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Most simian-human immunodeficiency viruses (SHIVs) bearing envelope (Env) glycoproteins from primary HIV-1 strains fail to infect rhesus macaques (RMs). We hypothesized that inefficient Env binding to rhesus CD4 (rhCD4) limits virus entry and replication and could be enhanced by substituting naturally occurring simian immunodeficiency virus Env residues at position 375, which resides at a critical location in the CD4-binding pocket and is under strong positive evolutionary pressure across the broad spectrum of primate lentiviruses. SHIVs containing primary or transmitted/founder HIV-1 subtype A, B, C, or D Envs with genotypic variants at residue 375 were constructed and analyzed in vitro and in vivo. Bulky hydrophobic or basic amino acids substituted for serine-375 enhanced Env affinity for rhCD4, virus entry into cells bearing rhCD4, and virus replication in primary rhCD4 T cells without appreciably affecting antigenicity or antibody-mediated neutralization sensitivity. Twenty-four RMs inoculated with subtype A, B, C, or D SHIVs all became productively infected with different Env375 variants-S, M, Y, H, W, or F-that were differentially selected in different Env backbones. Notably, SHIVs replicated persistently at titers comparable to HIV-1 in humans and elicited autologous neutralizing antibody responses typical of HIV-1. Seven animals succumbed to AIDS. These findings identify Env-rhCD4 binding as a critical determinant for productive SHIV infection in RMs and validate a novel and generalizable strategy for constructing SHIVs with Env glycoproteins of interest, including those that in humans elicit broadly neutralizing antibodies or bind particular Ig germ-line B-cell receptors.

Infected forearm nonunion is challenging to treat. We have used a vascularized pedicled bone graft from the distal ulna based on the posterior interosseous artery to treat forearm nonunion with current or previous signs of infection in six patients. Bone union was achieved after a mean of 3.8 months. After a mean follow-up of 25.7 months, no signs of persistent or reactivation of infection were seen in any patient. The mean Quick DASH score significantly improved from 77.4 to 17.6. In addition, the active range of motion of the wrist improved significantly after surgery. In our patients, a vascularized posterior interosseous pedicled bone from the distal ulna is a reliable vascularized bone graft for managing infected forearm nonunion., (© The Author(s) 2015.)

Even though intervertebral disc degeneration can be found in the natural course of alkaptonuria, detection of the disease by black disc color change in a patient without any other presentation of alkaptonuria is an exceptionally rare condition. We have reported a very rare case of alkaptonuria presented with low back pain and steppage gait in a 51-year-old male with a complaint of chronic low-back pain and steppage gait who was operated on for prolapsed lumbar disc herniation. Intraoperatively his lumbar disk was discovered to be black. The alkaptonuria diagnosis was considered after histopathological examination of the black disc material and elevated urinary concentration of homogentisic acid confirmed the diagnosis. To our knowledge, this presentation has not been reported previously in literature.

Autism spectrum disorder (ASD) is a fast-growing neurodevelopmental disorder throughout the world. Experiencing early life stresses (ELS) like maternal separation (MS) is associated with autistic-like behaviors. It has been proposed that disturbance in the gut-brain axis-mediated psychiatric disorders following MS. The role of disruption in the integrity of gut-brain barrier in ASD remains unclear. Addressing this knowledge gap, in this study we aimed to investigate role of the gut-brain barrier integrity in mediating autistic-like behaviors in mouse models of MS stress. To do this, mice neonates are separated daily from their mothers from postnatal day (PND) 2 to PND 14 for 3 hours. During PND58-60, behavioral tests related to autistic-like behaviors including three-chamber sociability, shuttle box, and resident-intruder tests were performed. Then, prefrontal cortex (PFC), hippocampus, and colon samples were dissected out for histopathological and molecular evaluations. Results showed that MS is associated with impaired sociability and social preference indexes, aggressive behaviors, and impaired passive avoidance memory. The gene expression of CLDN1 decreased in the colon, and the gene expression of CLDN5, CLDN12, and MMP9 increased in the PFC of the MS mice. MS is associated with decrease in the diameter of CA1 and CA3 areas of the hippocampus. In addition, MS led to histopathological changes in the colon. We concluded that, probably, disturbance in the gut-brain barrier integrities mediated the autistic-like behavior in MS stress in mice., (© 2024 International Society for Developmental Neuroscience.)

Epstein-Barr virus (EBV) can infect both B cells and epithelial cells (ECs), causing diseases such as mononucleosis and cancer. It enters ECs via Ephrin receptor A2 (EphA2). The function of interferon-induced transmembrane protein-1 (IFITM1) in EBV infection of ECs remains elusive. Here we report that IFITM1 inhibits EphA2-mediated EBV entry into ECs. RNA-sequencing and clinical sample analysis show reduced IFITM1 in EBV-positive ECs and a negative correlation between IFITM1 level and EBV copy number. IFITM1 depletion increases EBV infection and vice versa. Exogenous soluble IFITM1 effectively prevents EBV infection in vitro and in vivo. Furthermore, three-dimensional structure prediction and site-directed mutagenesis demonstrate that IFITM1 interacts with EphA2 via its two specific residues, competitively blocking EphA2 binding to EBV glycoproteins. Finally, YTHDF3, an m 6 A reader, suppresses IFITM1 via degradation-related DEAD-box protein 5 (DDX5). Thus, this study underscores IFITM1's crucial role in blocking EphA2-mediated EBV entry into ECs, indicating its potential in preventing EBV infection., (© 2024. The Author(s).)

Using the hybridoma technique, we developed a panel of anti-idiotypic monoclonal antibodies (aId-mAb) that mimic The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Receptor-Binding Domain (RBD) molecule against Fragment antigen-binding (Fab) of anti-SARS-CoV-2 (S1, RBD) antibodies. Investigated the in vivo and in vitro effects of these aId-mAbs we developed and examined their antigenic mimicry abilities. Among these 12 antibodies, 6 aId-mAbs (designated FY1B4, FY2A6, H9F3, E6G7, FY7E11, and FY8H3) were selected for further characterization in a series of experiments. First, competitive receptor binding assay results confirmed that six aId-mAbs could specifically bind to the ACE2 receptor in target cells and block the interaction between the RBD molecule and the ACE receptor. Moreover, we examined the immunological activities of these aId-mAbs in female BALB/c and showed that E6G7, H7E11, and H8H3 aId-mAbs induce an antibody response by mimicking RBD and stimulating the immune system. It is considered that these three aId-mAbs will be evaluated as SARS-CoV-2 vaccine candidate molecules in future studies., (© 2024. The Author(s).)

Objectives: This narrative review addresses relevant points about Chapare virus (CHAV) entry in oral cells, CHAV transmission, and preventive strategies in dental clinical settings. It is critical in dentistry due to the frequent presence of gingival hemorrhage occurred in CHAV-infected patients., Materials and Methods: Studies related to CHAV were searched in MEDLINE/PubMed, Scopus, EMBASE, and Web-of-Science databases without language restriction or year of publication., Results: Recently, the PAHO/WHO and CDC indicate a presence of human-to-human transmission of CHAV associated with direct contact with saliva, blood, or urine, and also through droplets or aerosols created in healthcare procedures. CHAV was detected in human oropharyngeal saliva and gingival bleeding was confirmed in all cases of CHAV hemorrhagic fever, including evidence of nosocomial CHAV transmission in healthcare workers. We revisited the human transferrin receptor 1 (TfR1) expression in oral, nasal, and salivary glands tissues, as well as, we firstly identified the critical residues in the pre-glycoprotein (GP) complex of CHAV that interacts with human TfR1 using cutting-edge in silico bioinformatics platforms associated with molecular dynamic analysis., Conclusions: In this multidisciplinary view, we also point out critical elements to provide perspectives on the preventive strategies for dentists and frontline healthcare workers against CHAV, and in the implementation of salivary diagnostic platforms for virus detection, which can be critical to an urgent plan to prevent human-to-human transmission based on current evidence., Clinical Relevance: The preventive strategies in dental clinical settings are pivotal due to the aerosol-generating procedures in dentistry with infected patients or suspected cases of CHAV infection., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Repeated intra-articular bleeding with subsequent development of chronic synovitis and cartilage changes, leading to haemophilic arthropathy, is one the most debilitating problems in haemophilic patients. Radiosynovectomy is a familiar therapeutic choice in management of chronic synovitis in haemophilia. We report the treatments results of synoviorthesis with 32P chromic phosphate with emphasis on clinical aspects. Between 2002 and 2006 we performed 66 procedures in 53 patients. Seven patients were excluded. The remaining 46 patients were followed for an average of 31 months. The mean age of patients at the time of injection was 15.9 years (range: 6–28). There were three repeat injections. According to Fernandez-pallazi and Cavilgia clinical classification ( Table 1 ) [ 23 ], nine joints were Stage II and 46 were Stage III. In latest follow-up, 77% of patients reported at least a 50% decrease in bleeding frequency after treatment ( P < 0.0001). The need for antihaemophilic factor consumption dropped by about 74% postradiosynovectomy ( P < 0.0001). In most of the injected joints, the range of motion remained stable or improved. A trend was found for the number of haemarthrosis to increase after a period of considerable improvement. Synoviorthesis using 32P effectively reduces the intra-articular bleeding rate and factor concentrate use. Durability of the response seems to be unpredictable, perhaps attributable to the late intervention. An early radiosynovectomy might be more helpful in terms of stability of response to treatment. [ABSTRACT FROM AUTHOR]

Phosphatidylserine (PS) receptors contribute to two crucial biological processes: apoptotic clearance and entry of many enveloped viruses. In both cases, they recognize PS exposed on the plasma membrane. Here we demonstrate that phosphatidylethanolamine (PE) is also a ligand for PS receptors and that this phospholipid mediates phagocytosis and viral entry. We show that a subset of PS receptors, including T-cell immunoglobulin (Ig) mucin domain protein 1 (TIM1), efficiently bind PE. We further show that PE is present in the virions of flaviviruses and filoviruses, and that the PE-specific cyclic peptide lantibiotic agent Duramycin efficiently inhibits the entry of West Nile, dengue, and Ebola viruses. The inhibitory effect of Duramycin is specific: it inhibits TIM1-mediated, but not L-SIGN-mediated, virus infection, and it does so by blocking virus attachment to TIM1. We further demonstrate that PE is exposed on the surface of apoptotic cells, and promotes their phagocytic uptake by TIM1-expressing cells. Together, our data show that PE plays a key role in TIM1-mediated virus entry, suggest that disrupting PE association with PS receptors is a promising broad-spectrum antiviral strategy, and deepen our understanding of the process by which apoptotic cells are cleared.

Hepatocellular carcinoma (HCC) is the 5(th) most common malignancy which is responsible for more than half million annual mortalities; also, it is the third leading cause of cancer related death. Unfavorable systemic side-effects of chemotherapeutic agents and susceptibility to the degradation of small interfering RNAs (siRNAs), which can knock down a specific gene involved in the disease, have hampered their clinical application. So, it could be beneficial to develop an efficient carrier for the stabilization and specific delivery of drugs and siRNA to cells. Targeted nanoparticles have gained considerable attention as an efficient drug and gene delivery system, which is due to their capability in achieving the highest accumulation of cytotoxic agents in tumor tissue, modifiable drug pharmacokinetic- and bio-distribution, improved effectiveness of treatment, and limited side-effects. Recent studies have shed more light on the advantages of novel drug loaded carrier systems vs free drugs. Most of the animal studies have reported improvement in treatment efficacy and survival rate using novel carrier systems. Targeted delivery may be achieved passively or actively. In passive targeting, no ligand as homing device is used, while targeting is achieved by incorporating the therapeutic agent into a macromolecule or nanoparticle that passively reaches the target organ. However, in active targeting, the therapeutic agent or carrier system is conjugated to a tissue or cell-specific receptor which is over-expressed in a special malignancy using a ligand called a homing device. This review covers a broad spectrum of targeted nanoparticles as therapeutic and non-viral siRNA delivery systems, which are developed for enhanced cellular uptake and targeted gene silencing in vitro and in vivo and their characteristics and opportunities for the clinical applications of drugs and therapeutic siRNA are discussed in this article. Asialoglycoprotein receptors, low-density lipoprotein, ganglioside GM1 cell surface ligand, epidermal growth factor receptor receptors, monoclonal antibodies, retinoic acid receptors, integrin receptors targeted by Arg-Gly-Asp peptide, folate, and transferrin receptors are the most widely studied cell surface receptors which are used for the site specific delivery of drugs and siRNA-based therapeutics in HCC and discussed in detail in this article.

The triggering receptor expressed on myeloid cells 2 (TREM2) is an Ig-like V-type receptor expressed by populations of myeloid cells in the central nervous system and periphery. Loss-of-function mutations in TREM2 cause a progressive, fatal neurodegenerative disorder called Nasu-Hakola disease. In addition, a TREM2 R47H coding variant was recently identified as a risk factor for late-onset Alzheimer disease. TREM2 binds various polyanionic molecules but no specific protein ligands have been identified. Here we show that TREM2 specifically binds apolipoprotein E, a well established participant in Alzheimer disease. TREM2-Ig fusions efficiently precipitate ApoE from cerebrospinal fluid and serum. TREM2 also binds recombinant ApoE in solution and immobilized ApoE as detected by ELISA. Furthermore, the Alzheimer disease-associated R47H mutation, and other artificial mutations introduced in the same location, markedly reduced the affinity of TREM2 for ApoE. These findings reveal a link between two Alzheimer disease risk factors and may provide important clues to the pathogenesis of Nasu-Hakola disease and other neurodegenerative disorders., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Unlabelled: The cytoplasmic tails of human and simian immunodeficiency virus (HIV and SIV, respectively) envelope glycoproteins contain a highly conserved, membrane-proximal endocytosis motif that prevents the accumulation of Env on the surface of infected cells prior to virus assembly. Using an assay designed to measure the killing of virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC), we show that substitutions in this motif increase the susceptibility of HIV-1- and SIV-infected cells to ADCC in a manner that directly correlates with elevated Env levels on the surface of virus-infected cells. In the case of HIV-1, this effect is additive with a deletion in vpu recently shown to enhance the susceptibility of HIV-1-infected cells to ADCC as a result of tetherin-mediated retention of budding virions on the cell surface. These results reveal a previously unappreciated role for the membrane-proximal endocytosis motif of gp41 in protecting HIV-1- and SIV-infected cells from antibody responses by regulating the amount of Env present on the cell surface., Importance: This study reveals an unappreciated role for the membrane-proximal endocytosis motif of gp41 in protecting HIV-1- and SIV-infected cells from elimination by Env-specific antibodies. Thus, strategies designed to interfere with this mechanism of Env internalization may improve the efficacy of antibody-based vaccines and antiretroviral therapies designed to enhance the immunological control of HIV-1 replication in chronically infected individuals., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

In the retina, rod and cone photoreceptors form distinct connections with different classes of downstream bipolar cells. However, the molecular mechanisms responsible for their selective connectivity are unknown. Here we identify a cell-adhesion protein, ELFN1, to be essential for the formation of synapses between rods and rod ON-bipolar cells in the primary rod pathway. ELFN1 is expressed selectively in rods where it is targeted to the axonal terminals by the synaptic release machinery. At the synapse, ELFN1 binds in trans to mGluR6, the postsynaptic receptor on rod ON-bipolar cells. Elimination of ELFN1 in mice prevents the formation of synaptic contacts involving rods, but not cones, allowing a dissection of the contributions of primary and secondary rod pathways to retinal circuit function and vision. We conclude that ELFN1 is necessary for the selective wiring of rods into the primary rod pathway and is required for high sensitivity of vision., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The management of early-stage osteonecrosis of the femoral head (ONFH) remains challenging. This study aimed to evaluate the effects of core decompression and concentrated bone marrow implantation on ONFH. The study recruited 28 hips with early ONFH randomly assigned into two groups of core decompression with (group A) and without (group B) bone marrow injection. Patients were evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, Visual Analogue Scale (VAS) pain index, and MRI. The mean WOMAC and VAS scores in all patients improved significantly (P<0.001). MRI showed a significant improvement in group A (P=0.046) and significant worsening in group B (P<0.001). Bone marrow stem cell injection with core decompression can be effective in early ONFH., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Primary knee osteoarthritis (OA) is one of the degenerative diseases that destroy auricular cartilage within knee joint and cause pain, varies deformity, decrease knee function. Total knee arthroplasty (TKA) is an effective intervention in order to relieve pain, improve function and QOL (quality of life) in patients with severe osteoarthritis of the knees that have different degrees of varus deformity. However, we are not aware of any study to shows if medial side defect in tibia has any association with outcome. We conceive this study of finding out if medial side defect of tibia affects the outcome. 124 patients (143 knees) with primary knee OA with different stages of defects participated in this study. Patients classified into two groups based on Rand classification of knee defects (patients with Rand I and II in group 1 and patients with Rand III and IV in group 2). Pain and knee alignment have been measured by Visual analog scale (VAS) and 3-joint X-ray and quality of life, knee function and radiographic have been measured by questionnaires of SF 36, WOMAC and KSS score. The mean follow-up was 18. 2 mounts (range 12 to 23 months). The results showed that all of the parameters improved significantly within groups (P≤0.001). Comparison TKA between two groups in the postoperative analysis shows that there was a significant difference between groups in pain, radiographic and functional KSS and WOMAC score (P≤0.05). So group 1 had better results in these parameters than group 2 after surgery. TKA is an effective intervention for all patients with severe osteoarthritis and varus deformity. However, the severity of medial tibial defects is an important determinant of outcome. Patients with a more severe deformity have less favorable outcome.

Unlabelled: Broadly cross-reactive neutralizing antibodies (bNabs) represent powerful tools to combat human immunodeficiency virus type 1 (HIV-1) infection. Here, we examined whether HIV-1-specific bNabs are capable of cross-neutralizing distantly related simian immunodeficiency viruses (SIVs) infecting central (Pan troglodytes troglodytes) (SIVcpzPtt) and eastern (Pan troglodytes schweinfurthii) (SIVcpzPts) chimpanzees (n = 11) as well as western gorillas (Gorilla gorilla gorilla) (SIVgor) (n = 1). We found that bNabs directed against the CD4 binding site (n = 10), peptidoglycans at the base of variable loop 3 (V3) (n = 5), and epitopes at the interface of surface (gp120) and membrane-bound (gp41) envelope glycoproteins (n = 5) failed to neutralize SIVcpz and SIVgor strains. In addition, apex V2-directed bNabs (n = 3) as well as llama-derived (heavy chain only) antibodies (n = 6) recognizing both the CD4 binding site and gp41 epitopes were either completely inactive or neutralized only a fraction of SIVcpzPtt strains. In contrast, one antibody targeting the membrane-proximal external region (MPER) of gp41 (10E8), functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Ig(mim2), CD4-218.3-E51, and CD4-218.3-E51-mim2), as well as mono- and bispecific anti-human CD4 (iMab and LM52) and CCR5 (PRO140, PRO140-10E8) receptor antibodies neutralized >90% of SIVcpz and SIVgor strains with low-nanomolar (0.13 to 8.4 nM) potency. Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5 and neutralized SIVcpz in chimpanzee CD4(+) T cells, with 50% inhibitory concentrations (IC50s) ranging from 3.6 to 40.5 nM. These findings provide new insight into the protective capacity of anti-HIV-1 bNabs and identify candidates for further development to combat SIVcpz infection., Importance: SIVcpz is widespread in wild-living chimpanzees and can cause AIDS-like immunopathology and clinical disease. HIV-1 infection of humans can be controlled by antiretroviral therapy; however, treatment of wild-living African apes with current drug regimens is not feasible. Nonetheless, it may be possible to curb the spread of SIVcpz in select ape communities using vectored immunoprophylaxis and/or therapy. Here, we show that antibodies and antibody-like inhibitors developed to combat HIV-1 infection in humans are capable of neutralizing genetically diverse SIVcpz and SIVgor strains with considerable breadth and potency, including in primary chimpanzee CD4(+) T cells. These reagents provide an important first step toward translating intervention strategies currently developed to treat and prevent AIDS in humans to SIV-infected apes., (Copyright © 2015 Barbian et al.)

Background: Surgical stress response is among the most severe stress tolerated by the patient, which needs suppression by anesthesia., Objectives: We assessed the effect of three methods of anesthesia on postoperative levels of pro-brain natriuretic peptide (pro-BNP) to determine the most effective one in preventing surgical stress response., Patients and Methods: In a randomized clinical trial, 120 patients who were 18 to 65 years old and met inclusion and exclusion criteria were selected and randomly allocated to three groups of 40:Group A, general anesthesia plus epidural catheter; Group B, general anesthesia and intravenous patient-controlled analgesia; and Group C, spinal anesthesia plus intravenous patient-controlled analgesia., Results: There was no difference between three groups for basic characteristics and variables and baseline pro-BNP levels; however, postoperative pro-BNP levels in Groups A, B, and C were respectively63.8 ± 10.1, 83.2 ± 12.3, and 51.5 ± 8.5 ng/L (ANOVA, P = 0.01)., Conclusions: The results of the current study suggested that spinal anesthesia plus intravenous patient-controlled analgesia have the most favorable cardiac effects regarding postoperative levels of pro-BNP.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus disease 2019 (COVID-19), which is a huge global health threat. Interleukin27 (IL-27) gene is a cytokine that produces antiviral proteins in an IFN-independent manner and stimulates both pro- and anti-inflammatory responses. Interferon induced transmembrane protein 3 (IFITM3) inhibits SARS-CoV2 infection by blocking SARSCoV-2 spike proteins which facilitate viral entrance and cell-to-cell fusion. The association between genetic variants and COVID-19 in Egyptians is still unclear. Hence, we sought to investigate the impact of the single nucleotide polymorphism of IL-27P28 rs153109 and IFITM3 rs12252 on the susceptibility and severity of SARS-CoV-2 in Egyptian patients. Methods: Our study included 242 SARS-CoV-2 patients were recruited from Main University Hospital, Alexandria University, Egypt, and 187 healthy controls. We subdivided the patient group into two subgroups: group A comprised mild/moderate cases (N = 42) (17.4%), and group B included severe/critical cases (N = 200) (82.6%). Genomic DNA was extracted from blood samples using the QIAamp DNA Blood Mini kit, then the PCR products of IL27 and IFITM3 were cut by FastDigest XhoI and MScI, respectively, for detection of SNPs of IL-27P28 rs153109 (-964A/G) and IFITM3 rs12252 (T>C). Results: The present study found a significant association between IL27 rs153109 (-964A/G) and SARS-CoV-2 infection susceptibility after adjusting for the risk factor (advanced age), IL27 rs153109 (-964A/G) AG genotype (OR = 2.791, 95% CI: 1.237–6.295, P = 0.013), AA genotype (OR = 2.385, 95% CI: 1.075–5.291, P = 0.033), and (AG+AA vs. GG) genotypes (OR = 2.558, 95% CI: 1.186–5.517, P = 0.017). On the other hand, the IFITM3 rs12252(T>C) CT genotype (OR = 1.419, 95% CI: 0.843–2.391, P = 0.188), CC genotype (OR = 2.132, 95% CI: 0.436–10.415, P = 0.350), and (C/T+C/C vs. TT) genotypes (OR = 1.466, 95% CI: 0.884–2.432, P = 0.138) did not show a statistically significant association with either susceptibility or the severity of SARS-CoV-2. Conclusion: IL27P28 rs153109 AG and AA genotypes of IL27 may be associated with the susceptibility of SARS-CoV-2 infection but not the severity. Concerning the IFITM3 rs12252 SNP, we could not confirm its influence on either susceptibility or the severity of SARS-CoV-2 in this Egyptian population. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 severity has been linked to immune factors, with excessive immune responses like cytokine storms contributing to mortality. However, the genetic basis of these immune responses is not well understood. This study aimed to explore the genetic connection between COVID-19 severity and blood cell traits, given their close relationship with immunity. Materials and methods: GWAS summary statistics for COVID-19 and blood cell counts were analyzed using Linkage Disequilibrium Score Regression (LDSC) to estimate genetic correlations and heritabilities. For traits with significant correlations, a Multi-Trait GWAS Analysis (MTAG) was performed to identify pleiotropic loci shared between COVID-19 and blood cell counts. Results: Our MTAG analysis identified four pleiotropic loci associated with COVID-19 severity, five loci linked to hospitalized cases, and one locus related to general patients. Among these, two novel loci were identified in the high-risk population, with rs55779981 located near RAVER1 and rs73009538 near CARM1. In hospitalized patients, two previously unrecognized loci were detected, namely, rs115545251 near GFI1 and rs3181049 near RAVER1 , while in general patients, rs11065822 near CUX2 emerged as a newly identified locus. We also identified potential target genes, including those involved in inflammation signaling (CARM1), endothelial dysfunction (INTS12), and antiviral immune response (RAVER1), which may require further investigation. Conclusion: Our study offers insights into the genetic overlap between COVID-19 and immune factors, suggesting potential directions for future research and clinical exploration. [ABSTRACT FROM AUTHOR]

The emergence of the COVID-19 pandemic made it critical to understand the immune and inflammatory responses to the SARS-CoV-2 virus. It became increasingly recognized that the immune response was a key mediator of illness severity and that its mechanisms needed to be better understood. Early infection of both tissue and immune cells, such as macrophages, leading to pyroptosis-mediated inflammasome production in an organ system critical for systemic oxygenation likely plays a central role in the morbidity wrought by SARS-CoV-2. Delayed transcription of Type I and Type III interferons by SARS-CoV-2 may lead to early disinhibition of viral replication. Cytokines such as interleukin-1 (IL-1), IL-6, IL-12, and tumor necrosis factor α (TNFα), some of which may be produced through mechanisms involving nuclear factor kappa B (NF-κB), likely contribute to the hyperinflammatory state in patients with severe COVID-19. Lymphopenia, more apparent among natural killer (NK) cells, CD8+ T-cells, and B-cells, can contribute to disease severity and may reflect direct cytopathic effects of SARS-CoV-2 or end-organ sequestration. Direct infection and immune activation of endothelial cells by SARS-CoV-2 may be a critical mechanism through which end-organ systems are impacted. In this context, endovascular neutrophil extracellular trap (NET) formation and microthrombi development can be seen in the lungs and other critical organs throughout the body, such as the heart, gut, and brain. The kidney may be among the most impacted extrapulmonary organ by SARS-CoV-2 infection owing to a high concentration of ACE2 and exposure to systemic SARS-CoV-2. In the kidney, acute tubular injury, early myofibroblast activation, and collapsing glomerulopathy in select populations likely account for COVID-19-related AKI and CKD development. The development of COVID-19-associated nephropathy (COVAN), in particular, may be mediated through IL-6 and signal transducer and activator of transcription 3 (STAT3) signaling, suggesting a direct connection between the COVID-19-related immune response and the development of chronic disease. Chronic manifestations of COVID-19 also include systemic conditions like Multisystem Inflammatory Syndrome in Children (MIS-C) and Adults (MIS-A) and post-acute sequelae of COVID-19 (PASC), which may reflect a spectrum of clinical presentations of persistent immune dysregulation. The lessons learned and those undergoing continued study likely have broad implications for understanding viral infections' immunologic and inflammatory consequences beyond coronaviruses. [ABSTRACT FROM AUTHOR]

The continuous emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants highlights the need to update coronavirus 2019 disease (COVID-19) vaccine components. Epitope-based vaccine designs targeting conserved and immunorecessive regions of SARS-CoV-2 are critically needed. Here, we report an engineered epitope-focused immunogen design based on a novel horseshoe-shaped natural protein scaffold, named ribonuclease inhibitor 1 (RNH1), that can multiply display of conserved neutralizing epitopes from SARS-CoV-2 S2 stem helix. The designed immunogen RNH1-S1139 demonstrates high binding affinity to S2-specific neutralizing antibodies and elicits robust epitope-targeted antibody responses either through homologous or heterologous vaccination regimens. RNH1-S1139 immune serum has been proven to have similar binding ability against SARS-CoV, SARS-CoV-2 and its variants, providing broad-spectrum protection as a membrane fusion inhibitor. Further studies showed that RNH1 has the potential to serve as a versatile scaffold that displays other helical epitopes from various antigens, including respiratory syncytial virus (RSV) F glycoprotein. Our proposed immunogen engineering strategy via tailored horseshoe-shape nano-scaffold supports the continued development of epitope-focused vaccines as part of a next-generation vaccine design. [ABSTRACT FROM AUTHOR]

The novel HIV-1 drugs GS-CA1 and the recently approved lenacapavir (GS-6207) target the viral structural protein capsid (CA). However, their multiple mechanisms of action have not been fully characterized. Here, we investigated the effects of GS-CA1 on the early stages of HIV-1 infection, specifically the steps involving the nuclear envelope, in comparison to the antiviral cytokine IFN-β. Mass spectrometry data indicated that nuclear envelope proteins were only modestly affected by either GS-CA1 treatment or HIV-1 infection, but combining the two had a more significant impact, altering the levels of many proteins including proteasomal components. GS-CA1 induced a small but clear accumulation of HIV-1 capsid cores at nuclear pores, as seen by microscopy, whereas IFN-β caused a strong accumulation of HIV-1 cores at the nuclear envelope but not specifically at nuclear pores. These observations are consistent with GS-CA1 inhibiting the nuclear translocation of HIV-1 capsid cores through nuclear pores. [ABSTRACT FROM AUTHOR]

Objective: Following a significant relaxation of restrictions in China on December 7, 2022, after a surge in SARS-CoV-2 infections, an uptick in women presenting with menstrual disorders was observed in clinics. This study aimed to explore the alterations in menstrual characteristics and associated factors post SARS-CoV-2 infection. Methods: A cross-sectional online survey was conducted among 869 non-amenorrheic adult Chinese females (aged 18–53) to study the changes in menstrual characteristics and other infection-related factors post initial SARS-CoV-2 infection. The reported menstrual changes (group A) were compared to the reported no menstrual changes (group B). Data collected included basic individual-level information such as age, height, weight, menstrual history, reproductive and menstrual disorders, chronic diseases, SARS-CoV-2 vaccination status, COVID-19 symptoms, and changes in menstrual characteristics (regularity, period volume, and degree of dysmenorrhea) post SARS-CoV-2 infection. Results: Of the 869 participants, 442 (50.9%, group A) reported alterations in at least one menstrual characteristic; 171 (19.7%) experienced an extended menstrual cycle, and 122 (14.0%) reported a decrease in menstrual volume. Participants who reported menstrual changes (group A) were more likely to have pre-existing chronic diseases (7.7% vs. 3.0%, P = 0.003) and exhibit more symptoms of COVID-19 during the acute (4.94 vs. 4.03, P < 0.001) and recovery (4.37 vs. 3.41, P < 0.001) phases. These participants were also more likely to report fever as a COVID-19 symptom (93.4% vs. 86.9%, P = 0.001) and experienced a longer duration of fever (2.25 vs. 1.96 days, P = 0.001) as compared to group B. Notably, group A with chronic diseases, fewer vaccine doses, and more COVID-19-related symptoms experienced more frequent menstrual changes post COVID-19 (P < 0.05) than group B. Conclusion: Participants with chronic diseases, fewer vaccination doses, and more COVID-19-related symptoms may experience more frequent menstrual changes post COVID-19 infection according to the self-report results in this study. [ABSTRACT FROM AUTHOR]

The recent SARS-CoV-2 pandemic has underscored the significance of viral infections, affecting billions of lives and costing trillions of dollars globally. Even beyond SARS-CoV-2, common infections with viruses like influenza, HIV, and herpesviruses have profound impacts beyond their typical manifestations, often triggering acute and chronic pain syndromes that can be life-altering. These virally induced pain states can arise through direct viral replication within neurons, or indirectly, via immune responses to infection in both the contexts of afferent signaling in the dorsal root ganglion (DRG) or subsequent higher order integration in intracranial systems. Varicella-zoster virus (VZV), influenza virus, and SARS-CoV-2 each provide a unique lens through which to examine the interplay between viral activity and pain. This perspective paper is not meant to be an exhaustive review of virally-induced neuropathic pain states. It seeks to explore curated aspects of the complexities of these pain states, identify research gaps, and suggest solutions using nanoscale molecular understanding and psychoneuroimmunological and biopsychosocial frameworks. Each subheading is accompanied by a list of related issues for study which we think will lead to advances in our understanding of the vexing pain phenotype associated with viral infection. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) has been a challenging pandemic since late 2019 and patients with COVID-19-related severe respiratory failure associated with high mortality rates worldwide. Genetic information such as single nucleotide polymorphisms (SNPs) serves as a predictor or prognostic factor in disease development and cancer progression. This study aimed to explore the clinical associations of SNPs with mild and severe COVID-19 symptoms in the Taiwanese population. Methods: SARS-CoV-2-infected patients in pilot cohort study (cohort 1, n = 39) and validation cohort (cohort 2, n = 71) were enrolled. The clinical significance of SNPs in those patients with mild and severe symptoms was investigated by whole exon sequencing, polymerase chain reaction and Sanger sequencing. Results: The current study investigated Taiwanese patients with COVID-19. We found that clinical parameters such as age, aspartate aminotransferase, blood urea nitrogen, C-reactive protein, ferritin, and segment were positively associated with severe COVID-19 symptoms but that albumin, lymphocytes, and basophils correlated negatively with severe symptoms in two independent cohorts. By conducting whole-exome sequencing, we identified a novel SNP, ZNF717-rs2918520, the GG genotype of which was significantly associated with severe symptoms in COVID-19 patients. Conclusions: Our findings highlight that the ZNF717-rs2918520 GG genotype may serve as a predictor for evaluating the severity of COVID-19 in Taiwan. [ABSTRACT FROM AUTHOR]

Betacoronaviruses pose an ongoing pandemic threat. Antigenic evolution of the SARS-CoV-2 virus has shown that much of the spontaneous antibody response is narrowly focused rather than broadly neutralizing against even SARS-CoV-2 variants, let alone future threats. One way to overcome this is by focusing the antibody response against better-conserved regions of the viral spike protein. This has been demonstrated empirically in prior work, but we posit that systematic design tools will further potentiate antigenic focusing approaches. Here, we present a design approach to predict stable chimeras between SARS-CoV-2 and other coronaviruses, creating synthetic spike proteins that display a desired conserved region, in this case S2, and vary other regions. We leverage AlphaFold to predict chimeric structures and create a new metric for scoring chimera stability based on AlphaFold outputs. We evaluated 114 candidate spike chimeras using this approach. Top chimeras were further evaluated using molecular dynamics simulation as an intermediate validation technique, showing good stability compared to low-scoring controls. Experimental testing of five predicted-stable and two predicted-unstable chimeras confirmed 5/7 predictions, with one intermediate result. This demonstrates the feasibility of the underlying approach, which can be used to design custom immunogens to focus the immune response against a desired viral glycoprotein epitope. Author summary: Viral spike glycoproteins often show great antigenic variability in the most immunogenic regions, while broadly neutralizing antibodies frequently recognize secondary sites. This raises the question of how to elicit antibodies against less immunogenic but more conserved antigenic regions. Prior proof-of-concept studies have shown that a series of chimeric antigens can elicit such responses if the highly immunogenic regions are varied and the desired antigenic regions are held fixed. This introduces a protein design question: how to select viral spike chimeras that have comparable or increased stability compared to wild-type parent sequences. This study leverages structural modeling with AlphaFold to predict the stability of chimeric coronavirus spike proteins, selecting a set of low-homology but high-stability chimeras. These chimeras were then computationally validated using molecular dynamics simulation and experimentally tested. The resulting chimeric spike proteins represent a starting point for further chimeric immunization strategies, and the underlying tools provide a general means to design chimeric proteins to assist future immunization strategies aimed at generating antigenically focused and potentially more broadly neutralizing immune responses. [ABSTRACT FROM AUTHOR]

SERINC5 (serine incorporator 5), a member of the serine incorporator family, has been identified as a retrovirus restriction factor that inhibits the fusion of virions with the plasma membrane, thus blocking the release of the viral core into target cells and subsequently attenuating viral infectivity. Several viruses, such as human immunodeficiency virus (HIV), murine leukemia virus (MLV), and equine infectious anemia virus (EIAV), have evolved mechanisms to antagonize the host protein SERINC5 through HIV Nef, MLV glycosylated Gag, and the EIAV S2 protein. These viral proteins degrade SERINC5 on the cell surface through the endolysosomal system. In addition to its direct antiviral ability, SERINC5 also modulates immunity to inhibit the replication of retroviruses and nonretroviruses. This review summarizes the interaction between SERINC5 and viral replication, providing a promising avenue for fighting viral diseases. [ABSTRACT FROM AUTHOR]

Background: Few previous studies have addressed the impact of COVID-19 infection status on assisted reproductive technology outcomes. The purpose of this study was to assess whether COVID-19 infection affects ovulation induction outcomes and the laboratory outcomes of women undergoing assisted reproductive technology treatment. Methods: In total, 363 patients were divided into three groups: the COVID-19 infection group (group A, n = 49), the COVID-19 recovery group (group B, n = 119) and the COVID-19 non-infection group (group C, n = 195). Intergroup comparisons of baseline characteristics, stimulation characteristics and laboratory outcomes were performed. Results: The Gn dosage in group A was significantly higher than those in groups B and C. The duration of Gn treatment was longer in group A than in group B. In group B, the number of high-quality blastocysts was lower than that in group C. The rates of blastocyst formation (42.56%) and high-quality blastocyst formation (12.05%) in group B were significantly lower than those in group A (51.51%; P = 0.003, 16.58%; P = 0.026) and C (48.20%; P = 0.005, 16.49%; P = 0.002). The high-quality blastocyst rate in group C (34.20%) was the highest and was different from that in group B (28.33%). The main risk factor for high-quality blastocyst formation according to multivariate logistic regression analysis was recovery from COVID-19 (0.599, 95% CI: 0.360–0.996; P = 0.048). Conclusion: Asymptomatic or mild COVID-19 infection prior to oocyte retrieval may not has a significant negative effect on ovulation induction outcomes or laboratory outcomes, although the number of Gn days and dose of Gn may increase. In addition, we should pay attention to infertile women recovering from COVID-19 infection and be aware of the significant reduction in the number of high-quality blastocysts in this population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses an ongoing threat to the efficacy of vaccines and therapeutic antibodies. Mutations predominantly affect the receptor-binding domain (RBD) of the spike protein, which mediates viral entry. The RBD is also a major target of monoclonal antibodies that were authorised for use during the pandemic. In this study, an in silico approach was used to investigate the mutational landscape of SARS-CoV-2 RBD variants, including currently circulating Omicron subvariants. A total of 40 single-point mutations were assessed for their potential effect on protein stability and dynamics. Destabilising effects were predicted for mutations such as L455S and F456L, while stabilising effects were predicted for mutations such as R346T. Conformational B-cell epitope predictions were subsequently performed for wild-type (WT) and variant RBDs. Mutations from SARS-CoV-2 variants were located within the predicted epitope residues and the epitope regions were found to correspond to the sites targeted by therapeutic antibodies. Furthermore, homology models of the RBD of SARS-CoV-2 variants were generated and were utilised for protein–antibody docking. The binding characteristics of 10 monoclonal antibodies against WT and 14 SARS-CoV-2 variants were evaluated. Through evaluating the binding affinities, interactions, and energy contributions of RBD residues, mutations that were contributing to viral evasion were identified. The findings from this study provide insight into the structural and molecular mechanisms underlying neutralising antibody evasion. Future antibody development could focus on broadly neutralising antibodies, engineering antibodies with enhanced binding affinity, and targeting spike protein regions beyond the RBD. [ABSTRACT FROM AUTHOR]

Spike protein is a surface glycoprotein of the SARS-CoV-2 coronavirus, providing interaction of the coronavirus with angiotensin-converting enzyme 2 (ACE2) on the host cell. The cytoplasmic tail of the S protein plays an important role in an intracellular transport and translocation of the glycoprotein to the plasma membrane. The cytoplasmic domain of the S protein contains binding sites for COPI, COPII, and SNX27, which are required for the intracellular trafficking of this glycoprotein. In addition, the cytoplasmic domain of the S protein contains S-palmitoylation sites. S-palmitoylation increases the hydrophobicity of the S protein by regulating its transport to the plasma membrane. The cytoplasmic tail of the S protein has a signaling sequence that provides interaction with the ERM family proteins, which may mediate communication between the cell membrane and the actin cytoskeleton. This review examines the role of the cytoplasmic tail of the SARS-CoV-2 S protein in its intracellular transport and translocation to the plasma membrane. Understanding these processes is necessary not only for the development of vaccines based on mRNA or adenovirus vectors encoding the full-length spike (S) protein, but also for the therapy of the new coronavirus infection (COVID-19). [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), the leading cause of dementia, is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. This condition casts a significant shadow on global health due to its complex and multifactorial nature. In addition to genetic predispositions, the development of AD is influenced by a myriad of risk factors, including aging, systemic inflammation, chronic health conditions, lifestyle, and environmental exposures. Recent advancements in understanding the complex pathophysiology of AD are paving the way for enhanced diagnostic techniques, improved risk assessment, and potentially effective prevention strategies. These discoveries are crucial in the quest to unravel the complexities of AD, offering a beacon of hope for improved management and treatment options for the millions affected by this debilitating disease. [ABSTRACT FROM AUTHOR]

Background/ Objectives: Long COVID or post-acute sequelae of SARS-CoV-2 infection (PASC) are symptoms that manifest despite passing the acute infection phase. These manifestations encompass a wide range of symptoms, the most common being fatigue, shortness of breath, and cognitive dysfunction. Genetic predisposition is clearly involved in the susceptibility of individuals to developing these persistent symptoms and the variation in the severity and forms. This review summarizes the role of genetic factors and gene polymorphisms in the development of major pulmonary vascular disorders associated with long COVID. Methods: A comprehensive review of current literature was conducted to examine the genetic contributions to pulmonary complications following SARS-CoV-2 infection. Studies investigating genetic polymorphisms linked to pulmonary hypertension, pulmonary thromboembolism, and pulmonary vascular endothelialitis were reviewed and summarized. Results: Findings show that specific genetic variants contribute to increased susceptibility to pulmonary vascular complications in long COVID patients. Variants associated with endothelial dysfunction, coagulation pathways, and inflammatory responses have been implicated in the development of pulmonary hypertension and thromboembolic events. Genetic predispositions influencing vascular integrity and immune responses appear to influence disease severity and progression. Conclusions: Understanding these mechanisms and genetic predispositions could pave the way for targeted therapeutic interventions to alleviate the burden on patients experiencing long COVID. [ABSTRACT FROM AUTHOR]

In 2021, at the height of the COVID-19 pandemic, coronavirus research spiked, with over 83,000 original research articles related to the word "coronavirus" added to the online resource PubMed. Just 2 years later, in 2023, only 30,900 original research articles related to the word "coronavirus" were added. While, irrefutably, the funding of coronavirus research drastically decreased, a possible explanation for the decrease in interest in coronavirus research is that projects on SARS-CoV-2, the causative agent of COVID-19, halted due to the challenge of establishing a good cellular or animal model system. Most laboratories do not have the capabilities to culture SARS-CoV-2 'in house' as this requires a Biosafety Level (BSL) 3 laboratory. Until recently, BSL 2 laboratory research on endemic coronaviruses was arduous due to the low cytopathic effect in isolated cell culture infection models and the lack of means to quantify viral loads. The purpose of this review article is to compare the human coronaviruses and provide an assessment of the latest techniques that use the endemic coronaviruses—HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1—as lower-biosafety-risk models for the more pathogenic coronaviruses—SARS-CoV-2, SARS-CoV, and MERS-CoV. [ABSTRACT FROM AUTHOR]

The first infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the coronavirus disease 2019 (COVID-19), occurred in December 2019. Within a single month, the disease reached other countries, spreading in a rapid and generalized manner worldwide to cause the COVID-19 pandemic. In Brazil, the number of COVID-19 cases surpassed 38 million. This study was conducted to produce antibodies against SARS-CoV-2 and investigate the immunogenic potential of synthetic peptides containing partial sequences of the main proteins (spike, membrane, and nucleocapsid proteins). In addition, we evaluated the ability of the antibodies to impair the interaction between the spike S1 protein and human ACE-2 protein, which is the main route of entry of the virus into host cells. By immunizing horses with synthetic peptides, we obtained hyperimmune sera with specific anti-SARS-CoV-2 antibodies, which were fragmented to release the F(ab')2 portion that binds to the different SARS-CoV-2 proteins as a recombinant S1-protein and proteins from a viral lysate. The other F(ab')2 samples also impaired the interaction between S1 protein and ACE-2 proteins, showing high potential to prevent viral spreading. [ABSTRACT FROM AUTHOR]

Background/Objectives: The SARS-CoV-2's high mutations and replication rates contribute to its high infectivity and resistance to current vaccinations and treatments. The primary cause of resistance to most current treatments aligns within the coding regions for the spike S protein of SARS-CoV-2 that has mutated. As a potential novel immunotherapy, we generated a novel fusion protein composed of a soluble ACE2 (sACE2) linked to llama-derived anti-CD16 that targets different variants of spike proteins and enhances natural killer cells to target infected cells. Methods: Here, we generated a novel sACE2-AntiCD16VHH fusion protein using a Gly4Ser linker, synthesized and cloned into the pLVX-EF1alpha-IRES-Puro vector, and further expressed in ExpiCHO-S cells and purified using Ni+NTA chromatography. Results: The fusion protein significantly blocked SARS-CoV-2 alpha, beta, delta, gamma, and omicron S-proteins binding and activating angiotensin-converting enzyme receptor-2 (ACE2) on ACE2-expressing RAW-Blue macrophage cells and the secretion of several key inflammatory cytokines, G-CSF, MIP-1A, and MCP-1, implicated in the cytokine release storm (CRS). The sACE2-Anti-CD16VHH fusion protein also bridged NK cells to ACE2-expressing human lung carcinoma A549 cells and significantly activated NK-dependent cytotoxicity. Conclusions: The findings show that a VHH directed against CD16 could be an excellent candidate to be linked to soluble ACE2 to generate a bi-specific molecule (sACE2-AntiCD16VHH) suitable for bridging effector cells and infected target cells to inhibit SARS-CoV-2 variant spike proteins binding to the ACE2 receptor in the RAW-Blue cell line and pro-inflammatory cytokines and to activate natural killer cell cytotoxicity. [ABSTRACT FROM AUTHOR]

Background: The rapid advancement of the pandemic caused by SARS-CoV-2 and its variants reinforced the importance of developing easy-to-edit vaccines with fast production, such as multi-epitope DNA vaccines. The present study aimed to construct a synthetic antigen multi-epitope SARS-CoV-2 to produce a DNA vaccine. Methods: A database of previously predicted Spike and Nucleocapsid protein epitopes was created, and these epitopes were analyzed for immunogenicity, conservation, population coverage, and molecular docking. Results: A synthetic antigen with 15 epitopes considered immunogenic, conserved even in the face of variants and that were able to anchor themselves in the appropriate HLA site, together had more than 90% worldwide coverage. A multi-epitope construct was developed with the sequences of these peptides separated from each other by linkers, cloned into the pVAX1 vector. This construct was evaluated in vivo as a DNA vaccine and elicited T CD4+ and T CD8+ cell expansion in the blood and spleen. In hematological analyses, there was an increase in lymphocytes, monocytes, and neutrophils between the two doses. Furthermore, based on histopathological analysis, the vaccines did not cause any damage to the organs analyzed. Conclusions: The present study generated a multi-epitope synthetic vaccine antigen capable of generating antibody-mediated and cellular immune responses. [ABSTRACT FROM AUTHOR]

Severe acute respiratory symptom coronavirus 2 (SARS-CoV-2) infection occurs via the attachment of the spike (S) protein's receptor binding domain (RBD) to human ACE2 (hACE2). Natural polymorphisms in hACE2, particularly at the interface, may alter RBD–hACE2 interactions, potentially affecting viral infectivity across populations. This study identified the effects of six naturally occurring hACE2 polymorphisms with high allele frequency in the African population (S19P, K26R, M82I, K341R, N546D and D597Q) on the interaction with the S protein RBD of the BA.4/5 Omicron sub-lineage through post-molecular dynamics (MD), inter-protein interaction and dynamic residue network (DRN) analyses. Inter-protein interaction analysis suggested that the K26R variation, with the highest interactions, aligns with reports of enhanced RBD binding and increased SARS-CoV-2 susceptibility. Conversely, S19P, showing the fewest interactions and largest inter-protein distances, agrees with studies indicating it hinders RBD binding. The hACE2 M82I substitution destabilized RBD–hACE2 interactions, reducing contact frequency from 92 (WT) to 27. The K341R hACE2 variant, located distally, had allosteric effects that increased RBD–hACE2 contacts compared to WThACE2. This polymorphism has been linked to enhanced affinity for Alpha, Beta and Delta lineages. DRN analyses revealed that hACE2 polymorphisms may alter the interaction networks, especially in key residues involved in enzyme activity and RBD binding. Notably, S19P may weaken hACE2–RBD interactions, while M82I showed reduced centrality of zinc and chloride-coordinating residues, hinting at impaired communication pathways. Overall, our findings show that hACE2 polymorphisms affect S BA.4/5 RBD stability and modulate spike RBD–hACE2 interactions, potentially influencing SARS-CoV-2 infectivity—key insights for vaccine and therapeutic development. [ABSTRACT FROM AUTHOR]

Bovine coronavirus (BCoV) exhibits dual tissue tropism, infecting both the respiratory and enteric tracts of cattle. Viral entry into host cells requires a coordinated interaction between viral and host proteins. However, the specific cellular receptors and co-receptors facilitating BCoV entry remain poorly understood. Similarly, the roles of host proteases such as Furin, TMPRSS2, and Cathepsin-L (CTS-L), known to assist in the replication of other coronaviruses, have not been extensively explored for BCoV. This study aims to identify novel BCoV receptors and host proteases that modulate viral replication and tissue tropism. Bovine cell lines were infected with BCoV isolates from enteric and respiratory origins, and the host cell gene expression profiles post-infection were analyzed using next-generation sequencing (NGS). Differentially expressed genes encoding potential receptors and proteases were further assessed using in-silico prediction and molecular docking analysis. These analyses focused on known coronavirus receptors, including ACE2, NRP1, DPP4, APN, AXL, and CEACAM1, to identify their potential roles in BCoV infection. Validation of these findings was performed using the qRT-PCR assays targeting individual genes. We confirmed the gene expression profiles of these receptors and enzymes in some BCoV (+/−) lung tissues. Results revealed high binding affinities of 9-O-acetylated sialic acid and NRP1 to BCoV spike (S) and hemagglutinin-esterase (HE) proteins compared to ACE2, DPP4, and CEACAM1. Additionally, Furin and TMPRSS2 were predicted to interact with the BCoV-S polybasic cleavage site (RRSRR|A), suggesting their roles in S glycoprotein activation. This is the first study to explore the interactions of BCoV with multiple host receptors and proteases. Functional studies are recommended to confirm their roles in BCoV infection and replication. [ABSTRACT FROM AUTHOR]

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Sudan ebolavirus (SUDV), like Ebola ebolavirus (EBOV), poses a significant threat to global health and security due to its high lethality. However, unlike EBOV, there are no approved vaccines or treatments for SUDV, and its structural interaction with the endosomal receptor NPC1 remains unclear. This study compares the glycoproteins of SUDV and EBOV (in their proteolytically primed forms) and their binding to human NPC1 (hNPC1). The findings reveal that the SUDV glycoprotein binds significantly more strongly to hNPC1 than the EBOV glycoprotein. Using cryo-EM, we determined the structure of the SUDV glycoprotein/hNPC1 complex, identifying four key residues in the SUDV glycoprotein that differ from those in the EBOV glycoprotein and influence hNPC1 binding: Ile79, Ala141, and Pro148 enhance binding, while Gln142 reduces it. Collectively, these residue differences account for SUDV's stronger binding affinity for hNPC1. This study provides critical insights into receptor recognition across all viruses in the ebolavirus genus, including their interactions with receptors in bats, their suspected reservoir hosts. These findings advance our understanding of ebolavirus cell entry, tissue tropism, and host range. The structural basis for human NPC1 recognition by Sudan ebolavirus provides key insights into receptor binding, cell entry, tissue tropism, and host range, not only for Sudan virus but for the entire ebolavirus genus. [ABSTRACT FROM AUTHOR]