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Viruses Oct 2016Morbilliviruses share considerable structural and functional similarities. Even though disease severity varies among the respective host species, the underlying... (Comparative Study)
Comparative Study Review
Morbilliviruses share considerable structural and functional similarities. Even though disease severity varies among the respective host species, the underlying pathogenesis and the clinical signs are comparable. Thus, insights gained with one morbillivirus often apply to the other members of the genus. Since the (CDV) causes severe and often lethal disease in dogs and ferrets, it is an attractive model to characterize morbillivirus pathogenesis mechanisms and to evaluate the efficacy of new prophylactic and therapeutic approaches. This review compares the cellular tropism, pathogenesis, mechanisms of persistence and immunosuppression of the (MeV) and CDV. It then summarizes the contributions made by studies on the CDV in dogs and ferrets to our understanding of MeV pathogenesis and to vaccine and drugs development.
Topics: Animals; Disease Models, Animal; Distemper Virus, Canine; Dogs; Ferrets; Humans; Immune Evasion; Immune Tolerance; Measles virus; Viral Tropism
PubMed: 27727184
DOI: 10.3390/v8100274 -
Communications Biology Jun 2023Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are related RNA viruses responsible for severe respiratory infections and resulting disease in...
Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are related RNA viruses responsible for severe respiratory infections and resulting disease in infants, elderly, and immunocompromised adults. Therapeutic small molecule inhibitors that bind to the RSV polymerase and inhibit viral replication are being developed, but their binding sites and molecular mechanisms of action remain largely unknown. Here we report a conserved allosteric inhibitory site identified on the L polymerase proteins of RSV and HMPV that can be targeted by a dual-specificity, non-nucleoside inhibitor, termed MRK-1. Cryo-EM structures of the inhibitor in complexes with truncated RSV and full-length HMPV polymerase proteins provide a structural understanding of how MRK-1 is active against both viruses. Functional analyses indicate that MRK-1 inhibits conformational changes necessary for the polymerase to engage in RNA synthesis initiation and to transition into an elongation mode. Competition studies reveal that the MRK-1 binding pocket is distinct from that of a capping inhibitor with an overlapping resistance profile, suggesting that the polymerase conformation bound by MRK-1 may be distinct from that involved in mRNA capping. These findings should facilitate optimization of dual RSV and HMPV replication inhibitors and provide insights into the molecular mechanisms underlying their polymerase activities.
Topics: Infant; Adult; Humans; Aged; Metapneumovirus; RNA-Dependent RNA Polymerase; Respiratory Syncytial Virus, Human; Respiratory Tract Infections; RNA, Messenger
PubMed: 37337079
DOI: 10.1038/s42003-023-04990-0 -
Viruses Nov 2016The measles virus (MeV) is a contagious pathogenic RNA virus of the family , genus , that can cause serious symptoms and even fetal complications. Here, we summarize... (Review)
Review
The measles virus (MeV) is a contagious pathogenic RNA virus of the family , genus , that can cause serious symptoms and even fetal complications. Here, we summarize current molecular advances in MeV research, and emphasize the connection between host cells and MeV replication. Although measles has reemerged recently, the potential for its eradication is promising with significant progress in our understanding of the molecular mechanisms of its replication and host-pathogen interactions.
Topics: Host-Pathogen Interactions; Humans; Immunity, Innate; Measles virus; Virus Replication
PubMed: 27854326
DOI: 10.3390/v8110308 -
Journal of Virology Jun 2023Langya virus (LayV) is a paramyxovirus in the genus, closely related to the deadly Nipah (NiV) and Hendra (HeV) viruses, that was identified in August 2022 through...
Langya virus (LayV) is a paramyxovirus in the genus, closely related to the deadly Nipah (NiV) and Hendra (HeV) viruses, that was identified in August 2022 through disease surveillance following animal exposure in eastern China. Paramyxoviruses present two glycoproteins on their surface, known as attachment and fusion proteins, that mediate entry into cells and constitute the primary antigenic targets for immune response. Here, we determine cryo-electron microscopy (cryo-EM) structures of the uncleaved LayV fusion protein (F) ectodomain in pre- and postfusion conformations. The LayV-F protein exhibits pre- and postfusion architectures that, despite being highly conserved across paramyxoviruses, show differences in their surface properties, in particular at the apex of the prefusion trimer, that may contribute to antigenic variability. While dramatic conformational changes were visualized between the pre- and postfusion forms of the LayV-F protein, several domains remained invariant, held together by highly conserved disulfides. The LayV-F fusion peptide (FP) is buried within a highly conserved, hydrophobic interprotomer pocket in the prefusion state and is notably less flexible than the rest of the protein, highlighting its "spring-loaded" state and suggesting that the mechanism of pre-to-post transition must involve perturbations to the pocket and release of the fusion peptide. Together, these results offer a structural basis for how the Langya virus fusion protein compares to its Henipavirus relatives and propose a mechanism for the initial step of pre- to postfusion conversion that may apply more broadly to paramyxoviruses. The genus is quickly expanding into new animal hosts and geographic locations. This study compares the structure and antigenicity of the Langya virus fusion protein to other henipaviruses, which have important vaccine and therapeutic development implications. Furthermore, the study proposes a new mechanism to explain the early steps of the fusion initiation process that can be more broadly applied to the family.
Topics: Animals; Cryoelectron Microscopy; Henipavirus; Peptides; Protein Conformation; Viral Fusion Proteins; Virus Internalization
PubMed: 37278642
DOI: 10.1128/jvi.00433-23 -
Viruses Apr 2022Nipah henipavirus (NiV) and Hendra henipavirus (HeV) are zoonotic emerging paramyxoviruses causing severe disease outbreaks in humans and livestock, mostly in Australia,... (Review)
Review
Nipah henipavirus (NiV) and Hendra henipavirus (HeV) are zoonotic emerging paramyxoviruses causing severe disease outbreaks in humans and livestock, mostly in Australia, India, Malaysia, Singapore and Bangladesh. Both are bat-borne viruses and in humans, their mortality rates can reach 60% in the case of HeV and 92% for NiV, thus being two of the deadliest viruses known for humans. Several factors, including a large cellular tropism and a wide zoonotic potential, con-tribute to their high pathogenicity. This review provides an overview of HeV and NiV pathogenicity mechanisms and provides a summary of their interactions with the immune systems of their different host species, including their natural hosts bats, spillover-hosts pigs, horses, and humans, as well as in experimental animal models. A better understanding of the interactions between henipaviruses and their hosts could facilitate the development of new therapeutic strategies and vaccine measures against these re-emerging viruses.
Topics: Animals; Chiroptera; Hendra Virus; Henipavirus Infections; Horses; Immune Evasion; Models, Animal; Nipah Virus; Swine
PubMed: 35632678
DOI: 10.3390/v14050936 -
Sub-cellular Biochemistry 2018Human respiratory syncytial virus (HRSV) is a non-segmented negative stranded RNA virus and is recognized as the most important viral agent of lower respiratory tract... (Review)
Review
Human respiratory syncytial virus (HRSV) is a non-segmented negative stranded RNA virus and is recognized as the most important viral agent of lower respiratory tract infection worldwide, responsible for up to 199,000 deaths each year. The only FDA-approved regime to prevent HRSV-mediated disease is pre-exposure administration of a humanized HRSV-specific monoclonal antibody, which although being effective, is not in widespread usage due to its cost. No HRSV vaccine exists and so there remains a strong need for alternative and complementary anti-HRSV therapies. The HRSV M2-1 protein is a transcription factor and represents an attractive target for the development of antiviral compounds, based on its essential role in the viral replication cycle. To this end, a detailed analysis of M2-1 structure and functions will aid in identifying rational targets for structure-based antiviral drug design that can be developed in future translational research. Here we present an overview of the current understanding of the structure and function of HRSV M2-1, drawing on additional information derived from its structural homologues from other related viruses.
Topics: Humans; Respiratory Syncytial Virus, Human; Structure-Activity Relationship; Viral Proteins; Virus Replication
PubMed: 29900500
DOI: 10.1007/978-981-10-8456-0_11 -
Viruses Oct 2019Canine distemper virus (CDV) and phocine distemper (PDV) are closely-related members of the family, genus , in the order . CDV has a broad host range among carnivores.... (Review)
Review
Canine distemper virus (CDV) and phocine distemper (PDV) are closely-related members of the family, genus , in the order . CDV has a broad host range among carnivores. PDV is thought to be derived from CDV through contact between terrestrial carnivores and seals. PDV has caused extensive mortality in Atlantic seals and other marine mammals, and more recently has spread to the North Pacific Ocean. CDV also infects marine carnivores, and there is evidence of infection of seals and other species in Antarctica. Recently, CDV has spread to felines and other wildlife species in the Serengeti and South Africa. Some CDV vaccines may also have caused wildlife disease. Changes in the virus haemagglutinin (H) protein, particularly the signaling lymphocyte activation molecule (SLAM) receptor binding site, correlate with adaptation to non-canine hosts. Differences in the phosphoprotein (P) gene sequences between disease and non-disease causing CDV strains may relate to pathogenicity in domestic dogs and wildlife. Of most concern are reports of CDV infection and disease in non-human primates raising the possibility of zoonosis. In this article we review the global occurrence of CDV and PDV, and present both historical and genetic information relating to these viruses crossing species barriers.
Topics: Animals; Animals, Wild; Cats; Cetacea; Climate Change; Distemper Virus, Canine; Distemper Virus, Phocine; Dogs; Host Specificity; Morbillivirus; Morbillivirus Infections; Pets; Primates; Viral Proteins
PubMed: 31615092
DOI: 10.3390/v11100944 -
Journal of Virology Feb 2024Nipah virus (NiV) and Hendra virus (HeV) are pathogenic paramyxoviruses that cause mild-to-severe disease in humans. As members of the genus, NiV and HeV use an...
Nipah virus (NiV) and Hendra virus (HeV) are pathogenic paramyxoviruses that cause mild-to-severe disease in humans. As members of the genus, NiV and HeV use an attachment (G) glycoprotein and a class I fusion (F) glycoprotein to invade host cells. The F protein rearranges from a metastable prefusion form to an extended postfusion form to facilitate host cell entry. Prefusion NiV F elicits higher neutralizing antibody titers than postfusion NiV F, indicating that stabilization of prefusion F may aid vaccine development. A combination of amino acid substitutions (L104C/I114C, L172F, and S191P) is known to stabilize NiV F in its prefusion conformation, although the extent to which substitutions transfer to other henipavirus F proteins is not known. Here, we perform biophysical and structural studies to investigate the mechanism of prefusion stabilization in F proteins from three henipaviruses: NiV, HeV, and Langya virus (LayV). Three known stabilizing substitutions from NiV F transfer to HeV F and exert similar structural and functional effects. One engineered disulfide bond, located near the fusion peptide, is sufficient to stabilize the prefusion conformations of both HeV F and LayV F. Although LayV F shares low overall sequence identity with NiV F and HeV F, the region around the fusion peptide exhibits high sequence conservation across all henipaviruses. Our findings indicate that substitutions targeting this site of conformational change might be applicable to prefusion stabilization of other henipavirus F proteins and support the use of NiV as a prototypical pathogen for henipavirus vaccine antigen design.IMPORTANCEPathogenic henipaviruses such as Nipah virus (NiV) and Hendra virus (HeV) cause respiratory symptoms, with severe cases resulting in encephalitis, seizures, and coma. The work described here shows that the NiV and HeV fusion (F) proteins share common structural features with the F protein from an emerging henipavirus Langya virus (LayV). Sequence alignment alone was sufficient to predict which known prefusion-stabilizing amino acid substitutions from NiV F would stabilize the prefusion conformations of HeV F and LayV F. This work also reveals an unexpected oligomeric interface shared by prefusion HeV F and NiV F. Together, these advances lay a foundation for future antigen design targeting henipavirus F proteins. In this way, Nipah virus can serve as a prototypical pathogen for the development of protective vaccines and monoclonal antibodies to prepare for potential henipavirus outbreaks.
Topics: Humans; Glycoproteins; Hendra Virus; Henipavirus; Henipavirus Infections; Nipah Virus; Peptides; Viral Fusion Proteins; Viral Proteins
PubMed: 38214525
DOI: 10.1128/jvi.01372-23 -
Virus Genes Aug 2023Human metapneumovirus (HMPV) is a major pathogen of acute respiratory tract infections (ARTIs) in children. Whole genome sequence analyses could help understand the...
Human metapneumovirus (HMPV) is a major pathogen of acute respiratory tract infections (ARTIs) in children. Whole genome sequence analyses could help understand the evolution and transmission events of this virus. In this study, we sequenced HMPV whole genomes to improve the identification of molecular epidemiology in Beijing, China. Nasopharyngeal aspirates of hospitalized children aged < 14 years old with ARTIs were screened for HMPV infection using qPCR. Fourteen pairs of overlapping primers were used to amplify whole genome sequences of HMPV from positive samples with high viral loads. The epidemiology of HMPV was analysed and 27 HMPV whole genome sequences were obtained. Sequence identity and the positional entropy analyses showed that most regions of HMPV genome are conserved, whereas the G gene contained many variations. Phylogenetic analysis identified 25 HMPV sequences that belonged to a newly defined subtype A2b1; G gene sequences from 24 of these contained a 111-nucleotide duplication. HMPV is an important respiratory pathogen in paediatric patients. The new subtype A2b1 with a 111-nucleotide duplication has become predominate in Beijing, China.
Topics: Whole Genome Sequencing; Metapneumovirus; Evolution, Molecular; Humans; Male; Female; Infant; Child, Preschool; Child; Adolescent; Paramyxoviridae Infections; Phylogeny
PubMed: 37150780
DOI: 10.1007/s11262-023-02001-2 -
Vaccine Jan 2017Despite the recent explosion in RSV vaccine development, there remain substantial hurdles to overcome before licensing of effective vaccines will allow widespread use,... (Review)
Review
Despite the recent explosion in RSV vaccine development, there remain substantial hurdles to overcome before licensing of effective vaccines will allow widespread use, particularly in high-risk populations. Incomplete understanding of mechanisms and correlates of protection against RSV mean that, for the time being, successful RSV vaccines must directly demonstrate efficacy, which necessitates large and costly clinical trials in naturally infected patients. To mitigate the risks inherent in progressing to these late-stage trials, experimental human RSV infection studies have recently been re-established, representing the interface between pre-clinical models and observational studies of patients. Not only can they be used for early proof-of-concept clinical trials to test vaccine efficacy, but human challenge studies also offer the potential to better understand protective immunity against RSV infection to improve vaccine design and delivery. In the past, controlled human infection studies with RSV have been instrumental in elucidating the influence of factors such as route of infection and type of inoculum on the course of disease. Recently, efficacy trials of novel RSV antiviral drugs have also been successfully undertaken. Now, with advances in technology, detailed investigations of human mucosal immunity in the RSV-infected airway are possible. These have indicated defects in RSV-induced humoral and CD8+ T cell immunity that may contribute to the recurrent symptomatic infection that occurs throughout life and should be circumvented by optimal vaccines. Here, we discuss the insights derived from RSV human challenge models; the major impediments to their more widespread uptake; and their potential benefit in accelerating vaccine development, including future directions to further enhance the relevance of these models to at-risk patient populations.
Topics: Host-Pathogen Interactions; Human Experimentation; Humans; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human
PubMed: 27889256
DOI: 10.1016/j.vaccine.2016.08.086