Role of Type I Interferon (IFN) in the Respiratory Syncytial Virus (RSV) Immune Response and Disease Severity

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in children <2 years of age. Increased morbidity and mortality have been reported in high-risk patients, such as premature infants, patients with cardiac disease, and severely immune compromised patients. Severe disease is associated with the virulence of the virus as well as host factors specifically including the innate immune response. The role of type I interferons (IFNs) in the response to RSV infection is important in regulating the rate of virus clearance and in directing the character of the immune response, which is normally associated with protection and less severe disease. Two RSV non-structural proteins, NS1 and NS2, as well as the envelope G glycoprotein are known to suppress type I IFN production and a robust type I IFN response to RSV does not occur in human infants or neonatal mouse models of RSV infection. Additionally, presence of type I IFNs are associated with mild symptoms in infants and administration of IFN-α prior to infection of neonatal mice with RSV reduces immunopathology. This evidence has driven RSV prophylaxis and therapeutic efforts to consider strategies for enhancing type I IFN production

Elevated levels of type 2 respiratory innate lymphoid cells in human infants with severe respiratory syncytial virus bronchiolitis

© 2019 by the American Thoracic Society. Rationale: Studies of the immune responses at the site of respiratory syncytial virus (RSV) infection are sparse despite nearly five decades of research into understanding RSV disease. Objectives: To investigate the role of mucosal innate immune responses to RSV and respiratory viral load in infants hospitalized with the natural disease. Methods: Cytokines, viral load, and type 2 innate lymphoid cell (ILC2) levels in nasal aspirates, collected within 24 hours of enrollment, from infants hospitalized with RSV infection were quantified. Measurements and Main Results: RSV severity in infants was categorized based on admission to the general ward (moderate) or the pediatric ICU (severe). Evaluable subjects included 30 patients with severe and 63 patients with moderate disease (median age, 74 d; range, 9-297 d). ILC2s were found in the nasal aspirates of patients with severe disease (0.051% of total respiratory CD451 cells) to a significantly greater extent than in patients with moderate disease (0.018%, P = 0.004). Levels of IL-4, IL-13, IL-33, and IL-1b were significantly higher in nasal aspirates of patients with severe disease compared with those of patients with moderate disease. Factors associated with disease severity were gestational age (odds ratio, 0.49; 95% confidence interval, 0.29-0.82; P = 0.007) and IL-4 (odds ratio, 9.67; 95% confidence interval, 2.45-38.15; P = 0.001). Conclusions: This study shows, for the first time, that elevated levels of ILC2s is associated with infant RSV severity. The findings highlight the dominance of type-2 responses to RSV infection in infants and suggest an important role of ILC2 in shaping the immune response early during RSV infection

Role of type I interferon (IFN) in the respiratory syncytial virus (RSV) immune response and disease severity

© 2019 Hijano, Vu, Kauvar, Tripp, Polack and Cormier. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in children patients, such as premature infants, patients with cardiac disease, and severely immune compromised patients. Severe disease is associated with the virulence of the virus as well as host factors specifically including the innate immune response. The role of type I interferons (IFNs) in the response to RSV infection is important in regulating the rate of virus clearance and in directing the character of the immune response, which is normally associated with protection and less severe disease. Two RSV non-structural proteins, NS1 and NS2, as well as the envelope G glycoprotein are known to suppress type I IFN production and a robust type I IFN response to RSV does not occur in human infants or neonatal mouse models of RSV infection. Additionally, presence of type I IFNs are associated with mild symptoms in infants and administration of IFN-α prior to infection of neonatal mice with RSV reduces immunopathology. This evidence has driven RSV prophylaxis and therapeutic efforts to consider strategies for enhancing type I IFN production

New mouse model of pulmonary hypertension induced by respiratory syncytial virus bronchiolitis

© 2018 American Physiological Society. All rights reserved. Pulmonary hypertension (PH) has been observed in up to 75% of infants with moderate to severe respiratory syncytial virus (RSV) bronchiolitis and is associated with significant morbidity and mortality in infants with congenital heart disease. The purpose of the present study was to establish a mouse model of PH secondary to RSV bronchiolitis that mimics the disease etiology as it occurs in infants. Neonatal mice were infected with RSV at 5 days of age and then reinfected 4 wk later. Serum-free medium was administered to age-matched mice as a control. Echocardiography and right ventricular systolic pressure (RVSP) measurements via right jugular vein catheterization were conducted 5 and 6 days after the second infection, respectively. Peripheral capillary oxygen saturation monitoring did not indicate hypoxia at 2–4 days post-RSV infection, before reinfection, and at 2–7 days after reinfection. RSV-infected mice had significantly higher RVSP than control mice. Pulsed-wave Doppler recording of the pulmonary blood flow by echocardiogram demonstrated a significantly shortened pulmonary artery acceleration time and decreased pulmonary artery acceleration time-to-ejection time ratio in RSV-infected mice. Morphometry showed that RSV-infected mice exhibited a significantly higher pulmonary artery medial wall thickness and had an increased number of muscularized pulmonary arteries compared with control mice. These findings, confirmed by RVSP measurements, demonstrate the development of PH in the lungs of mice infected with RSV as neonates. This animal model can be used to study the pathogenesis of PH secondary to RSV bronchiolitis and to assess the effect of treatment interventions. NEW & NOTEWORTHY This is the first mouse model of respiratory syncytial virus-induced pulmonary hypertension, to our knowledge. This model will allow us to decipher molecular mechanisms responsible for the pathogenesis of pulmonary hypertension secondary to respiratory syncytial virus bronchiolitis with the use of knockout and/or transgenic animals and to monitor therapeutic effects with echocardiography

Type I Interferon Potentiates IgA Immunity to Respiratory Syncytial Virus Infection During Infancy

© 2018, The Author(s). Respiratory syncytial virus (RSV) infection is the most frequent cause of hospitalization in infants and young children worldwide. Although mucosal RSV vaccines can reduce RSV disease burden, little is known about mucosal immune response capabilities in children. Neonatal or adult mice were infected with RSV; a subset of neonatal mice received interferon alpha (IFN-α) (intranasal) prior to RSV infection. B cells, B cell activating factor (BAFF) and IgA were measured by flow cytometry. RSV specific IgA was measured in nasal washes. Nasal associated lymphoid tissue (NALT) and lungs were stained for BAFF and IgA. Herein, we show in a mouse model of RSV infection that IFN-α plays a dual role as an antiviral and immune modulator and age-related differences in IgA production upon RSV infection can be overcome by IFN-α administration. IFN-α administration before RSV infection in neonatal mice increased RSV-specific IgA production in the nasal mucosa and induced expression of the B-cell activating factor BAFF in NALT. These findings are important, as mucosal antibodies at the infection site, and not serum antibodies, have been shown to protect human adults from experimental RSV infection

Centralized Inverted Decoupling Control

This paper presents a new methodology of multivariable centralized control based on the structure of inverted decoupling. The method is presented for general n×n processes, obtaining very simple general expressions for the controller elements with a complexity independent of the system size. The possible configurations and realizability conditions are stated. Then, the specification of performance requirements is carried out from simple open loop transfer functions for three common cases. As a particular case, it is shown that the resulting controller elements have PI structure or filtered derivative action plus a time delay when the process elements are given by first order plus time delay systems. Comparisons with other works demonstrate the effectiveness of this methodology through the use of several simulation examples and an experimental lab process

Decisions on socialization by urban land pooling approach to renovation of landscapes of Ho Chi Minh City embankments

Land pooling and readjustment (LPR) is a significant instrument which is used to the rapid development of urbanization. It is a way of urban expansion and renovation without any compulsory revoking of land. By this way, people should not be relocated like in other ordinary planning projects, but they are encouraged to contribute their land (or land value) for construction and modernization of infrastructure system. Therefore, after contribution, remaining land will increase its value, and living conditions will also be improved. Especially, this approach is effectively implemented in urban renovation projects in various countries and regions worldwide, i.e. Japan, Germany, Korea, Taiwan, The United States of America, Australia, India, and Thailand. Its effectiveness has been demonstrated for mitigating unusual urban growth in peripheral areas. This study aims to perform the significances of LPR instrument, as well as demonstrate its practical impacts by analyzing an implemented case-study of Tra Vinh city. Recommendation of deployment is also done as a solution for renovation of landscapes of Ho Chi Minh City (HCMC) embankments

IL-1 beta Promotes Expansion of IL-33(+) Lung Epithelial Stem Cells after Respiratory Syncytial Virus Infection during Infancy

Respiratory syncytial virus (RSV)-induced immunopathogenesis and disease severity in neonatal mice and human infants have been related to elevated pulmonary IL-33. Thus, targeting IL-33 has been suggested as a potential therapy for respiratory viral infections. Yet, the regulatory mechanisms on IL-33 during early life remain unclear. Here, using a neonatal mouse model of RSV, we demonstrate that IL-1 beta positively regulates but is not required for RSV-induced expression of pulmonary IL-33 in neonatal mice early after the initial infection. Exogenous IL-1 beta upregulates RSV-induced IL-33 expression by promoting the proliferation of IL-33(+) lung epithelial stem/progenitor cells. These cells are exclusively detected in RSV-infected neonatal rather than adult mice, partially explaining the IL-1 beta-independent IL-33 expression in RSV-infected adult mice. Furthermore, IL-10 aggravates IL-33-mediated T- helper cell type 2-biased immunopathogenesis upon reinfection. Collectively, our study demonstrates that IL-1 beta exacerbates IL-33-mediated RSV immunopathogenesis by promoting the proliferation of IL-33(+) epithelial stem/progenitor cells in early life

Deficiency in ST2 signaling ameliorates RSV-associated pulmonary hypertension

Pulmonary hypertension (PH) observed during respiratory syncytial virus (RSV) bronchiolitis is associated with morbidity and mortality, especially in children with congenital heart disease. Yet, the pathophysiological mechanisms of RSV-associated PH remain unclear. Therefore, this study aimed to investigate the pathophysiological mechanism of RSV-associated PH. We used a translational mouse model of RSV-associated PH, in which wild-type (WT) and suppression of tumorigenicity 2 (ST2) knockout neonatal mice were infected with RSV at 5 days old and reinfected 4 wk later. The development of PH in WT mice following RSV reinfection was evidenced by elevated right ventricle systolic pressure, shortened pulmonary artery acceleration time (PAT), and decreased PAT/ejection time (ET) ratio. It coincided with the augmentation of periostin and IL-13 expression and increased arginase bioactivity by both arginase 1 and 2 as well as induction of nitric oxide synthase (NOS) uncoupling. Absence of ST2 signaling prevented RSV-reinfected mice from developing PH by suppressing NOS uncoupling. In summary, ST2 signaling was involved in the development of RSV-associated PH. ST2 signaling inhibition may be a novel therapeutic target for RSV-associated PH. We report that the pathogenic role of ST2-mediated type 2 immunity and mechanisms contribute to RSV-associated pulmonary hypertension. Inhibiting ST2 signaling may be a novel therapeutic target for this condition