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Viral Immunology 2021The resolution revolution of cryo-electron microscopy (cryo-EM) has made a significant impact on the structural analysis of the multifunctional RNA polymerases. In...
The resolution revolution of cryo-electron microscopy (cryo-EM) has made a significant impact on the structural analysis of the multifunctional RNA polymerases. In recent months, several high-resolution structures of RNA polymerases of , which includes the human respiratory syncytial virus (HRSV) and human metapneumovirus (HMPV), have been determined by single-particle cryo-EM. These structures illustrated high similarities and minor differences between the polymerases and revealed the potential mechanisms of the RNA synthesis.
Topics: Cryoelectron Microscopy; DNA-Directed RNA Polymerases; Humans; Pneumovirus; Respiratory Syncytial Virus, Human
PubMed: 32429800
DOI: 10.1089/vim.2020.0018 -
Viruses Jan 2013Human metapneumovirus (HMPV) is a leading cause of respiratory infection that causes upper airway and severe lower respiratory tract infections. HMPV infection is... (Review)
Review
Human metapneumovirus (HMPV) is a leading cause of respiratory infection that causes upper airway and severe lower respiratory tract infections. HMPV infection is initiated by viral surface glycoproteins that attach to cellular receptors and mediate virus membrane fusion with cellular membranes. Most paramyxoviruses use two viral glycoproteins to facilitate virus entry-an attachment protein and a fusion (F) protein. However, membrane fusion for the human paramyxoviruses in the Pneumovirus subfamily, HMPV and respiratory syncytial virus (hRSV), is unique in that the F protein drives fusion in the absence of a separate viral attachment protein. Thus, pneumovirus F proteins can perform the necessary functions for virus entry, i.e., attachment and fusion. In this review, we discuss recent advances in the understanding of how HMPV F mediates both attachment and fusion. We review the requirements for HMPV viral surface glycoproteins during entry and infection, and review the identification of cellular receptors for HMPV F. We also review our current understanding of how HMPV F mediates fusion, concentrating on structural regions of the protein that appear to be critical for membrane fusion activity. Finally, we illuminate key unanswered questions and suggest how further studies can elucidate how this clinically important paramyxovirus fusion protein may have evolved to initiate infection by a unique mechanism.
Topics: Animals; Humans; Metapneumovirus; Paramyxoviridae Infections; Virus Internalization
PubMed: 23325326
DOI: 10.3390/v5010192 -
Seminars in Respiratory and Critical... Dec 2021Biomedical research has long strived to improve our understanding of the immune response to respiratory viral infections, an effort that has become all the more... (Review)
Review
Biomedical research has long strived to improve our understanding of the immune response to respiratory viral infections, an effort that has become all the more important as we live through the consequences of a pandemic. The disease course of these infections is shaped in large part by the actions of various cells of the innate and adaptive immune systems. While these cells are crucial in clearing viral pathogens and establishing long-term immunity, their effector mechanisms may also escalate into excessive, tissue-destructive inflammation detrimental to the host. In this review, we describe the breadth of the immune response to infection with respiratory viruses such as influenza and respiratory syncytial virus. Throughout, we focus on the host rather than the pathogen and try to describe shared patterns in the host response to different viruses. We start with the local cells of the airways, onto the recruitment and activation of innate and adaptive immune cells, followed by the establishment of local and systemic memory cells key in protection against reinfection. We end by exploring how respiratory viral infections can predispose to bacterial superinfection.
Topics: Humans; Immunity; Influenza, Human; Respiratory Syncytial Virus, Human; Respiratory System
PubMed: 34918319
DOI: 10.1055/s-0041-1736459 -
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 -
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 Feb 2023RNA viruses are known to induce a wide variety of respiratory tract illnesses, from simple colds to the latest coronavirus pandemic, causing effects on public health and... (Review)
Review
RNA viruses are known to induce a wide variety of respiratory tract illnesses, from simple colds to the latest coronavirus pandemic, causing effects on public health and the economy worldwide. Influenza virus (IV), parainfluenza virus (PIV), metapneumovirus (MPV), respiratory syncytial virus (RSV), rhinovirus (RhV), and coronavirus (CoV) are some of the most notable RNA viruses. Despite efforts, due to the high mutation rate, there are still no effective and scalable treatments that accompany the rapid emergence of new diseases associated with respiratory RNA viruses. Host-directed therapies have been applied to combat RNA virus infections by interfering with host cell factors that enhance the ability of immune cells to respond against those pathogens. The reprogramming of immune cell metabolism has recently emerged as a central mechanism in orchestrated immunity against respiratory viruses. Therefore, understanding the metabolic signature of immune cells during virus infection may be a promising tool for developing host-directed therapies. In this review, we revisit recent findings on the immunometabolic modulation in response to infection and discuss how these metabolic pathways may be used as targets for new therapies to combat illnesses caused by respiratory RNA viruses.
Topics: Humans; Coronavirus; Coronavirus Infections; Enterovirus Infections; Metapneumovirus; RNA; Respiratory Syncytial Virus, Human
PubMed: 36851739
DOI: 10.3390/v15020525 -
Journal of Virology Aug 2007Coupled translation, first described in the M2 gene of pneumovirus respiratory syncytial virus (RSV), is an alternative mechanism of translational initiation in which...
Coupled translation, first described in the M2 gene of pneumovirus respiratory syncytial virus (RSV), is an alternative mechanism of translational initiation in which the ribosomes which translate the first (M2-1) open reading frame (ORF) move a short distance upstream after termination and reinitiate translation from a second (M2-2) overlapping ORF. Here, we show that the same mechanism occurs in two closely related viruses, avian pneumovirus (APV) and pneumonia virus of mice (PVM), although with markedly different efficiencies. To identify the reasons for the variation in efficiency of coupled expression between RSV and APV, we used chimeric M2-1 genes containing different lengths of the M2-1 ORF from each virus. An essential component allowing coupled expression in the chimeras was a segment from the RSV M2-1 coding region containing a high degree of secondary structure. Additional sequences at the 5' end of the RSV M2-1 ORF also promoted coupled translation when the region with high levels of secondary structure was present. These data indicate that at least two distant parts of the mRNA transcript, together with a suitable overlapping region, are involved in the coupling process. Replacement of the last 102 nucleotides of the RSV M2-1 ORF with the equivalent APV sequence showed identical levels of coupled translation. Thus, the overlapping region can direct the ribosome back onto the start codon of the second ORF while the upstream coding sequence of the M2-1 ORF determines the levels of coupled expression.
Topics: Amino Acid Sequence; Animals; Cell Line, Tumor; Gene Expression Regulation, Viral; Humans; Metapneumovirus; Mice; Molecular Sequence Data; Murine pneumonia virus; Open Reading Frames; Protein Biosynthesis; RNA, Messenger; RNA, Viral; Recombinant Fusion Proteins; Ribosomes; Transcription, Genetic; Viral Matrix Proteins
PubMed: 17522208
DOI: 10.1128/JVI.00457-07 -
Veterinary Research 2007Bovine respiratory syncytial virus (BRSV) belongs to the pneumovirus genus within the family Paramyxoviridae and is a major cause of respiratory disease in young calves.... (Review)
Review
Bovine respiratory syncytial virus (BRSV) belongs to the pneumovirus genus within the family Paramyxoviridae and is a major cause of respiratory disease in young calves. BRSV is enveloped and contains a negative sense, single-stranded RNA genome encoding 11 proteins. The virus replicates predominantly in ciliated respiratory epithelial cells but also in type II pneumocytes. It appears to cause little or no cytopathology in ciliated epithelial cell cultures in vitro, suggesting that much of the pathology is due to the host's response to virus infection. RSV infection induces an array of pro-inflammatory chemokines and cytokines that recruit neutrophils, macrophages and lymphocytes to the respiratory tract resulting in respiratory disease. Although the mechanisms responsible for induction of these chemokines and cytokines are unclear, studies on the closely related human (H)RSV suggest that activation of NF-kappaB via TLR4 and TLR3 signalling pathways is involved. An understanding of the mechanisms by which BRSV is able to establish infection and induce an inflammatory response has been facilitated by advances in reverse genetics, which have enabled manipulation of the virus genome. These studies have demonstrated an important role for the non-structural proteins in anti-interferon activity, a role for a virokinin, released during proteolytic cleavage of the fusion protein, in the inflammatory response and a role for the SH and the secreted form of the G protein in establishing pulmonary infection. Knowledge gained from these studies has also provided the opportunity to develop safe, stable, live attenuated virus vaccine candidates.
Topics: Animals; Cattle; Cattle Diseases; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Bovine
PubMed: 17257568
DOI: 10.1051/vetres:2006053 -
Clinical Reviews in Allergy & Immunology Dec 2022The highest morbidity and mortality from respiratory syncytial virus (RSV) infection occurs in young infants. Immunization of expectant mothers during pregnancy has the... (Review)
Review
The highest morbidity and mortality from respiratory syncytial virus (RSV) infection occurs in young infants. Immunization of expectant mothers during pregnancy has the potential to substantially reduce the burden of RSV disease in a majority of infants. Correlates of protection (COP) are important in guiding the development of maternal RSV vaccines and the design of maternal RSV vaccine trials, as immune response to candidate vaccines should mirror protective RSV immunity at birth. Here, we review the literature reporting correlations between RSV immune measures at birth and clinical RSV outcomes during infancy. Less than a dozen studies have investigated immunological COP with RSV disease or related hospitalization, yielding inconsistent findings overall. The differences in findings between studies could be due to differences in inclusion/exclusion criteria (e.g., the inclusion of older infants who may benefit less from maternal antibodies or infants followed during inter-seasonal periods where RSV is absent), differences in semi-quantitative RSV antibody neutralization assays, or differences in RSV outcome measures such as the sensititivity/specificity of diagnostic tests. Future research in this field should seek to standardize RSV immunological measures and outcomes, expand the breadth of functional RSV measures beyond antibody neutralization, and consider infants' age and seasonality of RSV infection.
Topics: Infant; Infant, Newborn; Pregnancy; Female; Animals; Humans; Respiratory Syncytial Virus Infections; Antibodies, Viral; Sigmodontinae; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Viruses; Respiratory Syncytial Virus, Human
PubMed: 35689745
DOI: 10.1007/s12016-022-08948-8 -
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