The role of respiratory viruses in acute and chronic asthma

Respiratory infections can have dual effects related to asthma. First, there is increasing evidence that severe infections with RSV and PIV in infancy can alter lung development and physiology to increase the risks of subsequent wheezing and asthma. Second, infections with common cold viruses and influenza commonly precipitate wheezing symptoms in children and adults who already have established asthma, and RV appears to be the most important virus in producing exacerbations of the disease. The principal mechanisms by which this occurs appears to be viral replication in epithelial cells, triggering a cascade of inflammation involving granulocytes, macrophages, T cells, and secreted cytokines and mediators. The inflammatory process, although essential to clear the infection, augments pre-existing airway inflammation in asthma, leading to increased airway obstruction and lower respiratory tract symptoms. Greater understanding of virus-induced changes in inflammation and corresponding changes in airway physiology may lead to new therapeutic approaches to the treatment and prevention of virus-induced airway dysfunction.     

Alveolar-like Macrophages Attenuate Respiratory Syncytial Virus Infection

Respiratory Syncytial Virus (RSV) is the leading cause of acute lower respiratory infections in young children and infection has been linked to the development of persistent lung disease in the form of wheezing and asthma. Despite substantial research efforts, there are no RSV vaccines currently available and an effective monoclonal antibody targeting the RSV fusion protein (palivizumab) is of limited general use given the associated expense. Therefore, the development of novel approaches to prevent RSV infection is highly desirable to improve pediatric health globally. We have developed a method to generate alveolar-like macrophages (ALMs) from pluripotent stem cells. These ALMs have shown potential to promote airway innate immunity and tissue repair and so we hypothesized that ALMs could be used as a strategy to prevent RSV infection. Here, we demonstrate that ALMs are not productively infected by RSV and prevent the infection of epithelial cells. Prevention of epithelial infection was mediated by two different mechanisms: phagocytosis of RSV particles and release of an antiviral soluble factor different from type I interferon. Furthermore, intratracheal administration of ALMs protected mice from subsequent virus-induced weight loss and decreased lung viral titres and inflammation, indicating that ALMs can impair the pathogenesis of RSV infection. Our results support a prophylactic role for ALMs in the setting of RSV infection and warrant further studies on stem cell-derived ALMs as a novel cell-based therapy for pulmonary viral infections.     

The immunology of virus infection in asthma.

The respiratory tract is commonly infected by a range of viruses with overlapping pathologies. The majority of episodic exacerbations of asthma are associated with viral infection, in particular with rhinovirus infections. Experimental rhinovirus infection in human volunteers provides a useful model of natural virus-induced asthma. The asthmatic airway is characterized by an infiltrate of eosinophils and T-lymphocytes expressing the type 2 cytokines interleukin (IL)-4, IL-5 and IL-13. An effective antiviral immune response requires early viral clearance and appropriate termination of the immune response to minimize associated immunopathology and tissue damage. The antiviral immune response is made up of innate (nonspecific) and specific components, and requires the coordinated actions of many different cell types including neutrophils, macrophages, eosinophils, dendritic cells, epithelial cells, mast cells, natural killer cells and B- and T-lymphocytes. Coordination of this response involves numerous cytokines and chemokines. T-lymphocytes expressing type 1 cytokines including interferon-gamma play a key role. Pre-existing asthmatic inflammation in the lower airway may modify the immune response to viral infection by altering the balance of T-cell cytokine expression from type 1 towards a type 2 in what is always a mixed response. The consequence is delayed viral clearance, persistent virus-induced inflammation and amplification of the allergic inflammation.     

Respiratory viral infections as promoters of allergic sensitization and asthma in animal models.

Respiratory virus infections can trigger exacerbations of asthma and may also contribute to allergic sensitization to aeroallergens and the development of asthma. Conversely, atopy may predispose to more severe virus-induced airway disease. The animal models reviewed in this article support the hypothesis that respiratory virus infections can promote allergic sensitization and the development of asthma. Respiratory viruses can prevent induction of tolerance and enhance sensitization to inhaled allergens resulting in increased airway inflammation and airway hyperresponsiveness. Probable mechanisms involved in this enhanced sensitization are increased permeability of the airway mucosa to allergens and recruitment of dendritic cells to the respiratory epithelium during acute infection. Factors involved in augmenting the consequences of allergic airway sensitization appear to be T-cells, especially CD8+ T-cells as regulators of this process, interleukin-5 as a pivotal cytokine for eosinophilic airway inflammation and eosinophils themselves as effector cells triggering airway hyperresponsiveness. Depending on the timing of allergen exposure, respiratory virus infections which elicit a significant type 1 T-helper cell cytokine response may also downregulate allergic sensitization. Respiratory virus infections in animals previously sensitized to aeroallergens result in prolonged increases in inflammation and airway responsiveness, indicating that critical interactions between immune responses to allergen sensitization and the responses to infection can lead to more severe disease. Taken together, animal models have proved valuable in generating a number of plausible pathogenetic concepts, and can be used to address a host of unresolved questions regarding the immunology of respiratory virus infections, allergic sensitization and asthma.     

The role of viruses in development or exacerbation of atopic asthma

Respiratory viral infections in early childhood have been linked to the development of persistent wheezing and asthma. Epidemiologic data indicate that, for the majority of children, virus-induced wheezing is a self-limited condition, with no long-term consequences. For a substantial minority, however, virus-induced wheezing is associated with persistent asthma and the potential for enhanced allergic sensitization. For the most part, this subset of patients is genetically predisposed; they are atopic children in whom respiratory viral infections trigger the early development of asthma by mechanisms that have not been fully elucidated. Both inflammatory and noninflammatory mechanisms may be involved. It does not appear that viral infection per se in early life is responsible for the induction of atopic asthma. Data from animal models provide support for the concept that enhanced allergic sensitization caused by increased uptake of allergen during infection may play a critical role, as well as T-cell-mediated immune responses to viral infection, which may favor eosinophilic inflammatory responses and the development of altered airway function to inhaled methacholine. Recent advances in our understanding of the interactions between respiratory viruses and the development of reactive airway disease offer new possibilities for preventive treatment in children at risk for developing persistent wheezing and asthma exacerbation as a result of viral infection.     

Viral "bronchitis" in childhood: relationship to asthma and obstructive lung disease

Lower respiratory tract infections in children, including group, bronchiolitis, and bronchitis are frequently associated with recurrent episodes of wheezing. Different respiratory viruses assume greater importance at different ages of children. Respiratory syncytial virus is the most prevalent viral respiratory infection in preschool children, while rhinovirus is of increasing importance in older children. Asymptomatic virus shedding and mild respiratory infections do not provoke asthma symptoms nor do bacteria, except in association with sinusitis. Furthermore, epidemiologic studies strongly suggest that viral lower respiratory tract illness in early childhood is associated with pulmonary abnormalities, including bronchial hyperreactivity and peripheral airway obstruction that may persist for many years, and is possibly a cause of chronic airway obstruction in adulthood. Several different mechanisms have been identified by which respiratory viruses provoke asthma. No one single mechanism, however, adequately explains virus-induced asthma. Nonetheless, a common thread to these various proposed mechanisms is the ability of respiratory viruses to cause airway inflammation, either directly, through cytopathic effects, or indirectly, by increasing the inflammatory processes of respiratory cells. The consequence of these effects causes increased airway responsiveness and asthma.     

Th17 Lymphocytes in Respiratory Syncytial Virus Infection

Infection by respiratory syncytial virus (RSV) affects approximately 33 million infants annually worldwide and is a major cause of hospitalizations. Helper T lymphocytes (Th) play a central role in the immune response during such infections. However, Th lymphocytes that produce interleukin 17 (IL-17), known as Th17 lymphocytes, in addition to been protective can also cause pathology that accompany this type of infection. The protective effects of Th17 is associated with better prognosis in most infected individuals but heightened Th17 responses causes inflammation and pathology in others. Studies employing animal models haves shown that activated Th17 lymphocytes recruit neutrophils and facilitate tertiary lymphoid structure development in infected lungs. However, IL-17 also inhibits the ability of CD8⁺ lymphocytes to clear viral particles and acts synergistically with the innate immune system to exacerbate inflammation. Furthermore, IL-17 enhances IL-13 production which, in turn, promotes the activation of Th2 lymphocytes and excessive mucus production. Studies of these animal models have also shown that a lack of, or inadequate, responses by the Th1 subset of T lymphocytes enhances Th17-mediated responses and that this is detrimental during RSV co-infection in experimental asthma. The available evidence, therefore, indicates that Th17 can play contradictory roles during RSV infections. The factors that determine the shift in the balance between beneficial and adverse Th17 mediated effects during RSV infection remains to be determined.     

COPD Is Associated with Elevated IFN-β Production by Bronchial Epithelial Cells Infected with RSV or hMPV

IFN treatment may be a viable option for treating COPD exacerbations based on evidence of IFN deficiency in COPD. However, in vitro studies have used primarily influenza and rhinoviruses to investigate IFN responses. This study aims to investigate the susceptibility to infection and IFN response of primary bronchial epithelial cells (BECs) from COPD donors to infection with RSV and hMPV. BECs from five COPD and five healthy donors were used to establish both submerged monolayer and well-differentiated (WD) cultures. Two isolates of both RSV and hMPV were used to infect cells. COPD was not associated with elevated susceptibility to infection and there was no evidence of an intrinsic defect in IFN production in either cell model to either virus. Conversely, COPD was associated with significantly elevated IFN-β production in response to both viruses in both cell models. Only in WD-BECs infected with RSV was elevated IFN-β associated with reduced viral shedding. The role of elevated epithelial cell IFN-β production in the pathogenesis of COPD is not clear and warrants further investigation. Viruses vary in the responses that they induce in BECs, and so conclusions regarding antiviral responses associated with disease cannot be made based on single viral infections.     

The role of viral respiratory infections in the pathogenesis and exacerbation of asthma

Respiratory viral infections are implicated in both the pathogenesis and exacerbation of asthma. Infections with respiratory syncytial virus and parainfluenza virus are the major cause of wheezing-related respiratory infections early in life. Infections in early childhood affect the immune system and modify the risk for subsequent development of allergies and asthma. Later in life, rhinovirus and influenza are implicated frequently in the exacerbation of asthma. The management of respiratory viral infections includes adequate prophylaxis and treatment of acute infections. Insights into the mechanism of viral respiratory tract infections will provide therapeutic targets for treatment and possibly the prevention of virus-induced asthma.     

Differential production of inflammatory cytokines in primary infection with human metapneumovirus and with other common respiratory viruses of infancy

Viral respiratory infections are the most frequent cause of hospital admission for infants and young children during winter. However, the mechanisms of illness that are associated with viral lower-respiratory-tract infection (LRI) are unclear. A widely accepted hypothesis attributes the pathogenesis of viral LRI in infants to the induction of innate inflammatory responses. This theory is supported by studies showing that Toll-like receptor 4 is activated by respiratory syncytial virus (RSV), leading to production of inflammatory cytokines. We prospectively examined previously naive infants in Buenos Aires, Argentina, who had either upper- or lower-respiratory-tract symptoms. Infection with human metapneumovirus (hMPV) was second only to RSV in frequency. Both viruses were associated with rhinorrhea, cough, and wheezing; however, hMPV elicited significantly lower levels of respiratory inflammatory cytokines than did RSV. Symptoms in infants infected with influenza virus were different from those in infants infected with RSV, but cytokine responses were similar. These findings suggest that hMPV and RSV either cause disease via different mechanisms or share a common mechanism that is distinct from innate immune activation.     

Overview of virus-induced airway disease

Acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are the major cause of morbidity, mortality, and health costs of both diseases. Currently available treatments are poorly effective in both acute treatment of and prevention of acute exacerbations. New treatments for intervention and prophylaxis are therefore required; to facilitate their development, we must understand the causes and mechanisms of exacerbations. Respiratory viral infections (2/3 rhinoviruses) precipitate 80% or more of asthma exacerbations in children, and the majority of exacerbations of asthma and COPD in adults, but mechanisms of virus-induced lower airway inflammation and of host resistance against respiratory viruses are poorly understood. Development of in vitro experimental models of virus infection has identified interferon-beta and nitric oxide as possible therapeutic targets to augment antiviral immunity, and nuclear factor-kappaB as a target for development of anti-inflammatory therapies. In vivo models could also serve to identify and validate targets and as an experimental system to test candidate molecules as they emerge into clinical studies. Studies in asthma have paved the way for development of an asthma model; a similar experimental model in COPD would accelerate development of new therapies for these common diseases with enormous burdens of illness.     

Persistent Airway Hyperresponsiveness Following Recovery from Infection with Pneumonia Virus of Mice

Respiratory virus infections can have long-term effects on lung function that persist even after the acute responses have resolved. Numerous studies have linked severe early childhood infection with respiratory syncytial virus (RSV) to the development of wheezing and asthma, although the underlying mechanisms connecting these observations remain unclear. Here, we examine airway hyperresponsiveness (AHR) that develops in wild-type mice after recovery from symptomatic but sublethal infection with the natural rodent pathogen, pneumonia virus of mice (PVM). We found that BALB/c mice respond to a limited inoculum of PVM with significant but reversible weight loss accompanied by virus replication, acute inflammation, and neutrophil recruitment to the airways. At day 21 post-inoculation, virus was no longer detected in the airways and the acute inflammatory response had largely resolved. However, and in contrast to most earlier studies using the PVM infection model, all mice survived the initial infection and all went on to develop serum anti-PVM IgG antibodies. Furthermore, using both invasive plethysmography and precision-cut lung slices, we found that these mice exhibited significant airway hyperresponsiveness at day 21 post-inoculation that persisted through day 45. Taken together, our findings extend an important and versatile respiratory virus infection model that can now be used to explore the role of virions and virion clearance as well as virus-induced inflammatory mediators and their signaling pathways in the development and persistence of post-viral AHR and lung dysfunction.     

Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production

Acute exacerbations are the major cause of asthma morbidity, mortality, and health-care costs and are difficult to treat and prevent. The majority of asthma exacerbations are associated with rhinovirus (RV) infection, but evidence supporting a causal relationship is weak and mechanisms are poorly understood. We hypothesized that in asthmatic, but not normal, subjects RV infection would induce clinical, physiologic, and pathologic lower airway responses typical of an asthma exacerbation and that these changes would be related to virus replication and impaired T helper 1 (Th1)/IL-10 or augmented Th2 immune responses. We investigated physiologic, virologic, and immunopathologic responses to experimental RV infection in blood, induced sputum, and bronchial lavage in 10 asthmatic and 15 normal volunteers. RV infection induced significantly greater lower respiratory symptoms and lung function impairment and increases in bronchial hyperreactivity and eosinophilic lower airway inflammation in asthmatic compared with normal subjects. In asthmatic, but not normal, subjects virus load was significantly related to lower respiratory symptoms, bronchial hyperreactivity, and reductions in blood total and CD8⁺ lymphocytes; lung function impairment was significantly related to neutrophilic and eosinophilic lower airway inflammation. The same virologic and clinical outcomes were strongly related to deficient IFN-γ and IL-10 responses and to augmented IL-4, IL-5, and IL-13 responses. This study demonstrates increased RV-induced clinical illness severity in asthmatic compared with normal subjects, provides evidence of strong relationships between virus load, lower airway virus-induced inflammation and asthma exacerbation severity, and indicates augmented Th2 or impaired Th1 or IL-10 immunity are likely important mechanisms.     

Respiratory infections: their role in airway responsiveness and pathogenesis of asthma

A clear relationship between viral upper respiratory infections and exacerbations of asthma has been established in numerous clinical studies. However, a unifying concept to explain how respiratory viruses bring about these changes has not been established unless it is the ability of viral illnesses to promote the inflammatory process. These changes in inflammation potentially encompass several organ systems: airway epithelium, the autonomic nervous system, and immediate hypersensitivity reactions. Thus, enhanced airway reactivity in viral respiratory infections represents a complex orchestration of many factors and functions to create the end result of bronchial hyperresponsiveness. Insight into precisely how the respiratory virus initiates these changes should provide valuable and new information into the pathogenesis of asthma. Therefore, not only is virus-induced asthma an important clinical problem, but it may also serve as a window to mechanisms of airway hyperreactivity and asthma.     

Immune interaction between respiratory syncytial virus infection and allergen sensitization critically depends on timing of challenges.

Severe respiratory syncytial virus (RSV) infection has been hypothesized to be a risk factor for the development of allergy and asthma, but epidemiologic studies in humans have been inconclusive. By use of a well-characterized murine model of RSV infection and allergic sensitization with ovalbumin, the effect of a preceding severe RSV infection on the development of the pulmonary allergic inflammatory response and airway hyperresponsiveness (AHR) was tested. The impact of prior allergic sensitization on RSV-induced illness, as measured by weight loss, also was evaluated. RSV infection before allergic sensitization decreased allergen-induced AHR, production of interleukin-13 in lung tissue, and lung eosinophilia. In contrast, allergic sensitization before RSV infection increased AHR and decreased RSV-related weight loss and lung levels of interferon-gamma but did not alter viral clearance. These data provide evidence that RSV-associated AHR occurs in hosts with allergic responses and that allergic inflammation is diminished when preceded by RSV infection.     

呼吸道合胞病毒感染与慢性阻塞性肺疾病发病的免疫机制

慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是一种常见的呼吸系统疾病.随着近年来对病毒导致慢性阻塞性肺疾病急性加重(AECOPD)机制的深入研究以及呼吸道病毒检出率的提高,病毒感染在COPD发病机制中的作用受到了更多关注.呼吸道合胞病毒(respiratory syncytial vius,RSV)是常见的呼吸道病毒.有关RSV与宿主的免疫学的研究提示了COPD中RSV的易感性,可能成为某些COPD患者防治疾病发展的新方向.本文对病毒感染在AECOPD中的作用以及RSV感染与COPD发病机制的免疫研究进展现状作一综述.     

The cysteine-rich region of respiratory syncytial virus attachment protein inhibits innate immunity elicited by the virus and endotoxin

The attachment protein (glycoprotein) of respiratory syncytial virus (RSV) has long been associated with disease potentiation and respiratory symptoms. The glycoprotein has a conserved cysteine-rich region (GCRR) whose function is unknown and which is not necessary for efficient viral replication. In this report, we show that the GCRR is a powerful inhibitor of the innate immune response against RSV, and that early secretion of glycoprotein is critical to modulate inflammation after RSV infection. Importantly, the GCRR is also a potent inhibitor of cytokine production mediated by several TLR agonists, indicating that this peptide sequence displays broad antiinflammatory properties. These findings have important implications for RSV pathogenesis and describe an inhibitor of TLR-mediated inflammatory responses that could have clinical applications.     

Viral infection in asthma

In bronchial asthma, respiratory virus infection involves several issues: 1) respiratory virus infection in infancy is a risk factor for, and may predispose to, the development of asthma later in life; 2) respiratory virus infection is associated with the acute exacerbation of bronchial asthma; and, 3) glucocorticosteroids (GC) are not adequate for controlling asthma-related symptoms upon respiratory virus infection. Various cells, inflammatory mediators and cytokines participate in the production of airway inflammation upon respiratory virus infection. Bronchial epithelial cells are a site of infection and replication of respiratory virus. They actively participate in the production of airway inflammation: 1) they produce various proinflammatory cytokines, chemokines and mediators; and, 2) they undergo apoptosis, thereby impairing the repair process. It is therefore important to understand the role of bronchial epithelial cells in the pathophysiology of bronchial asthma. In this review, the interaction between viral infection and asthma is discussed to elucidate the role of bronchial epithelial cells in viral infection.