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Cell Reports May 2024DNA sensing is important for antiviral immunity. The DNA sensor cGAS synthesizes 2'3'-cyclic GMP-AMP (cGAMP), a second messenger that activates STING, which induces...
DNA sensing is important for antiviral immunity. The DNA sensor cGAS synthesizes 2'3'-cyclic GMP-AMP (cGAMP), a second messenger that activates STING, which induces innate immunity. cGAMP not only activates STING in the cell where it is produced but cGAMP also transfers to other cells. Transporters, channels, and pores (including SLC19A1, SLC46A2, P2X7, ABCC1, and volume-regulated anion channels (VRACs)) release cGAMP into the extracellular space and/or import cGAMP. We report that infection with multiple human viruses depletes some of these cGAMP conduits. This includes herpes simplex virus 1 (HSV-1) that targets SLC46A2, P2X7, and the VRAC subunits LRRC8A and LRRC8C for degradation. The HSV-1 protein UL56 is necessary and sufficient for these effects that are mediated at least partially by proteasomal turnover. UL56 thereby inhibits cGAMP uptake via VRAC, SLC46A2, and P2X7. Taken together, HSV-1 antagonizes intercellular cGAMP transfer. We propose that this limits innate immunity by reducing cell-to-cell communication via the immunotransmitter cGAMP.
Topics: Animals; Humans; HEK293 Cells; Herpes Simplex; Herpesvirus 1, Human; Nucleotides, Cyclic; Viral Proteins
PubMed: 38652659
DOI: 10.1016/j.celrep.2024.114122 -
Human Vaccines & Immunotherapeutics Dec 2024Few papers focus their attention on VZV vaccination effectiveness among people living with HIV (PLWH). Flanking the live attenuated vaccine (VZL) available, a newly... (Review)
Review
Few papers focus their attention on VZV vaccination effectiveness among people living with HIV (PLWH). Flanking the live attenuated vaccine (VZL) available, a newly recombinant vaccine (RZV) was recently introduced and approved for HZ prevention among adults. PLWH represents a population on which a particular attention should be applied, in order to guarantee the vaccine efficacy and safety. We performed a literature search in USNLM, PubMed, PubMed Central, PMC and Cochrane Library. From all the publications found eligible, data were extracted and processed per population, vaccine type, immunogenicity and ADRs. The review of the 13 included studies shows that both RZV and VZL are immunogenic and have an acceptable safety profile in adults and children living with HIV. However, given the lack of research available about vaccine efficacy in preventing VZV and HZ in PLWH, additional studies need to be performed, in order to achieve a full completeness of data.
Topics: Humans; Vaccines, Attenuated; HIV Infections; Herpes Zoster Vaccine; Vaccines, Synthetic; Herpes Zoster; Vaccines, Inactivated; Immunogenicity, Vaccine; Vaccine Efficacy; Herpesvirus 3, Human; Adult; Child; Vaccination; Chickenpox Vaccine
PubMed: 38650460
DOI: 10.1080/21645515.2024.2341456 -
Frontiers in Immunology 2024Bovine respiratory disease (BRD) is one of the most common diseases in the cattle industry worldwide; it is caused by multiple bacterial or viral coinfections, of which...
Bovine respiratory disease (BRD) is one of the most common diseases in the cattle industry worldwide; it is caused by multiple bacterial or viral coinfections, of which () and bovine herpesvirus type 1 (BoHV-1) are the most notable pathogens. Although live vaccines have demonstrated better efficacy against BRD induced by both pathogens, there are no combined live and marker vaccines. Therefore, we developed an attenuated and marker -BoHV-1 combined vaccine based on the HB150 and BoHV-1 gG-/tk- strain previously constructed in our lab and evaluated in rabbits. This study aimed to further evaluate its safety and protective efficacy in cattle using different antigen ratios. After immunization, all vaccinated cattle had a normal rectal temperature and mental status without respiratory symptoms. CD4, CD8, and CD19 cells significantly increased in immunized cattle and induced higher humoral and cellular immune responses, and the expression of key cytokines such as IL-4, IL-12, TNF-α, and IFN-γ can be promoted after vaccination. The 1.0 × 10 CFU of HB150 and 1.0 × 10 TCID BoHV-1 gG-/tk- combined strain elicited the most antibodies while significantly increasing IgG and cellular immunity after challenge. In conclusion, the HB150 and BoHV-1 gG-/tk- combined strain was clinically safe and protective in calves; the mix of 1.0 × 10 CFU of HB150 and 1.0 × 10 TCID BoHV-1 gG-/tk- strain was most promising due to its low amount of shedding and highest humoral and cellular immune responses compared with others. This study introduces an -BoHV-1 combined vaccine for application in the cattle industry.
Topics: Animals; Cattle; Herpesvirus 1, Bovine; Vaccines, Combined; Vaccines, Attenuated; Mycoplasma bovis; Viral Vaccines; Bacterial Vaccines; Cytokines; Antibodies, Viral; Antibodies, Bacterial; Mycoplasma Infections; Vaccines, Marker; Vaccination; Vaccine Efficacy; Immunity, Humoral; Bovine Respiratory Disease Complex
PubMed: 38646533
DOI: 10.3389/fimmu.2024.1367253 -
Virus Research Jul 2024Although all herpesviruses utilize a highly conserved replication machinery to amplify their viral genomes, different members may have unique strategies to modulate the...
Although all herpesviruses utilize a highly conserved replication machinery to amplify their viral genomes, different members may have unique strategies to modulate the assembly of their replication components. Herein, we characterize the subcellular localization of seven essential replication proteins of varicella-zoster virus (VZV) and show that several viral replication enzymes such as the DNA polymerase subunit ORF28, when expressed alone, are localized in the cytoplasm. The nuclear import of ORF28 can be mediated by the viral DNA polymerase processivity factor ORF16. Besides, ORF16 could markedly enhance the protein abundance of ORF28. Noteworthily, an ORF16 mutant that is defective in nuclear transport still retained the ability to enhance ORF28 abundance. The low abundance of ORF28 in transfected cells was due to its rapid degradation mediated by the ubiquitin-proteasome system. We additionally reveal that radicicol, an inhibitor of the chaperone Hsp90, could disrupt the interaction between ORF16 and ORF28, thereby affecting the nuclear entry and protein abundance of ORF28. Collectively, our findings imply that the cytoplasmic retention and rapid degradation of ORF28 may be a key regulatory mechanism for VZV to prevent untimely viral DNA replication, and suggest that Hsp90 is required for the interaction between ORF16 and ORF28.
Topics: Herpesvirus 3, Human; Humans; Viral Proteins; Virus Replication; Active Transport, Cell Nucleus; DNA-Directed DNA Polymerase; Cell Nucleus; Cytoplasm; Cell Line; DNA Replication
PubMed: 38643859
DOI: 10.1016/j.virusres.2024.199379 -
European Journal of Medicinal Chemistry May 2024New acyclic pyrimidine nucleoside phosphonate prodrugs with a 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid skeleton (O-DAPy nucleobase) were prepared...
Synthesis of LAVR-289, a new [(Z)-3-(acetoxymethyl)-4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid prodrug with pronounced antiviral activity against DNA viruses.
New acyclic pyrimidine nucleoside phosphonate prodrugs with a 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid skeleton (O-DAPy nucleobase) were prepared through a convergent synthesis by olefin cross-metathesis as the key step. Several acyclic nucleoside 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid prodrug exhibited in vitro antiviral activity in submicromolar or nanomolar range against varicella zoster virus (VZV), human cytomegalovirus (HCMV), human herpes virus type 1 (HSV-1) and type 2 (HSV-2), and vaccinia virus (VV), with good selective index (SI). Among them, the analogue 9c (LAVR-289) proved markedly inhibitory against VZV wild-type (TK+) (EC 0.0035 μM, SI 740) and for thymidine kinase VZV deficient strains (EC 0.018 μM, SI 145), with a low morphological toxicity in cell culture at 100 μM and acceptable cytostatic activity resulting in excellent selectivity. Compound 9c exhibited antiviral activity against HCMV (EC 0.021 μM) and VV (EC 0.050 μM), as well as against HSV-1 (TK-) (EC 0.0085 μM). Finally, LAVR-289 (9c) deserves further (pre)clinical investigations as a potent candidate broad-spectrum anti-herpesvirus drug.
Topics: Antiviral Agents; Prodrugs; Humans; DNA Viruses; Microbial Sensitivity Tests; Structure-Activity Relationship; Herpesvirus 1, Human; Molecular Structure; Herpesvirus 3, Human; Organophosphonates; Cytomegalovirus; Dose-Response Relationship, Drug; Vaccinia virus; Herpesvirus 2, Human
PubMed: 38643669
DOI: 10.1016/j.ejmech.2024.116412 -
Vaccine May 2024The application of recombinant herpesvirus of turkey, expressing the H9 hemagglutinin gene from low pathogenic avian influenza virus (LPAIV) H9N2 and the avian...
The application of recombinant herpesvirus of turkey, expressing the H9 hemagglutinin gene from low pathogenic avian influenza virus (LPAIV) H9N2 and the avian orthoavulavirus-1 (AOAV-1) (commonly known as Newcastle Disease virus (NDV)) fusion protein (F) as an rHVT-H9-F vaccine, is an alternative to currently used classical vaccines. This study investigated H9- and ND-specific humoral and mucosal responses, H9-specific cell-mediated immunity, and protection conferred by the rHVT-H9-F vaccine in specific pathogen-free (SPF) chickens. Vaccination elicited systemic NDV F- and AIV H9-specific antibody response but also local antibodies in eye wash fluid and oropharyngeal swabs. The ex vivo H9-specific stimulation of splenic and pulmonary T cells in the vaccinated group demonstrated the ability of vaccination to induce systemic and local cellular responses. The clinical protection against a challenge using a LPAIV H9N2 strain of the G1 lineage isolated in Morocco in 2016 was associated with a shorter duration of shedding along with reduced viral genome load in the upper respiratory tract and reduced cloacal shedding compared to unvaccinated controls.
Topics: Animals; Influenza A Virus, H9N2 Subtype; Chickens; Influenza in Birds; Influenza Vaccines; Antibodies, Viral; Virus Shedding; Specific Pathogen-Free Organisms; Newcastle disease virus; Poultry Diseases; Immunity, Cellular; Herpesvirus 1, Meleagrid; Vaccination; Immunity, Humoral; Genetic Vectors; Immunogenicity, Vaccine; Vaccines, Synthetic; Hemagglutinin Glycoproteins, Influenza Virus
PubMed: 38641498
DOI: 10.1016/j.vaccine.2024.04.038 -
Journal of Virology May 2024Alphaherpesvirus pseudorabies virus (PRV) causes severe economic losses to the global pig industry and has garnered increasing attention due to its broad host range...
Alphaherpesvirus pseudorabies virus (PRV) causes severe economic losses to the global pig industry and has garnered increasing attention due to its broad host range including humans. PRV has developed a variety of strategies to antagonize host antiviral innate immunity. However, the underlying mechanisms have not been fully elucidated. In our previous work, we demonstrated that non-muscle myosin heavy chain IIA (NMHC-IIA), a multifunctional cytoskeleton protein, attenuates innate immune responses triggered by RNA viruses. In the current study, we reported a previously unrecognized role of NMHC-IIA in counteracting PRV-induced cyclic GMP-AMP synthase (cGAS)-dependent type I interferon (IFN-I) production. Mechanistically, PRV infection led to an elevation of NMHC-IIA, strengthening the interaction between poly (ADP-ribose) polymerase 1 (PARP1) and cGAS. This interaction impeded cGAS recognition of PRV DNA and hindered downstream signaling activation. Conversely, inhibition of NMHC-IIA by Blebbistatin triggered innate immune responses and enhanced resistance to PRV proliferation both and . Taken together, our findings unveil that PRV utilizes NMHC-IIA to antagonize host antiviral immune responses via impairing DNA sensing by cGAS. This in-depth understanding of PRV immunosuppression not only provides insights for potential PRV treatment strategies but also highlights NMHC-IIA as a versatile immunosuppressive regulator usurped by both DNA and RNA viruses. Consequently, NMHC-IIA holds promise as a target for the development of broad-spectrum antiviral drugs.IMPORTANCECyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in counteracting alphaherpesvirus infections. Alphaherpesviruses exploit various strategies for antagonizing cGAS-STING-mediated antiviral immune responses. However, limited examples of pseudorabies virus (PRV)-caused immunosuppression have been documented. Our findings reveal a novel role of non-muscle myosin heavy chain IIA (NMHC-IIA) in suppressing PRV-triggered innate immune responses to facilitate viral propagation both and . In detail, NMHC-IIA recruits poly (ADP-ribose) polymerase 1 (PARP1) to augment its interaction with cGAS, which impairs cGAS recognition of PRV DNA. Building on our previous demonstration of NMHC-IIA's immunosuppressive role during RNA virus infections, these findings indicate that NMHC-IIA acts as a broad-spectrum suppressor of host antiviral innate immunity in response to both DNA and RNA viruses. Therefore, NMHC-IIA will be a promising target for the development of comprehensive antiviral strategies.
Topics: Animals; Humans; Mice; Cell Line; DNA, Viral; HEK293 Cells; Herpesvirus 1, Suid; Immunity, Innate; Interferon Type I; Myosin Heavy Chains; Nonmuscle Myosin Type IIA; Nucleotidyltransferases; Poly (ADP-Ribose) Polymerase-1; Pseudorabies; Signal Transduction; Swine
PubMed: 38639486
DOI: 10.1128/jvi.00483-24 -
AIDS Research and Therapy Apr 2024Erythema multiforme (EM) is an immune-mediated mucocutaneous condition characterized by hypersensitivity reactions to antigenic stimuli from infectious agents and... (Review)
Review
Erythema multiforme (EM) is an immune-mediated mucocutaneous condition characterized by hypersensitivity reactions to antigenic stimuli from infectious agents and certain drugs. The most commonly implicated infectious agents associated with EM include herpes simplex virus (HSV) and Mycoplasma pneumoniae. Other infectious diseases reported to trigger EM include human immunodeficiency virus (HIV) infection and several opportunistic infections. However, studies focusing on EM and human immunodeficiency virus (HIV) infection are scarce. even though the incidence of EM among HIV-infected individuals have increased, the direct and indirect mechanisms that predispose HIV-infected individuals to EM are not well understood. In turn, this makes diagnosing and managing EM in HIV-infected individuals an overwhelming task. Individuals with HIV infection are prone to acquiring microorganisms known to trigger EM, such as HSV, Mycobacterium tuberculosis, Treponema pallidum, histoplasmosis, and many other infectious organisms. Although HIV is known to infect CD4 + T cells, it can also directly bind to the epithelial cells of the oral and genital mucosa, leading to a dysregulated response by CD8 + T cells against epithelial cells. HIV infection may also trigger EM directly when CD8 + T cells recognize viral particles on epithelial cells due to the hyperactivation of CD8 + T-cells. The hyperactivation of CD8 + T cells was similar to that observed in drug hypersensitivity reactions. Hence, the relationship between antiretroviral drugs and EM has been well established. This includes the administration of other drugs to HIV-infected individuals to manage opportunistic infections. Thus, multiple triggers may be present simultaneously in HIV-infected individuals. This article highlights the potential direct and indirect role that HIV infection may play in the development of EM and the clinical dilemma that arises in the management of HIV-infected patients with this condition. These patients may require additional medications to manage opportunistic infections, many of which can also trigger hypersensitivity reactions leading to EM.
Topics: Humans; HIV Infections; Erythema Multiforme; Simplexvirus; Opportunistic Infections
PubMed: 38637892
DOI: 10.1186/s12981-024-00607-6 -
Virologica Sinica Jun 2024The pseudorabies virus (PRV) is identified as a double-helical DNA virus responsible for causing Aujeszky's disease, which results in considerable economic impacts...
The pseudorabies virus (PRV) is identified as a double-helical DNA virus responsible for causing Aujeszky's disease, which results in considerable economic impacts globally. The enzyme tryptophanyl-tRNA synthetase 2 (WARS2), a mitochondrial protein involved in protein synthesis, is recognized for its broad expression and vital role in the translation process. The findings of our study showed an increase in both mRNA and protein levels of WARS2 following PRV infection in both cell cultures and animal models. Suppressing WARS2 expression via RNA interference in PK-15 cells led to a reduction in PRV infection rates, whereas enhancing WARS2 expression resulted in increased infection rates. Furthermore, the activation of WARS2 in response to PRV was found to be reliant on the cGAS/STING/TBK1/IRF3 signaling pathway and the interferon-alpha receptor-1, highlighting its regulation via the type I interferon signaling pathway. Further analysis revealed that reducing WARS2 levels hindered PRV's ability to promote protein and lipid synthesis. Our research provides novel evidence that WARS2 facilitates PRV infection through its management of protein and lipid levels, presenting new avenues for developing preventative and therapeutic measures against PRV infections.
Topics: Herpesvirus 1, Suid; Virus Replication; Animals; Cell Line; Swine; Tryptophan-tRNA Ligase; Pseudorabies; Signal Transduction; Mitochondria; Host-Pathogen Interactions; Mice
PubMed: 38636706
DOI: 10.1016/j.virs.2024.04.003 -
PloS One 2024We analyzed the prevalence of active infection with common curable sexually transmitted infections (STIs) including N. gonorrhea, C. trachomatis, T. vaginalis, and T....
BACKGROUND
We analyzed the prevalence of active infection with common curable sexually transmitted infections (STIs) including N. gonorrhea, C. trachomatis, T. vaginalis, and T. pallidum, as well as active infection with HPV, herpes simplex virus types I (HSV-1) and II (HSV-2), M. hominis, M. genitalium, C. albicans, and Ureaplasma in 351 Lebanese women.
METHODS
A cross-sectional study, involving 351 sexually active women, 40 years or younger, who were recruited from outpatient Obstetrics and Gynecology clinic attendees between September 2016 and November 2017.
RESULTS
The prevalence of active infection was low at 0.3% for N. gonorrhea, 0.6% for HSV-2, 2.8% for C. trachomatis, and 2.9% for any curable STIs. Prevalence of active HPV infection was high assessed at 15.7% for high-risk and 12.2% for low-risk genotypes. Furthermore, the prevalence was 2.0% for M. genitalium, 6.8% for ureaplasma, 13.7% for Candida albicans, and 20.5% for M. hominis. No active infections with T. vaginalis, T. pallidum, or HSV-1 were observed. Significant age differences were noted in the prevalence of high-risk and low-risk HPV genotypes, but no such differences were noted in the prevalence of other infections. No appreciable variations were identified in the prevalence of key STIs based on smoking, marital status, or the number of sexual partners.
CONCLUSIONS
The study documented active infection with substantial prevalence for multiple STIs among women attending outpatient gynecology and obstetrics clinics in Lebanon. These findings underscore the importance of strengthening STI surveillance, linkage to care, and prevention interventions in reducing STI incidence among women.
Topics: Pregnancy; Humans; Female; Gonorrhea; Prevalence; Incidence; Cross-Sectional Studies; Papillomavirus Infections; Sexually Transmitted Diseases; Chlamydia trachomatis; Herpesvirus 2, Human; Ureaplasma; Neisseria gonorrhoeae
PubMed: 38635688
DOI: 10.1371/journal.pone.0301231