptors (TLRs) play a crucial role in the innate immune response against these viruses by recognizing pathogen-associated molecular patterns and initiating an inflammatory response. Significantly, TLRs commonly implicated in the immune response against viral infections include TLR2, TLR4, TLR6, TLR3, TLR7, and TLR8; limiting or allowing them to replicate and spread within the host. Modulating TLRs has emerged as a promising approach to combat arbovirus infections. This review summarizes recent advances in TLR modulation as a therapeutic target in arbovirus infections. Studies have shown that the activation of TLRs can enhance the immune response against arbovirus infections, leading to increased viral clearance and protection against disease. Conversely, inhibition of TLRs can reduce the excessive inflammation and tissue damage associated with arbovirus infection. Modulating TLRs represents a potential therapeutic strategy to combat arbovirus infections.

Sepsis, characterized as life-threatening organ dysfunction resulting from dysregulated host responses to infection, remains a significant challenge in clinical practice. Despite advancements in understanding host-bacterial interactions, molecular responses, and therapeutic approaches, the mortality rate associated with sepsis has consistently ranged between 10 and 16%. This elevated mortality highlights critical gaps in our comprehension of sepsis etiology. Traditionally linked to bacterial and fungal pathogens, recent outbreaks of acute viral infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), influenza virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), among other regional epidemics, have underscored the role of viral pathogenesis in sepsis, particularly when critically ill patients exhibit classic symptoms indicative of sepsis. However, many cases of viral-induced sepsis are frequently underdiagnosed because standard evaluations typically exclude viral panels. Moreover, these viruses not only activate conventional pattern recognition receptors (PRRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) but also initiate primary antiviral pathways such as cyclic guanosine monophosphate adenosine monophosphate (GMP-AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling and interferon response mechanisms. Such activations lead to cellular stress, metabolic disturbances, and extensive cell damage that exacerbate tissue injury while leading to a spectrum of clinical manifestations. This complexity poses substantial challenges for the clinical management of affected cases. In this review, we elucidate the definition and diagnosis criteria for viral sepsis while synthesizing current knowledge regarding its etiology, epidemiology, and pathophysiology, molecular mechanisms involved therein as well as their impact on immune-mediated organ damage. Additionally, we discuss clinical considerations related to both existing therapies and advanced treatment interventions, aiming to enhance the comprehensive understanding surrounding viral sepsis.

Apart from the skin and mucosal immune barrier, the first line of defense of the human immune system includes MDA5 (ifih1 gene) which acts as a cellular sensor protein for certain viruses including SARS-CoV-2. Upon binding with viral RNA, MDA5 activates cell-intrinsic innate immunity, humoral responses, and MAVS (mitochondrial antiviral signaling). MAVS signaling induces type I and III interferon (IFN) expressions that further induce ISGs (interferon stimulatory genes) expressions to initiate human cell-mediated immune responses and attenuate viral replication. SARS-CoV-2 counteracts by producing NSP1, NSP2, NSP3, NSP5, NSP7, NSP12, ORF3A, ORF9, N, and M protein and directs anti-MDA5 antibody production presumably to antagonize IFN signaling. Furthermore, COVID-19 resembles several diseases that carry anti-MDA5 antibodies and the current COVID-19 vaccines induced anti-MDA5 phenotypes in healthy individuals. GWAS (genome-wide association studies) identified several polymorphisms (SNPs) in the ifih1-ifn pathway genes including rs1990760 in ifih1 that are strongly associated with COVID-19, and the associated risk allele is correlated with reduced IFN production. The genetic association of SNPs in ifih1 and ifih1-ifn pathway genes reinforces the molecular findings of the critical roles of MDA5 in sensing SARS-CoV-2 and subsequently the IFN responses to inhibit viral replication and host immune evasion. Thus, MDA5 or its pathway genes could be targeted for therapeutic development of COVID-19.

Orf virus (ORFV) is an acute contact, epitheliotropic, zoonotic, and double-stranded DNA virus that causes significant economic losses in the livestock industry. The objective of this study is to design an immunoinformatics-based multi-epitope subunit vaccine against ORFV. Various immunodominant cytotoxic T lymphocytes (CTL), helper T lymphocytes (HTL), and B-cell epitopes from the B2L, F1L, and 080 protein of ORFV were selected and linked by short connectors to construct a multi-epitope subunit vaccine. Immunogenicity was enhanced by adding an adjuvant β-defensin to the N-terminal of the vaccine using the EAAAK linker. The vaccine exhibited a significant degree of antigenicity and solubility, without allergenicity or toxicity. The 3D formation of the vaccine was subsequently anticipated, improved, and verified. The optimized model exhibited a lower Z-score of -4.33, indicating higher quality. Molecular docking results demonstrated that the vaccine strongly binds to TLR2 and TLR4. Molecular dynamics results indicated that the docked vaccine-TLR complexes were stable. Immune simulation analyses further confirmed that the vaccine can induce a marked increase in IgG and IgM antibody titers, and elevated levels of IFN-γ and IL-2. Finally, the optimized DNA sequence of the vaccine was cloned into the vector pET28a (+) for high expression in the E.coli expression system. Overall, the designed multi-epitope subunit vaccine is highly stable and can induce robust humoral and cellular immunity, making it a promising vaccine candidate against ORFV.

Eikenella corrodens is a gram-negative, facultatively anaerobic bacterium typically found in the oropharynx and respiratory tract of humans. It is responsible for various infections, including head-and-neck infections, pericarditis, and abscesses of the deltoid, perirenal tissue, brain, and liver. Increasing antibiotic resistance requires urgent identification of novel drug targets to fight this bacterium. In this study, subtractive proteomics and immunoinformatics approaches were used to identify the most suitable candidates for multi-epitope vaccine development. A non-homologous and pathogenic protein, penicillin-binding protein 1A (PBP1A), was identified after extracting the entire proteome sequence of E. corrodens NCTC 10596. PBP1A is antigenic and necessary for pathogen survival. Helper T-cell (HTL), cytotoxic T-cell (CTL), and B-cell lymphocyte-inducing epitopes were integrated through immunoinformatic methods and rigorous immunological screening processes. Various physicochemical, allergenic, and antigenic properties were also evaluated to ensure the safety and immunogenicity of the vaccine candidates. Dynamic modeling and molecular docking techniques were used to examine the molecular interactions, thermodynamic stability, and binding affinities. The vaccine demonstrated a robust and consistent interaction with Toll-like receptors (TLRs), and its potential to elicit an immunological response was evaluated in silico. For in silico cloning, the final vaccine candidates were back-translated and cloned into an E. coli host to achieve high expression of the predicted protein. Computational analyses suggested that the proposed vaccine candidate shows promise for combating bacterial infections and eliciting a robust immune response. However, experimental validation is crucial to authenticate the precise safety and immunogenicity profiles of this vaccine.

Bovine respiratory syncytial virus (BRSV) is a major respiratory pathogen in cattle and is relevant to the livestock industry worldwide. BRSV is most severe in young calves and is often associated with stressful management events. The disease is responsible for economic losses due to lower productivity, morbidity, mortality, and prevention and treatment costs. As members of the same genus, bovine and human RSV share a high degree of homology and are similar in terms of their genomes, transmission, clinical signs, and epidemiology. This overlap presents an opportunity for One Health approaches and translational studies, with dual benefits; however, there is still a relative lack of studies focused on BRSV, and the continued search for improved prophylaxis highlights the need for a deeper understanding of its immunological features. BRSV employs different host-immunity-escaping mechanisms that interfere with effective long-term memory responses to current vaccines and natural infections. This review presents an updated description of BRSV's immunity processes, such as the PRRs and signaling pathways involved in BRSV infection, aspects of its pathogeny, and the evading mechanisms developed by the virus to thwart the immune response.

The COVID-19 pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has exposed the vulnerabilities and unpreparedness of the global healthcare system in dealing with emerging zoonoses. In the past two decades, coronaviruses (CoV) have been responsible for three major viral outbreaks, and the likelihood of future outbreaks caused by these viruses is high and nearly inevitable. Therefore, effective prophylactic universal vaccines targeting multiple circulating and emerging coronavirus strains are warranted.

This study utilized an immunoinformatic approach to identify evolutionarily conserved CD4+ (HTL) and CD8+ (CTL) T cells, and B-cell epitopes in the coronaviral spike (S) glycoprotein.

A total of 132 epitopes were identified, with the majority of them found to be conserved across the bat CoVs, pangolin CoVs, endemic coronaviruses, SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV). Their peptide sequences were then aligned and assembled to identify the overlapping regions. Eventually, two major peptide assemblies were derived based on their promising immune-stimulating properties.

In this light, they can serve as lead candidates for universal coronavirus vaccine development, particularly in the search for pan-coronavirus multi-epitope universal vaccines that can confer protection against current and novel coronaviruses.

Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by chronic urticarial rash and monoclonal immunoglobulin M (IgM) or IgG gammopathy. Viruses, including COVID-19, activate the innate immune system, therefore SchS, in which the innate immune system is improperly activated, is hypothesized to be exacerbated by viral infection. However, there were no reported SchS cases exacerbated by any viral infection. Here, we report a SchS case with an unusual IgA gammopathy manifested and exacerbated by COVID-19 infection. This report advocates the need for recognizing unusual cases of SchS with monoclonal IgA, and following up on paraprotein like IgA even when it is initially undetectable in cases with SchS symptoms. We also hypothesize that existing autoinflammatory diseases may be exacerbated by COVID-19 infection in the case of a combination of these diseases.

The potential of macrophage-mediated phagocytosis as a cancer treatment is promising. Blocking the CD47-SIRPα interaction with a CD47-specific antibody significantly enhances macrophage phagocytosis. However, concerns regarding their toxicity to nontumor cells remain substantial. Here, we engineered chimeric antigen receptor macrophages (CAR-Ms) by fusing a humanized single-chain variable fragment with FcγRIIa and integrating short hairpin RNA to silence SIRPα, thereby disrupting the CD47-SIRPα signaling pathway. These modified CAR-shSIRPα-M cells exhibited an M1-like phenotype, superior phagocytic function, substantial cytotoxic effects on HER2-positive tumor cells, and the ability to eliminate patient-derived organoids. In vivo, CAR-M cells significantly inhibited tumor growth and prolonged survival in tumor-bearing mice. Notably, CAR-shSIRPα-M cells enhanced cytotoxic T-cell infiltration into tumors, thereby enhancing the antitumor response in both the humanized immune system mouse model and immunocompetent mice. Mechanistically, SIRPα inhibition activated inflammatory pathways and the cGAS-STING signaling cascade in CAR-M cells, leading to increased production of proinflammatory cytokines, reactive oxygen species, and nitric oxide, thereby enhancing their antitumor effects. These findings underscore the potential of SIRPα inhibition as a novel strategy to increase the antitumor efficacy of CAR-M cells in cancer immunotherapy, particularly against solid tumors.

Toll-like receptors (TLRs) are a class of conserved pattern recognition receptors (PRRs) that are crucial for initiating the innate immune response and aiding in the clearance of pathogenic organisms. Many studies have identified TLR4 as a distinctive member of the TLR family, capable of activating both the Myeloid differentiation factor 88-dependent signaling pathway (MyD88-dependent) and the TIR-domain-containing adaptor inducing IFN-β dependent signaling pathway (TRIF-dependent). Nevertheless, the role of TLR4 in Cephalopoda is still largely unexplored. To elucidate the immune function of the OsTLR4-1 gene in Octopus sinensis, the OsTLR4-1 gene was first validated and analyzed in this study. The cDNA comprises a 2475 bp ORF region, encoding 824 amino acids. Evolutionary tree analysis indicated a high homology and a close phylogenetic relationship between the Octopus sinensis and other mollusks. RNA interference (RNAi) experiments demonstrated that the expression level of OsTLR4-1 gene and its protein in the lymphocytes of the RNAi group treated with OsTLR4-1 dsRNA was extremely significantly lower than that of the blank control group and negative control group (P < 0.01), and the expression of downstream genes of OsTLR4-1, including ligand MyD88, IRAK4, TRAF6, MKK6, Hsp90, COX2, TRAF3, and RIP1, were significantly down-regulated compared to the blank and negative control group (P < 0.01). Additionally, OsTLR4-1 expression in lymphocytes was highly significantly up-regulated in the LPS-treated group compared to the blank control group (P < 0.01), while its expression was extremely significantly lower in the LPS-treated group after OsTLR4-1 interference than in the blank control group (P < 0.01). The expression of its downstream effector genes Big Defensin (Big-Def) and histone H2A.V (H2A.V) was highly significantly up-regulated in lymphocytes in the LPS-treated group compared to the blank control group (P < 0.01), while their expression in the LPS-treated group after OsTLR4-1 interference was extremely significantly lower than that in the blank control group (P < 0.01). Through comparative transcriptome analysis of the RNAi group and the blank control group, it was found that differentially expressed genes were enriched in the Toll-like receptor signaling pathway, PI3K-AKT signaling pathway, P53 signaling pathway, MAPK signaling pathway, and NF-κB signaling pathway. qRT-PCR results of key genes in these pathways revealed a decrease in all genes except IκB and Jun2 genes. This study enhances our understanding of the immune function of the TLR gene family in O. sinensis and provides a foundation for further research into innate immune signaling pathways in cephalopods.

The bluetongue virus (BTV), transmitted by biting midges, poses a significant threat to livestock globally. This orbivirus induces bluetongue disease, leading to substantial economic losses in the agricultural sector. The current control measures have limitations, necessitating the development of novel, efficient vaccines. In this study, an immunoinformatics approach is employed to design a multi-epitope subunit vaccine for Ovis aries targeting six BTV serotypes. Focusing on the VP2 capsid protein, the vaccine incorporates B-cell, helper-T lymphocytes (HTL), and cytotoxic T-cell lymphocytes (CTL) epitopes. Molecular docking reveals stable interactions with TLR2 and TLR4 receptors, suggesting the stability of the complex, indicating the potential viability of the multi-epitope vaccine. The computational approach offers a rapid and tailored strategy for vaccine development, highlighting potential efficacy and safety against BTV outbreaks. This work contributes to understanding BTV and presents a promising avenue for effective control.

Discovered in late 2019, the SARS-CoV-2 coronavirus has caused the largest pandemic of the 21st century, claiming more than seven million lives. In most cases, the COVID-19 disease caused by the SARS-CoV-2 virus is relatively mild and affects only the upper respiratory tract; it most often manifests itself with fever, chills, cough, and sore throat, but also has less-common mild symptoms. In most cases, patients do not require hospitalization, and fully recover. However, in some cases, infection with the SARS-CoV-2 virus leads to the development of a severe form of COVID-19, which is characterized by the development of life-threatening complications affecting not only the lungs, but also other organs and systems. In particular, various forms of thrombotic complications are common among patients with a severe form of COVID-19. The mechanisms for the development of thrombotic complications in COVID-19 remain unclear. Accumulated data indicate that the pathogenesis of severe COVID-19 is based on disruptions in the functioning of various innate immune systems. The key role in the primary response to a viral infection is assigned to two systems. These are the pattern recognition receptors, primarily members of the toll-like receptor (TLR) family, and the complement system. Both systems are the first to engage in the fight against the virus and launch a whole range of mechanisms aimed at its rapid elimination. Normally, their joint activity leads to the destruction of the pathogen and recovery. However, disruptions in the functioning of these innate immune systems in COVID-19 can cause the development of an excessive inflammatory response that is dangerous for the body. In turn, excessive inflammation entails activation of and damage to the vascular endothelium, as well as the development of the hypercoagulable state observed in patients seriously ill with COVID-19. Activation of the endothelium and hypercoagulation lead to the development of thrombosis and, as a result, damage to organs and tissues. Immune-mediated thrombotic complications are termed "immunothrombosis". In this review, we discuss in detail the features of immunothrombosis associated with SARS-CoV-2 infection and its potential underlying mechanisms.

Head and neck cancer (HNC), primarily head and neck squamous cell carcinomas, originates from the squamous epithelium in areas like the oral cavity, lip, larynx, and oropharynx. With high morbidity impacting critical functions, combined treatments like surgery, radiation, and chemotherapy often fall short in advanced stages, highlighting the need for innovative therapies.

This review critically evaluates interleukin (IL) gene therapy for treating HNC. The discussion extends to key ILs in HNC, various gene therapy techniques and delivery methods. We particularly focus on the application of IL-2, IL-12, and IL-24 gene therapies, examining their mechanisms and outcomes in preclinical studies and clinical trials. The final sections address IL gene therapy challenges in HNC, exploring solutions and critically assessing future therapeutic directions.

Despite advancements in genomic and immunotherapy, significant challenges in HNC treatment persist, primarily due to the immunosuppressive nature of the tumor microenvironment and the adverse effects of current therapies. The therapeutic efficacy of IL gene therapy hinges on overcoming these hurdles through refined delivery methods that ensure targeted, tumor-specific gene expression. Future strategies should focus on refining gene delivery methods and combining IL gene therapy with other treatments to optimize efficacy and minimize toxicity.

Increasing evidence has been shown that OTUB1, a member of OTU deubiquitinases, is of importance in regulating the immune system. However, its molecular identification and functional characterization in teleosts are still rarely known. In this work, we cloned the otub1 of miiuy croaker (Miichthys miiuy), analyzed its sequence, structure, and evolution at genetic and protein levels, and determined its function in the antiviral immune response. The complete open reading frame (ORF) of miiuy croaker otub1 is 843 bp in length, encoding 280 amino acids. Miiuy croaker Otub1 has an OTU domain at the carboxyl terminus, which is a common functional domain that exists in OTU deubiquitinases. Molecular characteristics and evolution analysis results indicated that miiuy croaker Otub1, especially its functional domain, is highly conserved during evolution. The luciferase reporter assays showed that miiuy croaker Otub1 could significantly inhibit the poly(I:C) and Irf3-induced IFN1 and IFN-stimulated response element (ISRE) activation. Further experiments showed that miiuy croaker Otub1 decreases Irf3 protein abundance by promoting its proteasomal degradation. These data suggest that the evolutionarily conserved Otub1 acts as a suppressor in controlling antiviral immune response by promoting Irf3 proteasomal degradation in miiuy croaker.

Macrophages are dynamic innate immune cells that either reside in tissue, serving as sentinels, or recruited as monocytes from bone marrow into inflamed and infected tissue. In response to cues in the tissue microenvironment (TME), macrophages polarize on a continuum toward M1 or M2 with diverse roles in progression and resolution of disease. M1-like macrophages exhibit proinflammatory functions with antimicrobial and anti-tumorigenic activities, while M2-like macrophages have anti-inflammatory functions that generally resolve inflammatory responses and orchestrate a tissue healing process. Given these opposite phenotypes, proper spatiotemporal coordination of macrophage polarization in response to cues within the TME is critical to effectively resolve infectious disease and regulate wound healing. However, if this spatiotemporal coordination becomes disrupted due to persistent infection or dysregulated coagulation, macrophages' inappropriate response to these cues will result in the development of diseases with clinically unfavorable outcomes. Since plasticity and heterogeneity are hallmarks of macrophages, they are attractive targets for therapies to reprogram toward specific phenotypes that could resolve disease and favor clinical prognosis. In this review, we discuss how basic science studies have elucidated macrophage polarization mechanisms in TMEs during infections and inflammation, particularly coagulation. Therefore, understanding the dynamics of macrophage polarization within TMEs in diseases is important in further development of targeted therapies.

The contribution of placental immune responses to congenital Zika virus (ZIKV) syndrome remains poorly understood. Here, we leveraged a mouse model of ZIKV infection to identify mechanisms of innate immune restriction exclusively in the fetal compartment of the placenta. ZIKV principally infected mononuclear trophoblasts in the junctional zone, which was limited by mitochondrial antiviral-signaling protein (MAVS) and type I interferon (IFN) signaling mechanisms. Single nuclear RNA sequencing revealed MAVS-dependent expression of IFN-stimulated genes (ISGs) in spongiotrophoblasts but not in other placental cells that use alternate pathways to induce ISGs. ZIKV infection of Ifnar1-/- or Mavs-/- placentas was associated with greater infection of the adjacent immunocompetent decidua, and heterozygous Mavs+/- or Ifnar1+/- dams carrying immunodeficient fetuses sustained greater maternal viremia and tissue infection than dams carrying wild-type fetuses. Thus, MAVS-IFN signaling in the fetus restricts ZIKV infection in junctional zone trophoblasts, which modulates dissemination and outcome for both the fetus and the pregnant mother.

Hepatitis A and B are two crucial viral infections that still dramatically affect public health worldwide. Hepatitis A Virus (HAV) is the main cause of acute hepatitis, whereas Hepatitis B Virus (HBV) leads to the chronic form of the disease, possibly cirrhosis or liver failure. Therefore, vaccination has always been considered the most effective preventive method against pathogens. At this moment, we aimed at the immunoinformatic analysis of HAV-Viral Protein 1 (VP1) as the major capsid protein to come up with the most conserved immunogenic truncated protein to be fused by HBV surface antigen (HBs Ag) to achieve a bivalent vaccine against HAV and HBV using an AAY linker. Various computational approaches were employed to predict highly conserved regions and the most immunogenic B-cell and T-cell epitopes of HAV-VP1 capsid protein in both humans and BALB/c. Moreover, the predicted fusion protein was analyzed regarding primary and secondary structures and also homology validation. Afterward, the three-dimensional structure of vaccine constructs docked with various toll-like receptors (TLR) 2, 4 and 7. According to the bioinformatics tools, the region of 99-259 amino acids of VP1 was selected with high immunogenicity and conserved epitopes. T-cell epitope prediction showed that this region contains 32 antigenic peptides for Human leukocyte antigen (HLA) class I and 20 antigenic peptides in terms of HLA class II which are almost fully conserved in the Iranian population. The vaccine design includes 5 linear and 4 conformational B-cell lymphocyte (BCL) epitopes to induce humoral immune responses. The designed VP1-AAY-HBsAg fusion protein has the potency to be constructed and expressed to achieve a bivalent vaccine candidate, especially in the Iranian population. These findings led us to claim that the designed vaccine candidate provides potential pathways for creating an exploratory vaccine against Hepatitis A and Hepatitis B Viruses with high confidence for the identified strains.

Colder temperature exposure is a known trigger for pediatric asthma exacerbation. The induction of oxidative stress is a known pathophysiologic pathway for asthma exacerbation. However, the role of oxidative stress in linking colder temperature exposure and worsened pediatric asthma symptoms is poorly understood.

In a panel study involving 43 children with asthma, aged 5-13 years old, each child was visited 4 times with a 2-week interval. At each visit, nasal fluid, urine, and saliva samples were obtained and measured for biomarkers of oxidative stress in the nasal cavity (nasal malondialdehyde [MDA]), the circulatory system (urinary MDA), and the oral cavity (salivary MDA). Childhood Asthma-Control Test (CACT) was used to assess asthma symptoms.

When ambient daily-average temperature ranged from 7 to 18 °C, a 2 °C decrement in personal temperature exposures were significantly associated with higher nasal MDA and urinary MDA concentrations by 47-77% and 6-14%, respectively. We estimated that, of the decrease in child-reported CACT scores (indicating worsened asthma symptoms and asthma control) associated with colder temperature exposure, 14-57% were mediated by nasal MDA.

These results suggest a plausible pathway that colder temperature exposure worsens pediatric asthma symptoms partly via inducing nasal oxidative stress.

The role of oxidative stress in linking colder temperature exposure and worsened asthma symptoms is still poorly understood. Lower temperature exposure in a colder season was associated with higher nasal and systemic oxidative stress in children with asthma. Nasal MDA, a biomarker of nasal oxidative stress, mediated the associations between colder temperature exposures and pediatric asthma symptoms. The results firstly suggest a plausible pathway that colder temperature exposure worsens pediatric asthma symptoms partly via inducing oxidative stress in the nasal cavity.

The presence of moieties denoting viral infection is crucial to mount powerful cytotoxic T-cell immune responses acting through innate receptors such as Toll-like receptor 3. For cancer immunotherapy, several safe analogues of viral double-stranded RNA are under clinical development following compelling evidence for efficacy in mouse models. See related article by van Eijck et al., p. 3447.

Transmissible gastroenteritis virus (TGEV) is an etiological agent of enteric disease that results in high mortality rates in piglets. The economic impact of the virus is considerable, causing significant losses to the pig industry. The development of an efficacious subunit vaccine to provide promising protection against TGEV is of the utmost importance. The viral antigen, spike glycoprotein (S), is widely regarded as one of the most effective antigenic components for vaccine research. In this study, we employed immunoinformatics and molecular dynamics approaches to develop an 'ideal' multi-epitope vaccine. Firstly, the dominant, non-toxic, highly antigenic T (Th, CTL) and B cell epitopes predicted from the TGEV S protein were artificially engineered in tandem to design candidate subunit vaccines. Molecular docking and dynamic simulation results demonstrate that it exhibits robust interactions with toll-like receptor 4 (TLR4). Of particular significance was the finding that the vaccine was capable of triggering an immune response in mammals, as evidenced by the immune simulation results. The humoral aspect is typified by elevated levels of IgG and IgM, whereas the cellular immune aspect is capable of eliciting the robust production of interleukins and cytokines (IFN-γ and IL-2). Furthermore, the adoption of E. coli expression systems for the preparation of vaccines will also result in cost savings. This study offers logical guidelines for the development of a secure and efficacious subunit vaccine against TGEV, in addition to providing a novel theoretical foundation and strategy to prevent associated CoV infections.

The human immune system responds to harmful foreign invaders frequently encountered by the body and employs defense mechanisms to counteract such assaults. Various exogenous and endogenous factors play a prominent role in maintaining the balanced functioning of the immune system, which can result in immune suppression or immune stimulation. With the advent of different immune-modulatory agents, immune responses can be modulated or regulated to control infections and other health effects. Literature provides evidence on various immunomodulators from different sources and their role in modulating immune responses. Due to the limited efficacy of current drugs and the rise in drug resistance, there is a growing need for new therapies for infectious diseases. In this review, we aim to provide a comprehensive overview of different immune-modulating agents and immune therapies specifically focused on viral infectious diseases.

Rotavirus, a primary contributor to severe cases of infantile gastroenteritis on a global scale, results in significant morbidity and mortality in the under-five population, particularly in middle to low-income countries, including India. WHO-approved live-attenuated vaccines are linked to a heightened susceptibility to intussusception and exhibit low efficacy, primarily attributed to the high genetic diversity of rotavirus, varying over time and across different geographic regions. Herein, molecular data on Indian rotavirus A (RVA) has been reviewed through phylogenetic analysis, revealing G1P[8] to be the prevalent strain of RVA in India. The conserved capsid protein sequences of VP7, VP4 and VP6 were used to examine helper T lymphocyte, cytotoxic T lymphocyte and linear B-cell epitopes. Twenty epitopes were identified after evaluation of factors such as antigenicity, non-allergenicity, non-toxicity, and stability. These epitopes were then interconnected using suitable linkers and an N-terminal beta defensin adjuvant. The in silico designed vaccine exhibited structural stability and interactions with integrins (αvβ3 and αIIbβ3) and toll-like receptors (TLR2 and TLR4) indicated by docking and normal mode analyses. The immune simulation profile of the designed RVA multiepitope vaccine exhibited its potential to trigger humoral as well as cell-mediated immunity, indicating that it is a promising immunogen. These computational findings indicate potential efficacy of the designed vaccine against rotavirus infection.