Relationship of viral infections to wheezing illnesses and asthma

Viral infections can influence both the development and the severity of asthma. In early life, viral infections can either increase or, remarkably, decrease the risk of subsequent asthma. In children and adults with existing asthma, viral respiratory infections frequently cause acute airway obstruction and wheezing. This article discusses the influence of viral infections on mechanisms of virus-induced airway inflammation in relationship to the development, persistence and severity of asthma.     

Viral infections and atopy in asthma pathogenesis: new rationales for asthma prevention and treatment

Prospective birth cohort studies tracking asthma initiation and consolidation in community cohorts have identified viral infections occurring against a background of allergic sensitization to aeroallergens as a uniquely potent risk factor for the expression of acute severe asthma-like symptoms and for the ensuing development of asthma that can persist through childhood and into adulthood. A combination of recent experimental and human studies have suggested that underlying this bipartite process are a series of interactions between antiviral and atopic inflammatory pathways that are mediated by local activation of myeloid cell populations in the airway mucosa and the parallel programming and recruitment of their replacements from bone marrow. Targeting key components of these pathways at the appropriate stages of asthma provides new opportunities for the treatment of established asthma but, more crucially, for primary and secondary prevention of asthma during childhood.     

Gene-environment interaction effects on the development of immune responses in the 1st year of life

Asthma is a common disease that results from both genetic and environmental risk factors. Children attending day care in the 1st year of life have lower risks for developing asthma, although the mechanism for this "day care" effect is largely unknown. We investigated the interactions between day care exposure in the 1st 6 mo of life and genotypes for 72 polymorphisms at 45 candidate loci and their effects on cytokine response profiles and on the development of atopic phenotypes in the 1st year of life in the Childhood Onset of Asthma (COAST) cohort of children. Six interactions (at four polymorphisms in three loci) with "day care" that had an effect on early-life immune phenotypes were significant at P<.001. The estimated false-discovery rate was 33%, indicating that an estimated four P values correspond to true associations. Moreover, the "day care" effect at some loci was accounted for by the increased number of viral infections among COAST children attending day care, whereas interactions at other loci were independent of the number of viral infections, indicating the presence of additional risk factors associated with day care environment. This study identified significant gene-environment interactions influencing the early patterning of the immune system and the subsequent development of asthma and highlights the importance of considering environmental risk factors in genetic analyses.     

Respiratory syncytial virus predisposes mice to augmented allergic airway responses via IL-13-mediated mechanisms.

The development of severe childhood asthma may be influenced by several factors including environmental and infectious stimuli. The causal relationship between infectious viral responses, such as respiratory syncytial virus (RSV), and severe asthma during early childhood is unclear. In these studies, the ability for an initial RSV infection to exacerbate and promote a more severe asthmatic-type response was investigated by combining established murine models of disease. We examined the ability of RSV to induce exacerbation of allergic disease over a relatively long period, leading to development of severe airway responses including airway inflammation and hyperreactivity. The preferential production of IL-13 during a primary RSV infection appears to play a critical role for the exacerbation of cockroach allergen-induced disease. The depletion of IL-13 during RSV infections inhibited the exacerbation and acceleration of severe allergen-induced airway hyperreactivity. This was indicated by decreases in airway hyperreactivity and changes in lung chemokine production. These data suggest that the airway responses during asthma can be greatly affected by a previous RSV infection, even when infection occurs before allergen sensitization. Overall, infection of the airways with RSV can induce an IL-13-dependent change in airway function and promotes an environment that contributes to the development of severe allergic asthmatic responses.     

Emerging and re-emerging viral infections in Europe

Emerging viral infections are becoming a serious problem in Europe in the recent years. This is particularly true for severe acute respiratory syndrome (SARS), West Nile virus (WNV) disease, Toscana virus (TOSV) disease, and potentially for avian influenza virus (H5N1). In contrast, emergence or re-emergence of severe viral infections, including tick borne encephalitis virus, and viral haemorrhagic fever caused by Hantavirus and dengue virus have been frequently reported in several European countries. Laboratory diagnosis of these viral infections based on viral isolation or detection by immune electron microscopy, immunoassay and polymerase chain reaction (PCR) has dramatically improved in the recent years, and SARS represents a good example of a diagnostic approach to emerging viral infections. Finally, old and new promising agents are in the pipeline of pharmaceutical companies to treat emerging viral infections. However only prevention based on large epidemiological studies, and research and development of new vaccines may be able to control and eventually eradicate these deadly viral infections.     

Challenges presented by MERS corona virus,and SARS corona virus to global health

Numerous viral infections have arisen and affected global healthcare facilities. Millions of people are at severe risk of acquiring several evolving viral infections through several factors. In the present article we have described about risk factors, chance of infection, and prevention methods of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and severe acute respiratory syndrome (SARS-CoV), human coronaviruses (CoVs) frequently cause a normal cold which is mild and self-restricting. Zoonotic transmission of CoVs such as the newly discovered MERS-CoV and SARS-CoV, may be associated with severe lower respiratory tract infection. The present review provides the recent clinical and pathological information on MERS and SARS. The task is to transform these discoveries about MERS and SARS pathogenesis and to develop intervention methods that will eventually allow the effective control of these recently arising severe viral infections. Global health sector has learnt many lessons through the recent outbreak of MERS and SARS, but the need for identifying new antiviral treatment was not learned. In the present article we have reviewed the literature on the several facets like transmission, precautions and effectiveness of treatments used in patients with MERS-CoV and SARS infections.     

Molecular aspects of hepatitis B viral infection and the viral carcinogenesis

Of many viral causes of human cancer, few are of greater global importance than the hepatitis B virus (HBV). Over 250 million people worldwide are persistently infected with HBV. A significant minority of these develop severe pathologic consequences, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Earlier epidemiological evidence suggested a link between chronic HBV infection and HCC. Further, the existence of related animal viruses that induce acute and chronic infections of the liver, and eventually HCC, confirms the concept that HBV belongs to one of the few human oncogenic viruses. Although it is clear that chronic HBV infections are major risk factors, relatively little is understood about how the viral factors contribute to hepatocarcinogenesis. This review will introduce molecular aspects of the viral infection, and highlight recent findings on the viral contribution to hepatocarcinogenesis.     

Impact of rhinitis on airway inflammation: biological and therapeutic implications

There is increasing evidence for a close link between the upper and the lower respiratory tracts and the fact that rhinitis has an important impact on asthma. Several clinical and experimental observations suggest a similar immunopathology between the upper and lower airways in allergic subjects. The common inflammatory process that develops in the respiratory tract explains some of the complex interactions among different clinical diseases such as rhinitis, sinusitis, asthma, bronchial hyperresponsiveness and viral infections. There are also non-inflammatory mechanisms that may contribute to the link between rhinitis and asthma. Moreover, the outcomes of various pharmacological treatments of rhinitis have recently provided further support for the hypothesis of the united airways. We discuss some of the recent observations on the nose-lung interaction and some of the novel therapeutic approaches used to treat rhinitis and asthma that arise from this.     

Genome-virome interactions: examining the role of common viral infections in complex disease

New technologies have widened our view of 'complex diseases': those with both genetic and environmental risk factors. In this Review, we explore recent genetic and virological evidence implicating host-virus interactions in three diseases: type 1 diabetes, inflammatory bowel disease and asthma. The viruses implicated in these diseases cause mucosal infections that affect most of the population but are asymptomatic or mild in many hosts. These findings place a new emphasis on common viral infections as important environmental factors in the pathogenesis of complex diseases, and they compel the field to pursue a better understanding of host interactions with the human virome.     

Community study of role of viral infections in exacerbations of asthma in 9-11 year old children.

OBJECTIVE--To study the association between upper and lower respiratory viral infections and acute exacerbations of asthma in schoolchildren in the community. DESIGN--Community based 13 month longitudinal study using diary card respiratory symptom and peak expiratory flow monitoring to allow early sampling for viruses. SUBJECTS--108 Children aged 9-11 years who had reported wheeze or cough, or both, in a questionnaire. SETTING--Southampton and surrounding community. MAIN OUTCOME MEASURES--Upper and lower respiratory viral infections detected by polymerase chain reaction or conventional methods, reported exacerbations of asthma, computer identified episodes of respiratory tract symptoms or peak flow reductions. RESULTS--Viruses were detected in 80% of reported episodes of reduced peak expiratory flow, 80% of reported episodes of wheeze, and in 85% of reported episodes of upper respiratory symptoms, cough, wheeze, and a fall in peak expiratory flow. The median duration of reported falls in peak expiratory flow was 14 days, and the median maximum fall in peak expiratory flow was 81 l/min. The most commonly identified virus type was rhinovirus. CONCLUSIONS--This study supports the hypothesis that upper respiratory viral infections are associated with 80-85% of asthma exacerbations in school age children.     

Functional Limitations of Plasmacytoid Dendritic Cells Limit Type I Interferon,T Cell Responses and Virus Control in Early Life

Infant mortality from viral infection remains a major global health concern: viruses causing acute infections in immunologically mature hosts often follow a more severe course in early life, with prolonged or persistent viral replication. Similarly, the WE strain of lymphocytic choriomeningitis virus (LCMV-WE) causes acute self-limiting infection in adult mice but follows a protracted course in infant animals, in which LCMV-specific CD8⁺ T cells fail to expand and control infection. By disrupting type I IFNs signaling in adult mice or providing IFN-α supplementation to infant mice, we show here that the impaired early life T cell responses and viral control result from limited early type I IFN responses. We postulated that plasmacytoid dendritic cells (pDC), which have been identified as one major source of immediate-early IFN-I, may not exert adult-like function in vivo in the early life microenvironment. We tested this hypothesis by studying pDC functions in vivo during LCMV infection and identified a coordinated downregulation of infant pDC maturation, activation and function: despite an adult-like in vitro activation capacity of infant pDCs, the expression of the E2-2 pDC master regulator (and of critical downstream antiviral genes such as MyD88, TLR7/TLR9, NF-κB, IRF7 and IRF8) is downregulated in vivo at baseline and during LCMV infection. A similar pattern was observed in response to ssRNA polyU, a model ligand of the TLR7 viral sensor. This suggests that the limited T cell-mediated defense against early life viral infections is largely attributable to / regulated by infant pDC responses and provides incentives for novel strategies to supplement or stimulate immediate-early IFN-α responses.     

Asthma, viruses, and nitric oxide

Over the last two decades there has been a worldwide increase in the morbidity and mortality associated with asthma, a chronic inflammatory disease of the airways. There is a growing body of evidence that suggests there is an association between upper respiratory viral infections, particularly rhinovirus infections, and asthma exacerbations. Virally induced airways hyperreactivity has been associated with elevated numbers of inflammatory cells in the bronchial mucosa. Upon virus infection, respiratory epithelial cells produce proinflammatory cytokines, including IL-6, IL-8, RANTES, and GM-CSF, which could contribute to the increased inflammatory cell recruitment noted in the airways. Whether or not a viral infection triggers an asthma attack may depend upon many factors, including the types of inflammatory cells recruited to the airways, the viral load, and variations in the host antiviral response. There is evidence to support the idea that eosinophils from asthmatic and symptomatic atopic subjects may be primed to respond to chemotactic cytokines produced by infected epithelial cells. Rhinovirus infections may therefore enhance airway eosinophilia in asthmatics, leading to airway hyperresponsiveness and impaired pulmonary function. Nitric oxide is a potent inhibitor of both rhinovirus-induced cytokine production and viral replication and may play an important role in the host response to viral infections. Based upon these observations, we speculate that nitric oxide donors may represent a novel therapeutic approach for the treatment of rhinovirus infections and viral exacerbations of asthma.     

Diagnosis and treatment of viral diseases in recipients of allogeneic hematopoietic stem cell transplantation

Viral infections are important causes of morbidity and mortality after allogeneic stem cell hematopoietic transplantation (allo-HSCT). Although most viral infections present with asymptomatic or subclinical manifestations, viruses may result in fatal complications in severe immunocompromised recipients. Reactivation of latent viruses, such as herpesviruses, is frequent during the immunosuppression that occurs with allo-HSCT. Viruses acquired from community, such as the respiratory and gastrointestinal viruses, are also important pathogens of post-transplant viral diseases. Currently, molecular diagnostic methods have replaced or supplemented traditional methods, such as viral culture and antigen detection, in diagnosis of viral infections. The utilization of polymerase chain reaction facilitates the early diagnosis. In view of lacking efficacious agents for treatment of viral diseases, prevention of viral infections is extremely valuable. Application of prophylactic strategies including preemptive therapy reduces viral infections and diseases. Adoptive cellular therapy for restoring virus-specific immunity is a promising method in the treatment of viral diseases.     

The life cycle and pathogenesis of human cytomegalovirus infection: lessons from proteomics

Viruses have coevolved with their hosts, acquiring strategies to subvert host cellular pathways for effective viral replication and spread. Human cytomegalovirus (HCMV), a widely-spread β-herpesvirus, is a major cause of birth defects and opportunistic infections in HIV-1/AIDS patients. HCMV displays an intricate system-wide modulation of the human cell proteome. An impressive array of virus–host protein interactions occurs throughout the infection. To investigate the virus life cycle, proteomics has recently become a significant component of virology studies. Here, we review the mass spectrometry-based proteomics approaches used in HCMV studies, as well as their contribution to understanding the HCMV life cycle and the virus-induced changes to host cells. The importance of the biological insights gained from these studies clearly demonstrate the impact that proteomics has had and can continue to have on understanding HCMV biology and identifying new therapeutic targets.     

Childhood brain tumours,early infections and immune stimulation: A pooled analysis of the ESCALE and ESTELLE case-control studies (SFCE,France)

BackgroundFew studies have investigated whether early infections and factors potentially related to early immune stimulation might be involved in the aetiology of childhood brain tumours (CBT). In this study, we investigated the associations between CBT with early day-care attendance, history of early common infections, atopic conditions (asthma/wheezing, eczema, allergic rhinitis), early farm residence/visits and contact with animals.MethodsWe pooled data from two nationwide French case-control studies, the ESCALE and ESTELLE studies. Children with a CBT diagnosed between 1 and 14 years of age were identified directly from the French National Registry of Childhood Cancers, while population controls were recruited from telephone subscribers. Odds-ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression adjusted for potential confounders.ResultsThe analyses included 469 cases and 2719 controls. We found no association between attending a day-care centre (OR: 0.9, 95%CI: 0.7–1.2) or having had repeated common infections (OR: 0.9, 95%CI: 0.7–1.2) in the first year of life and the risk of CBT. There was also no association with a history of asthma/wheezing (OR: 0.8, 95%CI: 0.56–1.1). Farm visits (OR: 0.6, 95%CI: 0.5–0.8) as well as contact with pets (OR: 0.8, 95%CI: 0.6–1.0) in the first year of life were inversely associated with CBT.ConclusionsOur findings suggest a protective effect of early farm visits and contact with pets, but not with other markers of early immune stimulation. This might be related to immune stimulation but needs further investigation.     

Salmonella Typhimurium-specific bacteriophage ΦSH19 and the origins of species specificity in the Vi01-like phage family

Background

PHYVV and PepGMV are plant viruses reported in Mexico and Southern US as causal agents of an important pepper disease known as "rizado amarillo". Mixed infections with PHYVV and PepGMV have been reported in several hosts over a wide geographic area. Previous work suggested that these viruses might interact at the replication and/or movement level in a complex manner. The aim of present report was to study some aspects of a synergistic interaction between PHYVV and PepGMV in pepper plants. These include analyses of symptom severity, viral DNA concentration and tissue localization of both viruses in single and mixed infections.

Results

Mixed infections with PepGMV and PHYVV induced symptoms more severe than those observed in single viral infections. Whereas plants infected with either virus (single infection) presented a remission stage with a corresponding decrease in viral DNA levels, double-infected plants did not present symptom remission and both viral DNA concentrations dramatically increased. In situ hybridization experiments revealed that both viruses are restricted to the vascular tissue. Interestingly, the amount of viral DNA detected was higher in plants inoculated with PepGMV than that observed in PHYVV-infected plants. During mixed infections, the location of both viruses remained similar to the one observed in single infections, although the number of infected cells increases. Infections with the tripartite mixture PHYVV (A+B) + PepGMV A produced a similar synergistic infection to the one observed after inoculation with both full viruses. On the contrary, tripartite mixture PepGMV (A+B) + PHYVV A did not produce a synergistic interaction. In an attempt to study the contribution of individual genes to the synergism, several mutants of PHYVV or PepGMV were inoculated in combination with the corresponding wild type, second virus (wt PepGMV or wt PHYVV). All combinations tested resulted in synergistic infections, with exception of the TrAP mutant of PepGMV (PepGMV TrAP-) + PHYVV.

Conclusion

In this report, we have demonstrated that synergistic interaction between PHYVV and PepGMV during a mixed infection is mainly due to an increased DNA concentration of both viruses, without any noticeable effect on the localization of either virus on infected plant tissue. Our results have shown that the viral component A from PepGMV is important for synergism during PHYVV-PepGMV mixed infections.     

Exploring cell tropism as a possible contributor to influenza infection severity

Several mechanisms have been proposed to account for the marked increase in severity of human infections with avian compared to human influenza strains, including increased cytokine expression, poor immune response, and differences in target cell receptor affinity. Here, the potential effect of target cell tropism on disease severity is studied using a mathematical model for in-host influenza viral infection in a cell population consisting of two different cell types. The two cell types differ only in their susceptibility to infection and rate of virus production. We show the existence of a parameter regime which is characterized by high viral loads sustained long after the onset of infection. This finding suggests that differences in cell tropism between influenza strains could be sufficient to cause significant differences in viral titer profiles, similar to those observed in infections with certain strains of influenza A virus. The two target cell mathematical model offers good agreement with experimental data from severe influenza infections, as does the usual, single target cell model albeit with biologically unrealistic parameters. Both models predict that while neuraminidase inhibitors and adamantanes are only effective when administered early to treat an uncomplicated seasonal infection, they can be effective against more severe influenza infections even when administered late.     

The Pattern of Adipose Tissue Accumulation during Early Infancy Provides an Environment for the Development of Dengue Hemorrhagic Fever

Background

Dengue is the most prevalent arthropod-borne viral illness in humans with half of the world’s population at risk. During early infancy, severe dengue can develop after a primary dengue virus infection. There has been a clinical observation that severe dengue during the first year of life is seen only in chubby infants.

Methodology/Principal Findings

We examined the associations between the development of severe dengue and adipose tissue accumulation patterns during the first year of life in a prospective observational clinical study of infants and dengue virus infections. We found that adipose tissue contains two potential targets for dengue virus infection and production- adipocytes and adipose tissue macrophages. During the first year of life, total body adiposity and visceral adipose tissue stores were at their highest levels in early infancy. Early infancy was also characterized by a relative decrease in alternatively activated (anti-inflammatory) macrophages, and a relative increase in circulating pro-inflammatory cytokines.

Conclusions/Significance

The data has been used to propose a model where the adipose tissue accumulation pattern and pro-inflammatory environment during early infancy provide the conditions for the potential development of severe dengue in immune-susceptible infants.     

Innate Immunity and the Inter-exposure Interval Determine the Dynamics of Secondary Influenza Virus Infection and Explain Observed Viral Hierarchies

Influenza is an infectious disease that primarily attacks the respiratory system. Innate immunity provides both a very early defense to influenza virus invasion and an effective control of viral growth. Previous modelling studies of virus–innate immune response interactions have focused on infection with a single virus and, while improving our understanding of viral and immune dynamics, have been unable to effectively evaluate the relative feasibility of different hypothesised mechanisms of antiviral immunity. In recent experiments, we have applied consecutive exposures to different virus strains in a ferret model, and demonstrated that viruses differed in their ability to induce a state of temporary immunity or viral interference capable of modifying the infection kinetics of the subsequent exposure. These results imply that virus-induced early immune responses may be responsible for the observed viral hierarchy. Here we introduce and analyse a family of within-host models of re-infection viral kinetics which allow for different viruses to stimulate the innate immune response to different degrees. The proposed models differ in their hypothesised mechanisms of action of the non-specific innate immune response. We compare these alternative models in terms of their abilities to reproduce the re-exposure data. Our results show that 1) a model with viral control mediated solely by a virus-resistant state, as commonly considered in the literature, is not able to reproduce the observed viral hierarchy; 2) the synchronised and desynchronised behaviour of consecutive virus infections is highly dependent upon the interval between primary virus and challenge virus exposures and is consistent with virus-dependent stimulation of the innate immune response. Our study provides the first mechanistic explanation for the recently observed influenza viral hierarchies and demonstrates the importance of understanding the host response to multi-strain viral infections. Re-exposure experiments provide a new paradigm in which to study the immune response to influenza and its role in viral control.