Type I conventional dendritic cells relate to disease severity in virus-induced asthma exacerbations.

Rationale: Rhinoviruses are the major precipitant of asthma exacerbations and individuals with asthma experience more severe/prolonged rhinovirus infections. Concurrent viral infection and allergen exposure synergistically increase exacerbation risk. Although dendritic cells orchestrate immune responses to both virus and allergen, little is known about their role in viral asthma exacerbations.

Pulmonary Innate Lymphoid Cell Responses during Rhinovirus-induced Asthma Exacerbations : A Clinical Trial.

Type 2 innate lymphoid cells (ILC2s) are significant sources of type 2 cytokines, which are implicated in the pathogenesis of asthma and asthma exacerbations. The role of ILC2s in virus-induced asthma exacerbations is not well characterized. To characterize pulmonary ILC responses following experimental rhinovirus challenge in patients with moderate asthma and healthy subjects.

Virus-induced Volatile Organic Compounds Are Detectable in Exhaled Breath during Pulmonary Infection.

Chronic obstructive pulmonary disease (COPD) is a condition punctuated by acute exacerbations commonly triggered by viral and/or bacterial infection. Early identification of exacerbation triggers is important to guide appropriate therapy, but currently available tests are slow and imprecise. Volatile organic compounds (VOCs) can be detected in exhaled breath and have the potential to be rapid tissue-specific biomarkers of infection etiology.

miR-122 promotes virus-induced lung disease by targeting SOCS1.

Virus-induced respiratory tract infections are a major health burden in childhood, and available treatments are supportive rather than disease modifying. Rhinoviruses (RVs), the cause of approximately 80% of common colds, are detected in nearly half of all infants with bronchiolitis and the majority of children with an asthma exacerbation. Bronchiolitis in early life is a strong risk factor for the development of asthma.

Rhinovirus-induced CCL17 and CCL22 in Asthma Exacerbations and Differential Regulation by STAT6.

The interplay of type-2 inflammation and antiviral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma; however, mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells and mice we assessed mechanisms regulating CCL17 and CCL22 expression.

Engineered Oncolytic Poliovirus PVSRIPO Subverts MDA5-Dependent Innate Immune Responses in Cancer Cells.

We are pursuing cancer immunotherapy with a neuro-attenuated recombinant poliovirus, PVSRIPO. PVSRIPO is the live attenuated type 1 (Sabin) poliovirus vaccine carrying a heterologous internal ribosomal entry site (IRES) of human rhinovirus type 2 (HRV2). Intratumoral infusion of PVSRIPO is showing promise in the therapy of recurrent WHO grade IV malignant glioma (glioblastoma), a notoriously treatment-refractory cancer with dismal prognosis.

Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations.

Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms. Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections. Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations.

Cytokine Responses to Rhinovirus and Development of Asthma, Allergic Sensitization, and Respiratory Infections during Childhood.

Rationale: Immunophenotypes of antiviral responses, and their relationship with asthma, allergy, and lower respiratory tract infections, are poorly understood.

Objectives: We characterized multiple cytokine responses of peripheral blood mononuclear cells to rhinovirus stimulation, and their relationship with clinical outcomes.

Methods: In a population-based birth cohort, we measured 28 cytokines after stimulation with rhinovirus-16 in 307 children aged 11 years.

Plasmacytoid dendritic cells drive acute asthma exacerbations.

Background: Although acute exacerbations, mostly triggered by viruses, account for the majority of hospitalizations in asthmatic patients, there is still very little known about the pathophysiologic mechanisms involved. Plasmacytoid dendritic cells (pDCs), prominent cells of antiviral immunity, exhibit proinflammatory or tolerogenic functions depending on the context, yet their involvement in asthma exacerbations remains unexplored.

Objectives: We sought to investigate the role of pDCs in allergic airway inflammation and acute asthma exacerbations.

Viral infections in allergy and immunology: How allergic inflammation influences viral infections and illness.

Viral respiratory tract infections are associated with asthma inception in early life and asthma exacerbations in older children and adults. Although how viruses influence asthma inception is poorly understood, much research has focused on the host response to respiratory viruses and how viruses can promote; or how the host response is affected by subsequent allergen sensitization and exposure. This review focuses on the innate interferon-mediated host response to respiratory viruses and discusses and summarizes the available evidence that this response is impaired or suboptimal.

Update on Biomarkers to Monitor Clinical Efficacy Response During and Post Treatment in Allergen Immunotherapy.

Allergen immunotherapy (AIT) is an immune modulating treatment for allergic diseases. Although highly effective, some patients do not respond to the treatment. To date there are no surrogate biomarkers that are predictive of the clinical response to AIT.

A Comprehensive Evaluation of Nasal and Bronchial Cytokines and Chemokines Following Experimental Rhinovirus Infection in Allergic Asthma: Increased Interferons (IFN-γ and IFN-λ) and Type 2 Inflammation (IL-5 and IL-13).

Background: Rhinovirus infection is a major cause of asthma exacerbations.

Objectives: We studied nasal and bronchial mucosal inflammatory responses during experimental rhinovirus-induced asthma exacerbations.

Methods: We used nasosorption on days 0, 2-5 and 7 and bronchosorption at baseline and day 4 to sample mucosal lining fluid to investigate airway mucosal responses to rhinovirus infection in patients with allergic asthma (n=28) and healthy non-atopic controls (n=11), by using a synthetic absorptive matrix and measuring levels of 34 cytokines and chemokines using a sensitive multiplex assay.

Efficacy of novel antibody-based drugs against rhinovirus infection: In vitro and in vivo results.

Rhinoviruses (RVs) cause the common cold and are associated with exacerbations of chronic inflammatory respiratory diseases, especially asthma and chronic obstructive pulmonary disease (COPD). We have assessed the antiviral drugs Anaferon for Children (AC) and Ergoferon (containing AC as one of the active pharmaceutical ingredients) in in vitro and in vivo experimental models, in order to evaluate their anti-rhinoviral and immunomodulatory potential. HeLa cells were pretreated with AC, and levels of the interferon-stimulated gene (ISG), 2'-5'-oligoadenylate synthetase 1 (OAS1-A) and viral replication were analyzed.

Mucosal Type 2 Innate Lymphoid Cells Are a Key Component of the Allergic Response to Aeroallergens.

Rationale: Newly characterized type 2 innate lymphoid cells (ILC2s) display potent type 2 effector functionality; however, their contribution to allergic airways inflammation and asthma is poorly understood. Mucosal biopsy used to characterize the airway mucosa is invasive, poorly tolerated, and does not allow for sequential sampling.

Objectives: To assess the role of ILC2s during nasal allergen challenge in subjects with allergic rhinitis using novel noninvasive methodology.

Tbet Deficiency Causes T Helper Cell Dependent Airways Eosinophilia and Mucus Hypersecretion in Response to Rhinovirus Infection.

Current understanding of adaptive immune, particularly T cell, responses to human rhinoviruses (RV) is limited. Memory T cells are thought to be of a primarily T helper 1 type, but both T helper 1 and T helper 2 memory cells have been described, and heightened T helper 2/ lessened T helper 1 responses have been associated with increased RV-induced asthma exacerbation severity. We examined the contribution of T helper 1 cells to RV-induced airways inflammation using mice deficient in the transcription factor T-Box Expressed In T Cells (Tbet), a critical controller of T helper 1 cell differentiation.

Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium.

Background: Exacerbations of asthma and COPD are triggered by rhinoviruses. Uncontrolled inflammatory pathways, pathogenic bacterial burden and impaired antiviral immunity are thought to be important factors in disease severity and duration. Macrolides including azithromycin are often used to treat the above diseases, but exhibit variable levels of efficacy.

Nasal Lipopolysaccharide Challenge and Cytokine Measurement Reflects Innate Mucosal Immune Responsiveness.

Background: Practical methods of monitoring innate immune mucosal responsiveness are lacking. Lipopolysaccharide (LPS) is a component of the cell wall of Gram negative bacteria and a potent activator of Toll-like receptor (TLR)-4. To measure LPS responsiveness of the nasal mucosa, we administered LPS as a nasal spray and quantified chemokine and cytokine levels in mucosal lining fluid (MLF).

A short-term mouse model that reproduces the immunopathological features of rhinovirus-induced exacerbation of COPD.

Viral exacerbations of chronic obstructive pulmonary disease (COPD), commonly caused by rhinovirus (RV) infections, are poorly controlled by current therapies. This is due to a lack of understanding of the underlying immunopathological mechanisms. Human studies have identified a number of key immune responses that are associated with RV-induced exacerbations including neutrophilic inflammation, expression of inflammatory cytokines and deficiencies in innate anti-viral interferon.

Interleukin-18 is associated with protection against rhinovirus-induced colds and asthma exacerbations.

Rhinoviruses cause the common cold and exacerbations of asthma. Animal models of infection have identified a protective role for interleukin-18 (IL-18). Following experimental rhinovirus infection, we observed increased respiratory symptoms in healthy and asthmatic subjects with low nasal and bronchial IL-18 levels.

IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo.

Rationale: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell-derived cytokine IL-33 plays a central role in exacerbation pathogenesis through augmentation of type 2 inflammation.

Objectives: To assess whether rhinovirus induces a type 2 inflammatory response in asthma in vivo and to define a role for IL-33 in this pathway.

Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation.

Rhinoviruses (RVs), which are the most common cause of virally induced asthma exacerbations, account for much of the burden of asthma in terms of morbidity, mortality, and associated cost. Interleukin-25 (IL-25) activates type 2-driven inflammation and is therefore potentially important in virally induced asthma exacerbations. To investigate this, we examined whether RV-induced IL-25 could contribute to asthma exacerbations.

Human rhinovirus 16 causes Golgi apparatus fragmentation without blocking protein secretion.

The replication of picornaviruses has been described to cause fragmentation of the Golgi apparatus that blocks the secretory pathway. The inhibition of major histocompatibility complex class I upregulation and cytokine, chemokine and interferon secretion may have important implications for host defense. Previous studies have shown that disruption of the secretory pathway can be replicated by expression of individual nonstructural proteins; however the situation with different serotypes of human rhinovirus (HRV) is unclear.

Oncolytic polio virotherapy of cancer.

Recently, the century-old idea of targeting cancer with viruses (oncolytic viruses) has come of age, and promise has been documented in early stage and several late-stage clinical trials in a variety of cancers. Although originally prized for their direct tumor cytotoxicity (oncolytic virotherapy), recently, the proinflammatory and immunogenic effects of viral tumor infection (oncolytic immunotherapy) have come into focus. Indeed, a capacity for eliciting broad, sustained antineoplastic effects stemming from combined direct viral cytotoxicity, innate antiviral activation, stromal proinflammatory stimulation, and recruitment of adaptive immune effector responses is the greatest asset of oncolytic viruses.