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Frontiers in Immunology 2024There are considerable avenues through which currently licensed influenza vaccines could be optimized. We tested influenza vaccination in a mouse model with two...
There are considerable avenues through which currently licensed influenza vaccines could be optimized. We tested influenza vaccination in a mouse model with two adjuvants: Sendai virus-derived defective interfering (SDI) RNA, a RIG-I agonist; and an amphiphilic imidazoquinoline (IMDQ-PEG-Chol), a TLR7/8 agonist. The negatively charged SDI RNA was formulated into lipid nanoparticles (LNPs) facilitating direct delivery of SDI RNA to the cytosol, where RIG-I sensing induces inflammatory and type I interferon responses. We previously tested SDI RNA and IMDQ-PEG-Chol as standalone and combination adjuvants for influenza and SARS-CoV-2 vaccines. Here, we tested two different ionizable lipids, K-Ac7-Dsa and S-Ac7-Dog, for LNP formulations. The LNPs were incorporated with SDI RNA to determine its potential as a combination adjuvant with IMDQ-PEG-Chol by evaluating the host immune response to vaccination and infection in immunized BALB/c mice. Adjuvanticity of IMDQ-PEG-Chol with and without empty or SDI-loaded LNPs was validated with quadrivalent inactivated influenza vaccine (QIV), showing robust induction of antibody titers and T-cell responses. Depending on the adjuvant combination and LNP formulation, humoral and cellular vaccine responses could be tailored towards type 1 or type 2 host responses with specific cytokine profiles that correlated with the protective responses to viral infection. The extent of protection conferred by different vaccine/LNP/adjuvant combinations was tested by challenging mice with a vaccine-matched strain of influenza A virus A/Singapore/gp1908/2015 IVR-180 (H1N1). Groups that received either LNP formulated with SDI or IMDQ-PEG-Chol, or both, showed very low levels of viral replication in their lungs at 5 days post-infection (DPI). These studies provide evidence that the combination of vaccines with LNPs and/or adjuvants promote antigen-specific cellular responses that can contribute to protection upon infection. Interestingly, we observed differences in humoral and cellular responses to vaccination between different groups receiving K-Ac7-Dsa or S-Ac7-Dog lipids in LNP formulations. The differences were also reflected in inflammatory responses in lungs of vaccinated animals to infection, depending on LNP formulations. Therefore, this study suggests that the composition of the LNPs, particularly the ionizable lipid, plays an important role in inducing inflammatory responses , which is important for vaccine safety and to prevent adverse effects upon viral exposure.
Topics: Animals; Influenza Vaccines; Nanoparticles; Mice; Adjuvants, Immunologic; Mice, Inbred BALB C; Orthomyxoviridae Infections; Female; Lipids; Vaccination; Adjuvants, Vaccine; Antibodies, Viral; Disease Models, Animal; Sendai virus; Influenza, Human; Liposomes
PubMed: 38711520
DOI: 10.3389/fimmu.2024.1370564 -
Virus Research Jul 2024Cnaphalocrocis medinalis granulovirus (CnmeGV), belonging to Betabaculovirus cnamedinalis, can infect the rice pest, the rice leaf roller. In 1979, a CnmeGV isolate,... (Comparative Study)
Comparative Study
Cnaphalocrocis medinalis granulovirus (CnmeGV), belonging to Betabaculovirus cnamedinalis, can infect the rice pest, the rice leaf roller. In 1979, a CnmeGV isolate, CnmeGV-EP, was collected from Enping County, China. In 2014, we collected another CnmeGV isolate, CnmeGV-EPDH3, at the same location and obtained the complete virus genome sequence using Illumina and ONT sequencing technologies. By combining these two virus isolates, we updated the genome annotation of CnmeGV and conducted an in-depth analysis of its genome features. CnmeGV genome contains abundant tandem repeat sequences, and the repeating units in the homologous regions (hrs) exhibit overlapping and nested patterns. The genetic variations within EPDH3 population show the high stability of CnmeGV genome, and tandem repeats are the only region of high genetic variation in CnmeGV genome replication. Some defective viral genomes formed by recombination were found within the population. Comparison analysis of the two virus isolates collected from Enping showed that the proteins encoded by the CnmeGV-specific genes were less conserved relative to the baculovirus core genes. At the genomic level, there are a large number of SNPs and InDels between the two virus isolates, especially in and around the bro genes and hrs. Additionally, we discovered that CnmeGV acquired a segment of non-ORF sequence from its host, which does not provide any new proteins but rather serves as redundant genetic material integrated into the viral genome. Furthermore, we observed that the host's transposon piggyBac has inserted into some virus genes. Together, dsDNA viruses could acquire non-coding genetic material from their hosts to expand the size of their genomes. These findings provide new insights into the evolution of dsDNA viruses.
Topics: Genome, Viral; Animals; Genetic Variation; Phylogeny; China; Granulovirus; Whole Genome Sequencing; Oryza; Tandem Repeat Sequences; Plant Diseases; Recombination, Genetic
PubMed: 38710287
DOI: 10.1016/j.virusres.2024.199390 -
Homozygous variant in abolishing triokinase activities is associated with isolated immunodeficiency.Journal of Medical Genetics May 2024Triokinase and FMN cyclase (TKFC) is a bifunctional enzyme involved in fructose metabolism. Triokinase catalyses the phosphorylation of fructose-derived glyceraldehyde...
BACKGROUND
Triokinase and FMN cyclase (TKFC) is a bifunctional enzyme involved in fructose metabolism. Triokinase catalyses the phosphorylation of fructose-derived glyceraldehyde (GA) and exogenous dihydroxyacetone (DHA), while FMN cyclase generates cyclic FMN. TKFC regulates the antiviral immune response by interacting with IFIH1 (MDA5). Previously reported pathogenic variants in are associated with either a multisystemic disease or isolated hypotrichosis with loose anagen hairs.
METHODS
Whole-exome sequencing identified a homozygous novel variant in (c.1624G>A; p.Gly542Arg) in an individual with a complex primary immunodeficiency disorder. The variant was characterised using enzymatic assays and yeast studies of mutant recombinant proteins.
RESULTS
The individual presented with chronic active Epstein-Barr virus disease and multiple bacterial and viral infections. Clinical investigations revealed hypogammaglobulinaemia, near absent natural killer cells and decreased memory B cells. Enzymatic assays showed that this variant displayed defective DHA and GA kinase activity while maintaining FMN cyclase activity. An allogenic bone marrow transplantation corrected the patient's immunodeficiency.
CONCLUSION
Our report suggests that TKFC may have a role in the immunological system. The pathological features associated with this variant are possibly linked with DHA/GA kinase inactivation through a yet an unknown mechanism. This report thus adds a possible new pathway of immunometabolism to explore further.
PubMed: 38697782
DOI: 10.1136/jmg-2024-109853 -
Proceedings of the National Academy of... May 2024Targeting proteins to specific subcellular destinations is essential in prokaryotes, eukaryotes, and the viruses that infect them. Chimalliviridae phages encapsulate...
Targeting proteins to specific subcellular destinations is essential in prokaryotes, eukaryotes, and the viruses that infect them. Chimalliviridae phages encapsulate their genomes in a nucleus-like replication compartment composed of the protein chimallin (ChmA) that excludes ribosomes and decouples transcription from translation. These phages selectively partition proteins between the phage nucleus and the bacterial cytoplasm. Currently, the genes and signals that govern selective protein import into the phage nucleus are unknown. Here, we identify two components of this protein import pathway: a species-specific surface-exposed region of a phage intranuclear protein required for nuclear entry and a conserved protein, PicA (Protein importer of chimalliviruses A), that facilitates cargo protein trafficking across the phage nuclear shell. We also identify a defective cargo protein that is targeted to PicA on the nuclear periphery but fails to enter the nucleus, providing insight into the mechanism of nuclear protein trafficking. Using CRISPRi-ART protein expression knockdown of PicA, we show that PicA is essential early in the chimallivirus replication cycle. Together, our results allow us to propose a multistep model for the Protein Import Chimallivirus pathway, where proteins are targeted to PicA by amino acids on their surface and then licensed by PicA for nuclear entry. The divergence in the selectivity of this pathway between closely related chimalliviruses implicates its role as a key player in the evolutionary arms race between competing phages and their hosts.
Topics: Viral Proteins; Bacteriophages; Protein Transport; Cell Nucleus; Virus Replication
PubMed: 38687783
DOI: 10.1073/pnas.2321190121 -
Emerging Microbes & Infections Dec 2024Hepatitis B virus (HBV) infection remains a major public health problem and, in associated co-infection with hepatitis delta virus (HDV), causes the most severe viral...
Hepatitis B virus (HBV) infection remains a major public health problem and, in associated co-infection with hepatitis delta virus (HDV), causes the most severe viral hepatitis and accelerated liver disease progression. As a defective satellite RNA virus, HDV can only propagate in the presence of HBV infection, which makes HBV DNA and HDV RNA the standard biomarkers for monitoring the virological response upon antiviral therapy, in co-infected patients. Although assays have been described to quantify these viral nucleic acids in circulation independently, a method for monitoring both viruses simultaneously is not available, thus hampering characterization of their complex dynamic interactions. Here, we describe the development of a dual fluorescence channel detection system for pan-genotypic, simultaneous quantification of HBV DNA and HDV RNA through a one-step quantitative PCR. The sensitivity for both HBV and HDV is about 10 copies per microliter without significant interference between these two detection targets. This assay provides reliable detection for HBV and HDV basic research in vitro and in human liver chimeric mice. Preclinical validation of this system on serum samples from patients on or off antiviral therapy also illustrates a promising application that is rapid and cost-effective in monitoring HBV and HDV viral loads simultaneously.
Topics: Hepatitis Delta Virus; Humans; Hepatitis B virus; Animals; Hepatitis D; Hepatitis B; Mice; Viral Load; RNA, Viral; Coinfection; DNA, Viral; Genotype; Sensitivity and Specificity
PubMed: 38687692
DOI: 10.1080/22221751.2024.2350167 -
European Journal of Gastroenterology &... Jun 2024Data on the management of Hepatitis B-Delta (HB-D) by hepatogastroenterologists (HGs) practicing in nonacademic hospitals or private practices are unknown in France.
BACKGROUND
Data on the management of Hepatitis B-Delta (HB-D) by hepatogastroenterologists (HGs) practicing in nonacademic hospitals or private practices are unknown in France.
OBJECTIVE
We aimed to evaluate the knowledge and practices of HGs practicing in nonacademic settings regarding HB-D.
METHODS
A Google form document was sent to those HGs from May to September 2021.
RESULTS
A total of 130 HGs (mean age, 45 years) have participated in this survey. Among HBsAg-positive patients, Delta infection was sought in only 89% of cases. Liver fibrosis was assessed using FibroScan in 77% of the cases and by liver biopsy in 81% of the cases. A treatment was proposed for patients with >F2 liver fibrosis in 49% of the cases regardless of transaminase levels and for all the patients by 39% of HGs. Responding HGs proposed a treatment using pegylated interferon in 50% of cases, bulevirtide in 45% of cases and a combination of pegylated interferon and bulevirtide in 40.5% of cases. Among the criteria to evaluate the treatment efficacy, a decrease or a normalization of transaminases was retained by 89% of responding HGs, a reduction of liver fibrosis score for 70% of them, an undetectable delta RNA and HBsAg for 55% of them and a 2 log 10 decline in delta viremia for 62% of the cases.
CONCLUSION
Hepatitis Delta screening was not systematically performed in HBsAg-positive patients despite the probable awareness and knowledge of the few responders who were able to prescribe treatments of hepatitis delta.
Topics: Adult; Female; Humans; Male; Middle Aged; Antiviral Agents; Biopsy; France; Gastroenterologists; Gastroenterology; Health Knowledge, Attitudes, Practice; Hepatitis B Surface Antigens; Hepatitis Delta Virus; Liver Cirrhosis; Practice Patterns, Physicians'; Hepatitis D
PubMed: 38683191
DOI: 10.1097/MEG.0000000000002707 -
Antiviral Research Jun 2024With the increasing momentum and success of monoclonal antibody therapy in conventional medical practices, there is a revived emphasis on the development of monoclonal... (Review)
Review
With the increasing momentum and success of monoclonal antibody therapy in conventional medical practices, there is a revived emphasis on the development of monoclonal antibodies targeting the hepatitis B surface antigen (anti-HBs) for the treatment of chronic hepatitis B (HBV) and hepatitis D (HDV). Combination therapies of anti-HBs monoclonal antibodies, and novel anti-HBV compounds and immunomodulatory drugs presenting a promising avenue to enhanced therapeutic outcomes in HBV/HDV cure regimens. In this review, we will cover the role of antibodies in the protection and clearance of HBV infection, the association of anti-HBV surface antigen antibodies (anti-HBs) in protection against HBV and how antibody effector functions, beyond neutralization, are likely necessary. Lastly, we will review clinical data from previous and ongoing clinical trials of passive antibody therapy to provide a state-of-the-are perspective on passive antibody therapies in combinations with additional novel agents.
Topics: Humans; Immunization, Passive; Hepatitis D; Hepatitis B virus; Hepatitis B Antibodies; Hepatitis B, Chronic; Animals; Hepatitis B Surface Antigens; Antibodies, Monoclonal; Hepatitis B; Antiviral Agents; Hepatitis Delta Virus
PubMed: 38679166
DOI: 10.1016/j.antiviral.2024.105893 -
Cell Reports. Medicine May 2024Stimulator of interferon genes (STING)-dependent signaling is requisite for effective anti-microbial and anti-tumor activity. STING signaling is commonly defective in...
Stimulator of interferon genes (STING)-dependent signaling is requisite for effective anti-microbial and anti-tumor activity. STING signaling is commonly defective in cancer cells, which enables tumor cells to evade the immunosurveillance system. We evaluate here whether intrinsic STING signaling in such tumor cells could be reconstituted by creating recombinant herpes simplex viruses (rHSVs) that express components of the STING signaling pathway. We observe that rHSVs expressing STING and/or cGAS replicate inefficiently yet retain in vivo anti-tumor activity, independent of oncolytic activity requisite on the trans-activation of extrinsic STING signaling in phagocytes by engulfed microbial dsDNA species. Accordingly, the in vivo effects of virotherapy could be simulated by nanoparticles incorporating non-coding dsDNA species, which comparably elicit the trans-activation of phagocytes and augment the efficacy of established cancer treatments including checkpoint inhibition and radiation therapy. Our results help elucidate mechanisms of virotherapeutic anti-tumor activity as well as provide alternate strategies to treat cancer.
Topics: Animals; Phagocytes; Humans; Mice; DNA; Membrane Proteins; Signal Transduction; Nucleotidyltransferases; Cell Line, Tumor; Neoplasms; Simplexvirus; Mice, Inbred C57BL; Oncolytic Virotherapy
PubMed: 38677283
DOI: 10.1016/j.xcrm.2024.101528 -
Chimia Apr 2024RNA, widely recognized as an information-carrier molecule, is capable of catalyzing essential biological processes through ribozymes. Despite their ubiquity, specific...
RNA, widely recognized as an information-carrier molecule, is capable of catalyzing essential biological processes through ribozymes. Despite their ubiquity, specific functions in a biological context and phenotypes based on the ribozymes' activity are often unknown. Here, we present the discovery of a subgroup of minimal HDV-like ribozymes, which reside 3' to viral tRNAs and appear to cleave the 3'-trailers of viral premature tRNA transcripts. This proposed tRNA-processing function is unprecedented for any ribozymes, thus, we designate this subgroup as theta ribozymes. Most theta ribozymes were identified in Caudoviricetes bacteriophages, the main constituent (>90%) of the mammalian gut virome. Intriguingly, our findings further suggest the involvement of theta ribozymes in the transition of certain bacteriophages between distinct genetic codes, thus possibly contributing to the phage lysis trigger. Our discovery expands the limited repertoire of biological functions attributed to HDV-like ribozymes and provides insights into the fascinating world of RNA catalysis.
Topics: RNA, Catalytic; RNA, Viral; RNA, Transfer; Bacteriophages; Hepatitis Delta Virus
PubMed: 38676609
DOI: 10.2533/chimia.2024.200