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Abstract This chapter reviews the main viral pathogens of the respiratory tract, the immune responses they induce, currently available vaccines, and vaccines that are in development to control them. The main viruses responsible for acute respiratory infection in people include respiratory syncytial, influenza, human parainfluenza, human metapneumo- human rhino- corona- and adenoviruses.
Licensed vaccines are available only for influenza virus, with vaccines against the other pathogens either in clinical trials or in preclinical stages of development.
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The majority of studies evaluating respiratory virus vaccines measure serum antibody responses, because, although both cellular and humoral responses contribute to the clearance of a primary infection, neutralizing antibodies are known to protect against secondary infection. Humoral responses can be readily detected after vaccination with inactivated or subunit vaccines; however, fewer individuals seroconvert after vaccination with live vaccines.
Alternative immune mechanisms such as mucosal antibody responses are probably responsible for protection by live attenuated vaccines, and immune correlates of protection are under investigation.
The mucosa of our respiratory system is, therefore, in direct and continual contact with the environment and, as such, is highly exposed to microorganisms, some of which may be pathogenic. Respiratory infections are among the leading causes of acute illness and mortality worldwide, being responsible for nearly 4 million deaths annually, the majority of which occur in infants and children in developing countries Girard et al.
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However, despite the public health importance of these infections, licensed vaccines are currently available only for influenza viruses. Protective immunity against respiratory virus infection is a complex interplay between systemic and mucosal responses. However, immune responses generated during a natural infection may not provide complete protection from reinfection and may actually contribute to the pathogenesis of disease reviewed in Sections Pathogenesis and Immune Responses to Respiratory Virus Infection.
Vaccine-induced immune responses must, therefore, aim to be more protective and less pathogenic than those induced naturally.
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In addition, our understanding of the relative contribution of mucosal and systemic immunity to protection remains incomplete. For example, it is well known that inactivated vaccines against influenza given intramuscularly i.
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However, it is also evident that some intranasal vaccines are protective owing to the induction of mucosal immunity, despite less impressive systemic immune responses anti aging new jersey in Section Respiratory Virus Vaccines. Unfortunately, standardized methods of measuring mucosal immune responses are lacking, and reliable correlates of protection for vaccines that protect through mucosal immunity have not been identified.
In this chapter, we review the main viral pathogens of the respiratory tract, the immune responses they induce, current vaccines, and vaccines that are in development to control them. Virology The viruses that infect the respiratory tract belong to various families and vary in their genome composition, the presence or absence of an envelope, and their replicative cycles.
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These viruses anti aging new jersey cells lining the respiratory tract by first attaching to the cell through the interaction of viral envelope glycoproteins, with one or more cellular receptors in the host cell plasma membrane.
The RSV and HMPV F protein are also known to bind GAGs, and anti aging new jersey indicate that the F protein of these viruses is involved in attachment by interacting with the cellular proteins nucleolin and integrin αvβ1, respectively Tayyari et al. Upon binding to the host cell, the F protein undergoes a conformational change that exposes a hydrophobic fusion peptide, which is responsible for the fusion of the paramyxovirus envelope and the host cell plasma membrane.
After viral fusion, the genome is released into the cytoplasm, viral genes are transcribed, and viral genomes are replicated Collins and Crowe,Collins and Melero, The paramyxovirus genome comprises single-stranded, negative-sense, nonsegmented RNA.
This is achieved by a viral RNA-dependent RNA polymerase the large, L, protein that is packaged into the virion and enters the host cell upon infection.
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There is also evidence that transcription is enhanced by the M protein and that the switch from transcription to replication is mediated by the M protein Collins and Crowe,Collins and Melero, Once transcribed, viral structural proteins assemble and newly synthesized viral genomes are packaged into virions that bud from the plasma membrane.
The matrix, or M protein, lines the inner surface of the viral envelope and may play a role in budding Henderson et al.
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In addition, the HN protein of HPIV is also involved in budding and in clearing sialic acid residues from the plasma membrane Karron and Collins, To complete the replication cycle, paramyxoviruses have evolved multiple mechanisms to prevent the activation of cellular defenses anti aging new jersey response to infection, such as the nonstructural NS proteins 1 and 2 of RSV Collins and Crowe, and the C or V proteins of HPIV Karron and Collins, One additional protein found in paramyxoviruses is the short transmembrane glycoprotein SH that is anchored to the envelope and shares structural features with viroporins, a group of hydrophobic molecules that insert into the membrane of infected cells and increase their permeability to small molecules and ions Gonzalez and Carrasco, Influenza Viruses The Orthomyxoviridae family includes influenza viruses, which bind to terminal sialic acid—galactose linkages by the hemagglutinin HA envelope anti aging new jersey.
Orthomyxovirus attachment to the host cell initiates receptor-mediated endocytosis and endosome acidification.
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Protons are permitted to enter the influenza virion via the M2 ion channel, and acidification results in a conformational change in the HA protein, revealing the fusion peptide that initiates membrane fusion between the viral envelope and the endosome membrane reviewed by Palese and Shaw The HA is synthesized as a precursor HA0 that is cleaved into its active form HA1 and HA2 by cellular proteases, and the amino acid sequence at the cleavage site determines the type of protease that is able to activate the HA.
If trypsin-like proteases are required for cleavage, the virus is limited in its tissue tropism to the respiratory tract of humans and the gastrointestinal tract of birds; however, the presence of multiple basic residues at the cleavage site extends the range of proteases that can cleave the HA, resulting in a disseminated, often lethal, infection in poultry Wright et al. Once the virus envelope has fused with the endosome, the influenza genome enters the cytoplasm.
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The orthomyxovirus genome comprises seven or eight segments of single-stranded, negative-sense RNA, and each segment encodes one or more proteins. Together, these are known as the viral ribonucleoprotein complex. Viral mRNA molecules exit the nucleus and are translated in the cytoplasm by the host cell machinery.
Structural proteins assemble at the plasma membrane, where newly synthesized viral genomes are packaged and virions bud Palese and Shaw, How the individual segments traffic to the plasma membrane and are packaged remain active areas of research.
The matrix M1 protein lines the virion beneath the envelope and may be important for morphology and viral assembly at the plasma membrane.
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In addition, the neuraminidase NA protein permits budding by cleaving sialic acid residues from the host cell plasma membrane Palese and Shaw, To complete the replication cycle, influenza viruses inhibit interferon IFN production and signaling. Coronaviruses and Rhinoviruses The genomes of coronaviruses and rhinoviruses comprise positive-sense, single-stranded RNA that can be translated by the host cell machinery in the cytoplasm Kennedy et al.
Coronaviruses, which belong to the Coronaviridae family, are enveloped and attach to host epithelial cells by the spike S envelope proteins Blau and Holmes, Fusion occurs at the plasma membrane, or after endocytosis, and the genome is translated into a polyprotein, which is then posttranslationally processed into structural proteins that form viral particles and nonstructural anti aging new jersey that aid in viral genome replication Lai et al.
Rhinoviruses, Svájci delphi anti aging fejlesztő belong to the Picornaviridae family, are not enveloped and instead have a capsid of icosahedral symmetry comprising four proteins, VP1—4 reviewed by Greenberg,Kennedy et al.
Adenoviruses Adenoviruses are nonenveloped and possess a capsid of icosahedral symmetry. At each of the 12 corners, a fiber protrudes from the capsid that makes contact with the host cell receptor to initiate receptor-mediated endocytosis. Acidification of the endosome results in conformational changes in the capsid that lead to viral uncoating and the release of the double-stranded DNA genome into the cell.
The genome is transported into the nucleus, where it is transcribed into RNA, which is alternatively spliced into monocistronic mRNAs that are translated by the host cell machinery into early gene products. Early gene products remodel the intracellular environment to favor viral replication and are responsible for viral replication.
The late phase of the viral life cycle is concerned with the production of structural proteins in sufficient quantities to ensure adequate packaging of the newly synthesized genomes and maximizing the production of progeny virions, which are released by cell lysis Berk, Clinical Features and Epidemiology Respiratory viruses can infect various parts of the respiratory tract and cause a range of illness. Mild upper respiratory tract URT infection URTI can be complicated by sinusitis or otitis media, and a lower respiratory tract LRT infection LRTI can lead to bronchiolitis or pneumonia and possible anti aging new jersey respiratory complications such as sensitization to asthma.
RSV and influenza are also recognized as an important cause of LRTIs in the elderly anti aging new jersey in those with cardiopulmonary disease or immunosuppression Schmidt, Moreover, influenza pandemics occur at irregular and unpredictable intervals with widespread morbidity and anti aging new jersey and economic consequences.
In addition, although there have been no cases of severe acute respiratory syndrome SARS sinceseveral novel coronaviruses have anti aging new jersey identified, including the virus responsible for Middle East respiratory syndrome MERS Zaki et al.
Given the clinical significance of these infections, and the fact that licensed vaccines are available only for influenza viruses, there is an unmet need for vaccines. Organikus anti aging olajok arcra Humans are the only natural host for RSV, with infections occurring in annual epidemics during winter and spring months in temperate climates and the rainy season in the tropics Girard et al.
The virus is highly contagious, with most children being infected in the first year of life.
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The peak of severe disease usually occurs before 6 months of age, with the peak incidence of hospitalization in 2- to 3-month-old infants Collins and Melero, Reinfection is also common. Moreover, reinfection is independent of antigenic changes in the virus, implying that the protective immunity mounted during an infection does not protect against subsequent reinfection Collins and Melero, This is of note when attempting to induce protective immune responses by vaccination.
In the United States, one study estimated that 2.