key: cord-0008410-34ckdbni
authors: von Messling, Veronika Al; Griffin, Diane E.
title: How respiratory viruses overcome mucosal defenses and exploit the unique environment of the respiratory tract
date: 2012-05-01
journal: Curr Opin Virol
DOI: 10.1016/j.coviro.2012.04.002
sha: f265cbe3da8427e2ff2060700dc542eb4b3fd837
doc_id: 8410
cord_uid: 34ckdbni

nan

Respiratory infections remain among the leading causes of death worldwide, in high-income as well as middle-and low-income countries (www.who.int/ mediacentre/factsheets/fs310/index.html). In addition, these infections result in important morbidity, and the annual costs associated with health care and absenteeism at work were estimated around $15 billion in the United States alone [1] . The management of respiratory infections also plays an important role in livestock husbandry aiming to avoid economic losses associated with poor growth and reproduction rates, veterinary care, and excess mortality [2, 3] . A large proportion of these infections are caused by viruses, some well known such as measles and influenza, some recently emerged, such as SARS, Nipah, and PRRSV. Respiratory viruses can be found in many viral families, and they can be restricted to the respiratory tract, or use the respiratory tract as a portal of entry to establish a systemic infection.

How the mucosal immune system has evolved to counter infection is discussed by Shintaro Sato and Hiroshi Kiyono. The respiratory tract is divided into the upper and lower compartments, with the upper portion colonized by a resident flora and regularly exposed to inhaled pathogens and other potentially noxious substances. In contrast, the lower respiratory tract is sterile. Cells in the epithelial layer covering the luminal side of the respiratory tract have well-developed cilia and produce mucus. Mucociliary clearance resulting from the cilial-mediated transport of mucus-trapped foreign bodies toward the mouth thus represents the first line of defense against pathogenic organisms. Upon infection, respiratory epithelial cells mount a vigorous innate immune response characterized by the expression of type I interferons (IFN) and various inflammatory cytokines, rapidly attracting granulocytes and NK T cells to the respiratory tract. Once a pathogen comes in contact with the mucosa, it is taken up by specialized antigen sampling cells and then processed and presented by antigen-presenting cells to immune effector cells. This direct link between the outer environment and lymphatic tissue accelerates the development of a pathogen-specific adaptive immune response, but also provides respiratory pathogens with direct access to immune cells. The resulting adaptive immune response is uniquely adapted to provide a strong mucosal defense. In addition to favoring antibody class switching to IgA, the resulting IgA + B cells express CCR10 leading to migration to distant epithelia that express its ligand CCL28. Mucosal immunization can thus induce IgA responses at local as well as distant sites.

The events involved in the repair and regeneration of the respiratory tissue following infection are discussed by Stacey Gorski, Matthew Hufford, and Thomas Braciale. Virus replication and host responses contribute to the death of respiratory epithelial and resident immune cells leading to loss of epithelial barrier integrity and lung microarchitecture. While the overall regenerative capacity of the respiratory tract is well documented, the mechanisms and cell types involved in this process are only starting to be characterized. The elimination of viral antigen removes the primary trigger for the activation of innate and adaptive immune cells, and regulatory T cells and the expression of regulatory cytokines will dampen and ultimately end the inflammatory response. The subsequent restoration of the respiratory epithelium first involves the production of a provisional matrix, which is then covered by proliferating epithelial cells. The activation and recruitment of pulmonary stem cells to the site of injury likely plays an important role in this restoration. There also is increasing evidence that this process is aided by innate immune cells. In addition to lymphoid tissue inducer (LTi) and LTi-like cells producing the tissue-protective cytokine IL-22 and other type 2 cytokines may contribute to tissue repair via alternatively activated macrophages and induction of a measured profibrotic response. A better understanding of the regulation of these different processes could lead to new recoveryaccelerating therapeutic approaches.

Hendra and Nipah viruses are prominent examples of newly emerging pathogens that invade their hosts via the respiratory tract to establish a systemic infection. The review by Glenn Marsh and Linfa Wang discusses the reasons underlying the high virulence and broad host range of these viruses. The widespread cellular distribution of their receptors ephrin B2 and B3 allows Henipaviruses to infect almost every cell type, and the intracellular activation of their fusion protein supports rapid cell-to-cell dissemination. This efficient replication and spread in combination with the viral interference with innate immune activation, explains much of the extreme virulence observed. The high evolutionary conservation of their cellular receptors ephrin B2 and B3 also provides these viruses access to a broad range of potential host species, making a successful eradication unlikely. The development of efficient treatments and safe vaccines is thus of paramount importance.

In contrast, measles virus (MeV), another respiratory virus that causes systemic disease, only infects humans and certain non-human primates. Rory de Vries, Annelies Mesman, Teunis Geijtenbeek, Paul Duprex, and Rik de Swart discuss the recent advances in our understanding of MeV pathogenesis obtained from the characterization of GFP-expressing wild type viruses in macaques. It appears that antigen sampling and presenting cells in the respiratory tract are the initial targets of the virus, followed by amplification and systemic dissemination via SLAM/CD150-expressing immune cells. The recent discovery of nectin-4 as MeV exit receptor illustrates the importance of respiratory tract infection in MeV egress and transmission. As for the Henipaviruses, MeV also interferes with innate immune activation, and its strong lymphotropism profoundly impacts the acute response and produces long-term immunosuppression. This leaves patients vulnerable to secondary viral or bacterial infections that account for most MeV-associated mortality. Likely due to species-specific differences in the structure of the cellular receptors and the efficacy of interference with immune recognition, MeV has a narrow host range, making it an attractive target for eradication. The ongoing campaign is progressing, with 2020 as a tentative target date.

The porcine reproductive and respiratory syndrome virus (PRRSV) also uses the respiratory tract to initially infect macrophages and then establishes a long-lasting infection in lymphatic tissues. Clinical manifestations vary from subclinical to lethal depending on the age of the pig and the presence of other pathogens. In adult animals, the infection is generally asymptomatic but results in stillbirth or weak piglets, while in younger animals respiratory disease, often in the context of co-infections with other respiratory pathogens, is predominant. Ranjni Chand, Benjamin Trible and Raymond Rowland discuss how the virus escapes immune recognition over extended periods of time by biasing the antibody response against structural surface proteins. In addition to the glycan shielding of neutralizing epitopes, a recent comparison of ORF5 sequences revealed a high variability of T and B cell epitopes, indicating that antigenic drift may contribute to immune evasion. It is complemented by an inhibition of different innate immune activation pathways involving several nonstructural proteins. These factors are now being incorporated into the development of the next generation of vaccines that aim to lessen the impact of this virus on the pig industry.

SARS-coronavirus (SARS-CoV) manifests primarily as a respiratory disease, but up to 20% of patients also experience gastrointestinal symptoms. While most of the younger patients develop a 'flu-like' disease and recover, older individuals frequently go on to develop acute respiratory distress syndrome (ARDS) characterized by a severe dysregulation of the cytokine response. How the infection interferes with different aspects of the innate immune response is discussed by Allison Totura and Ralph Baric. Toll-like receptors (TLRs) are likely involved in the early detection of the virus, because transgenic mice lacking the common adapter molecule MyD88 experienced more severe disease. The infection results in rapid induction of NF-kB transcribed inflammatory cytokines, while activation of type I IFN responses are delayed for up to 48 hours, indicating interactions with different aspects of RIG-I-like receptor signaling pathways. Several viral proteins contribute to the observed immunomodulation, but it remains unclear which constellations of virus and host factors lead to severe disease.

Similar to SARS-CoV, influenza A virus can trigger excessive cytokine responses that contribute to severe lung pathology and death. Thijs Kuiken, Beatrice Riteau, Ron Fouchier, and Guus Rimmelzwaan discuss the virus-host interactions determining influenza virulence. Most seasonal influenza viruses infect mainly the upper respiratory tract and are rapidly controlled first by innate and then by adaptive immune responses. In contrast, highly pathogenic influenza viruses target the lower respiratory tract and may even spread to other organs, including the gastrointestinal tract and the central nervous system. Infection of the lower respiratory tract due to receptor specificity or efficient replication generally leads to a more severe inflammatory response, and virus modulation of these responses further exacerbates the inflammation. A highly pathogenic virus has thus the potential to elicit a self-perpetuating inflammatory response, ultimately resulting in ARDS and death even though infectious virus has been cleared.

Rhinoviruses belong to the large group of pathogens that can cause the common cold. To date, over 100 serotypes have been identified, explaining frequent infections and the annual cold outbreaks. In an immunocompetent host, these viruses are restricted to the upper respiratory tract and result in a neutrophilic inflammatory response leading to rhinorrhea and nasal obstruction. Individuals with respiratory comorbidities are more likely to experience involvement of the lower respiratory tract characterized by cough, wheezing, and shortness of breath. Joshua Kennedy, Ronald Turner, Thomas Braciale, Peter Heyman and Larry Borish discuss the lack of cytopathology associated with rhinovirus infection and the role of the host response in clinical disease. While the virus does not kill the infected cells, infection results in disruption of the integrity of the epithelial membrane, thereby facilitating the infection with secondary pathogens. Furthermore, this disruption may also give access to the basolateral surface of the epithelia, which expresses TLRs and other pattern recognition receptors, to allergens and foreign bodies, possibly explaining the observed exacerbation of asthma. Rhinoviruses rapidly induce innate immune activation in a naïve host, resulting in the expression of type I IFNs, as well as chemokines and growth factors that attract neutrophils and eosinophils to the site of infection. The extent of granulocytosis not only correlates with disease severity, but also contributes to virus clearance. While neutralizing antibodies are mainly involved in protection from reinfection with the same serotype, the kinetics of virus clearance suggest the presence of crossreacting T cells from previous infections with other serotypes. Thus, vaccination strategies aiming at eliciting or reinforcing such cellular responses against conserved epitopes could lead to considerable reduction in morbidity.

Henrick Schomacker, Anne Schaap-Nutt, Peter Collins, and Alexander Schmidt discuss the pathogenesis of human parainfluenza viruses (HPIVs). In adults, HPIVs are also part of the common cold complex, but these viruses can cause severe infections and even require hospitalization during the primary infection of infants and young children. In polarized human airway epithelium cultures, HPIVs only infect ciliated cells and cause few cytopathic effects. This localized infection in combination with viral interference with innate immune activation is thought to reduce immune recognition and prolong viral replication. The magnitude of virus replication in turn correlates with disease severity. The infection results in the development of neutralizing systemic IgG and mucosal IgA antibodies, but more than one infection is likely needed to maintain protective mucosal immunity. However, pre-existing immunity results in mild or asymptomatic disease upon reinfection.

The pathogenesis of human respiratory syncytial virus (RSV) shares many similarities with HPIVs. It also leads to severe lower respiratory tract infections in infants and young children, while causing mostly mild cold-like disease in adults, and the level of replication correlates with disease severity. In addition to the nonstructural proteins that inhibit different innate immunity signaling pathways, RSV also produces a secreted form of its envelope glycoprotein G, which acts as decoy to capture neutralizing antibodies, reduces the action of host fraktalkine, and functions as TLR antagonist. The adaptive immune response associated with RSV infections has a strong Th2 bias, which may lead to a predisposition for asthma later in life. Sylvia van Drunen Little-van den Hurk and Ellen Watkiss discuss the unique characteristics of RSV immunopathology.

Regardless of their phylogenetic diversity, respiratory viruses have evolved to overcome the challenges posed by the unique environment of the respiratory tract. Advances in the genetic manipulation of the respective viruses and the increasing availability of reagents and genomic information for the different host species are providing exciting new insights in the underlying pathogenesis mechanisms. It is becoming increasingly clear that manipulation of the host response can result in severe immunopathology, which in many cases contributes more importantly to the observed pathology than the virus infection itself.

Economic costs of respiratory tract infections in the United States

Evaluation of factors associated with increased dairy cow mortality on United States dairy operations

A successful national control programme for enzootic respiratory diseases in pigs in Switzerland