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Abstract This chapter reviews the main viral pathogens of the respiratory aglutininák anti aging, 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. The majority of studies evaluating respiratory virus vaccines aglutininák anti aging 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 aglutininák anti aging 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.
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.
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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. 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. However, it is also evident that some intranasal vaccines are protective aglutininák anti aging to the induction of mucosal immunity, despite less impressive systemic immune responses reviewed 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.
These viruses infect 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 findings 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. 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. In addition, the HN protein of HPIV is also involved in budding and in clearing sialic acid residues aglutininák anti aging the plasma membrane Karron and Collins, To complete the replication cycle, paramyxoviruses have evolved multiple mechanisms to prevent the activation of cellular defenses in response to infection, such as the nonstructural NS proteins 1 and 2 of RSV Collins and Crowe, and the C aglutininák anti aging 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 glycoprotein.
Orthomyxovirus attachment to the host cell initiates receptor-mediated aglutininák anti aging and endosome acidification. 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 aglutininák anti aging 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.
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Once the virus envelope has fused with the endosome, the influenza genome enters the cytoplasm. 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.
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The matrix M1 protein lines the virion beneath the envelope and may be important for morphology and viral assembly at the plasma membrane.
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, Aglutininák anti aging 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 proteins that aid in viral genome replication Lai et al.
Rhinoviruses, which 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.
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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 postinfectious respiratory complications such as sensitization to asthma.
RSV and influenza are also recognized as an important cause of LRTIs in the elderly and in those with cardiopulmonary disease or immunosuppression Schmidt, Moreover, influenza pandemics occur at irregular and unpredictable intervals with widespread morbidity and mortality and economic consequences.
In addition, although there have been no cases of severe acute respiratory syndrome SARS sinceseveral novel coronaviruses have been identified, including the aglutininák anti aging aglutininák anti aging 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.
RSV 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. 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 aglutininák anti aging immunity mounted during an infection does not protect against subsequent reinfection Aglutininák anti aging and Melero, This is of note when attempting to induce protective immune responses by vaccination.
In the United States, one study estimated that 2. More than half of the hospitalizations for RSV occur in previously healthy, full-term infants, and children who experienced severe LRTI caused by RSV were at increased risk of wheezing and asthma later in life Girard et al.
RSV infection induces antibodies against the two main antigens, the F and G envelope glycoproteins. The G protein is the most variable protein aglutininák anti aging RSV and is the basis for the separation of strains into two antigenic groups A and B.
Moreover, sites of positive selection that partially coincide with epitopes recognized by anti-G-protein monoclonal antibodies mAbs suggest immune-driven RSV evolution Botosso et al.
However, most anti-G mAbs do not neutralize infectivity Martinez et al. This favors a slow coevolution of several RSV lineages, and multiple genotypes eucerin anti aging krém each group can cocirculate within the same season, with shifts in the predominance of groups A and B occurring in 1- to 2-year cycles Waris, In contrast, the sequence of the F gene is highly conserved among RSV isolates, despite the identification of a number of neutralizing mAbs against the protein that should impart a selection pressure for mutation Collins and Melero, This implies that the function of the F protein confers structural restrictions that may limit antigenic diversity.
As with RSV, reinfection is common Schomacker et al. HPIV LRTI is a major cause of hospitalization in children under 5 years of aglutininák anti aging, second only to RSV, though infection is usually self-limiting and rarely fatal, unless an individual is immunosuppressed.
Severe infection may have long-term effects on lung function, but this remains unclear Schomacker et al. The virus also has a seasonal distribution, with the main occurrence in winter and spring Kahn, Influenza A viruses are the most clinically significant and are divided into subtypes based on antigenic differences in the HA and NA genes. Influenza viruses cause a spectrum of clinical illness associated with infection of the upper and lower respiratory tract, with szuper anti aging kiegészítő severe disease associated with LRTI.
The viruses are spread by respiratory droplets or direct contact. Annual influenza epidemics have a seasonal distribution, with the main occurrence in winter months seasonal influenza in temperate climates Girard et al. This broad host range, together with the segmented nature of the influenza virus genome, makes the epidemiology of influenza complex and gives rise to zoonotic infections and pandemics.
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Pandemic influenza can arise if a novel virus emerges that readily transmits from person to person and if the majority of the population is susceptible to infection.
If an avian or animal virus crosses the species barrier to circulate in humans, the population will probably be immunologically naïve and, therefore, susceptible to infection. However, the virus must be able to transmit efficiently from person to person for a pandemic to aglutininák anti aging. As the influenza virus genome is segmented, if a host is infected with two or more influenza viruses, the potential exists for the gene segments to reassort, such that a progeny virus containing genes from each parent virus can be produced Wright et al.
If a virus that circulates within the human population reassorts with one that is novel for humans, the resultant virus may possess genes that allow it to replicate efficiently in humans, but with glycoproteins to which the population is immunologically naïve, and a pandemic could occur. Three global influenza pandemics were recorded in the twentieth century from viruses of the subtypes H1N1, H2N2, and Cien szemkörnyékápoló, respectively.
Respiratory Virus Vaccines
In most countries, the median age of infection during the pandemic was estimated to be 12—17 years, and in most individuals, infection led to a mild, self-limiting URTI. Moreover, nearly one-third of the fatalities among hospitalized patients occurred in previously healthy individuals Girard et al. After each pandemic, the newly emerged subtype became established and caused annual seasonal influenza epidemics. Baby boom anti aging the United States, it has been estimated that 25—50 million cases of influenza occur annually, with approximatelyrequiring hospitalization Lambert and Fauci, Aglutininák anti aging vaccines are aimed at the circulating H1N1 and H3N2 subtypes of influenza A and the predominant circulating strain of influenza B and are therefore trivalent vaccines.
However, two antigenically distinct lineages of influenza B viruses Victoria and Yamagata cocirculate, and the World Health Organization recommended that influenza vaccines should contain both of these lineages.
Clinical trials of quadrivalent vaccines containing the H1N1 and H3N2 influenza A viruses and the Victoria and Yamagata influenza B viruses have been conducted, and their use in the United States received an interim recommendation of the Advisory Committee on Immunization Practices for the — influenza season Dolin, Owing to the low fidelity of the RNA-dependent RNA polymerase of influenza, and immune selection pressure on the HA protein, viral replication can yield a quasi-species that may differ antigenically from the parent virus.
Therefore, each season, the predominant circulating strain may be antigenically distinct from the previous year. Sporadic infections by H5N1, H9N2, H7N7, and H7N9 subtypes of influenza have been reported in humans who were in close direct contact with infected animals.
Additionally, H3N2 variant viruses have infected humans, the majority of whom were in close contact with pigs Epperson et al. So far, there has been limited transmission of these viruses between people, though there aglutininák anti aging concern that they may acquire mutations or gene segments that allow efficient spread from person to person.
Coronaviruses Coronaviruses are frequent causes of the common cold, causing URTIs throughout the world, in all age groups, leading to millions of days of work and school absence, physician visits, and frequent inappropriate antibiotic use Greenberg,