IFN-γ Attenuates Eosinophilic Inflammation but Is Not Essential for Protection against RSV-Enhanced Asthmatic Comorbidity in Adult Mice

The susceptibility to respiratory syncytial virus (RSV) infection in early life has been associated with a deficient T-helper cell type 1 (Th1) response. Conversely, healthy adults generally do not exhibit severe illness from RSV infection. In the current study, we investigated whether Th1 cytokine IFN-γ is essential for protection against RSV and RSV-associated comorbidities in adult mice. We found that, distinct from influenza virus, prior RSV infection does not induce significant IFN-γ production and susceptibility to secondary Streptococcus pneumoniae infection in adult wild-type (WT) mice. In ovalbumin (OVA)-induced asthmatic mice, RSV super-infection increases airway neutrophil recruitment and inflammatory lung damage but has no significant effect on OVA-induced eosinophilia. Compared with WT controls, RSV infection of asthmatic Ifng−/− mice results in increased airway eosinophil accumulation. However, a comparable increase in eosinophilia was detected in house dust mite (HDM)-induced asthmatic Ifng−/− mice in the absence of RSV infection. Furthermore, neither WT nor Ifng−/− mice exhibit apparent eosinophil infiltration during RSV infection alone. Together, these findings indicate that, despite its critical role in limiting eosinophilic inflammation during asthma, IFN-γ is not essential for protection against RSV-induced exacerbation of asthmatic inflammation in adult mice.

Nosocomial RSV-related in-hospital mortality in children <5 years: a global case series

Background According to the World Health Organization the global burden of nosocomial infections is poorly characterized as surveillance systems for nosocomial infection are lacking. Nosocomial infections occur at higher rates in low- and lower-middle-income countries (LMICs) than in high-income countries (HICs). Current global RSV burden estimates are largely based on community-acquired disease. We aimed to characterize children with nosocomial RSV-related mortality and to understand the potential impact of RSV immunization strategies. Methods RSV GOLD is a global registry of children younger than 5 years who died with laboratory-confirmed RSV infection. We compared clinical and demographic characteristics of children with nosocomial and community-acquired RSV in-hospital mortality. Results We included 231 nosocomial and 931 community-acquired RSV-related in-hospital deaths from 65 countries. Median age at death was similar for both groups (5.4 vs 6 months). As expected, a higher proportion of children with nosocomial infection had comorbidities (87% vs 57%; p<0.001) or was born preterm (46% vs 24%; p<0.001) than children with community-acquired infection. The proportion of nosocomial deaths among all RSV deaths was lower in LMICs than in upper-middle-income countries (UMICs) and HICs (12% vs 18% and 26%, respectively). Conclusions This is the first global case series of children dying with nosocomial RSV infection. Future infant-targeted immunization strategies can prevent the majority of nosocomial RSV-related deaths. Although nosocomial RSV deaths are expected to occur at highest rates in LMICs, the number of reported nosocomial RSV deaths was low in these countries. Hospital-based surveillance is needed to capture the full burden of nosocomial RSV mortality in LMICs.

Lack of Type I Interferon Signaling Ameliorates Respiratory Syncytial Virus-Induced Lung Inflammation and Restores Antioxidant Defenses

Respiratory syncytial virus (RSV) infection in mouse and human lung is associated with pathogenic inflammation and oxidative injury. RSV impairs antioxidant responses by increasing the degradation of transcription factor NF-E2-related factor 2 (NRF2), which controls the expression of several antioxidant enzymes (AOEs). In addition to its protective effects, type I IFNs have been increasingly recognized as important mediators of host pathogenic responses during acute respiratory viral infections. We used a mouse model of RSV infection to investigate the effect of lack of type I interferon (IFN) receptor on viral-mediated clinical disease, airway inflammation, NRF2 expression, and antioxidant defenses. In the absence of type I IFN signaling, RSV-infected mice showed significantly less body weight loss and airway obstruction, as well as a significant reduction in cytokine and chemokine secretion and airway inflammation. Lack of type I IFN receptor was associated with greatly reduced virus-induced promyelocytic leukemia lung protein expression, which we showed to be necessary for virus-induced NRF2 degradation in a cell model of infection, resulting in restoration of NRF2 levels, AOE expression, and airway antioxidant capacity. Our data support the concept that modulation of type I IFN production and/or signaling could represent an important therapeutic strategy to ameliorate severity of RSV-induced lung disease.

A systems genomics approach uncovers molecular associates of RSV severity

Respiratory syncytial virus (RSV) infection results in millions of hospitalizations and thousands of deaths each year. Variations in the adaptive and innate immune response appear to be associated with RSV severity. To investigate the host response to RSV infection in infants, we performed a systems-level study of RSV pathophysiology, incorporating high-throughput measurements of the peripheral innate and adaptive immune systems and the airway epithelium and microbiota. We implemented a novel multi-omic data integration method based on multilayered principal component analysis, penalized regression, and feature weight back-propagation, which enabled us to identify cellular pathways associated with RSV severity. In both airway and immune cells, we found an association between RSV severity and activation of pathways controlling Th17 and acute phase response signaling, as well as inhibition of B cell receptor signaling. Dysregulation of both the humoral and mucosal response to RSV may play a critical role in determining illness severity.

Role of ARP2/3 Complex-Driven Actin Polymerization in RSV Infection

Respiratory syncytial virus (RSV) is the leading viral agent causing bronchiolitis and pneumonia in children under five years old worldwide. The RSV infection cycle starts with macropinocytosis-based entry into the host airway epithelial cell membrane, followed by virus transcription, replication, assembly, budding, and spread. It is not surprising that the host actin cytoskeleton contributes to different stages of the RSV replication cycle. RSV modulates actin-related protein 2/3 (ARP2/3) complex-driven actin polymerization for a robust filopodia induction on the infected lung epithelial A549 cells, which contributes to the virus’s budding, and cell-to-cell spread. Thus, a comprehensive understanding of RSV-induced cytoskeletal modulation and its role in lung pathobiology may identify novel intervention strategies. This review will focus on the role of the ARP2/3 complex in RSV’s pathogenesis and possible therapeutic targets to the ARP2/3 complex for RSV.

NSvc4 Encoded by Rice Stripe Virus Targets Host Chloroplasts to Suppress Chloroplast-Mediated Defense

Our previous research found that NSvc4, the movement protein of rice stripe virus (RSV), could localize to the actin filaments, endoplasmic reticulum, plasmodesmata, and chloroplast, but the roles of NSvc4 played in the chloroplast were opaque. Here, we confirm the accumulation of NSvc4 in the chloroplasts and the N-terminal 1–73 amino acids of NSvc4 are sufficient to localize to chloroplasts. We provide evidence to show that chloroplast-localized NSvc4 can impair the chloroplast-mediated immunity. Expressing NSvc4 in Nicotiana benthamiana leaves results in the decreased expression of defense-related genes NbPR1, NbPR2, and NbWRKY12 and the inhibition of chloroplast-derived ROS production. In addition, generation of an infectious clone of potato virus X (PVX) carrying NSvc4 facilitates PVX infection in N. benthamiana plants. Moreover, we identify two chloroplast-related host factors, named NbGAPDH-A and NbPsbQ1, both of which can interact with NSvc4. Knockdown of NbGAPDH-A or NbPsbQ1 can both promote RSV infection. Our results decipher a detailed function of NSvc4 in the chloroplast.

Pertussis and pertussis-like syndrome in young children

The most common infectious diseases with a risk of severe, non-smooth course and unfavorable outcome in young children, including the first year of life, are pertussis and respiratory syncytial viral infection (RSV infection), often occurring with pertussis-like syndrome.Objective: to establish clinical and laboratory differential diagnostic criteria for pertussis and RSV infection in children of the first year of life.Materials and methods: A retrospective comparative study was conducted, which included patients of the first year of life (from 1 month to 11 months and 29 days), regardless of the duration of hospitalization and duration of the disease: 48 patients with pertussis and 26 with acute RSV infection.Results: The compared groups of patients were comparable in age, the number of severe forms (4.6 ± 0.5 months, 17% for pertussis and 4.0 ± 0.2 months, 16% for RS infection). The disease in both cases began subacute, however, with RSV infection 92% of children were hospitalized in the first 5 days from the onset of the disease, with pertussis — in the first week of the period of convulsive cough — 47.9%, in the second week — 41.7%, in the third week — 10.4%. 52% of patients with RSV infection had no fever or (in 32%) did not exceed 1—3 days. In 41.3% of patients it was subfebrile (37—38 °C), in 21.1% it was febrile (38—39 °C). In patients with pertussis the onset of the disease took place against the background of normal body temperature. In patients with RSV infection, bronchiolitis was recorded in 24% of cases, obstructive bronchitis — in 60%. Patients with pertussis, 89.6% of whom were not vaccinated and 10.4% did not complete the initial course of vaccination, had a typical paroxysmal cough with reprises. Complications in the form of respiratory rhythm disturbances were recorded in 14.6% of cases, pneumonia — in 6.3%. Comparison of hematological parameters revealed highly significant differences in the levels of leukocytosis and relative lymphocytosis (p < 0.001), as well as thrombocytosis (p < 0.01), with the predominance of all indicators in patients with pertussis.Conclusion. Differential diagnostic criteria for the similarity of the clinical picture may be established hematological differences: pronounced leukocytosis due to lymphocytosis, increasing in dynamics, and thrombocytosis in pertussis and normocytosis with moderate lymphocytosis, a possible tendency to thrombocytosis in severe RSV infection.

Myocarditis in the Presence of Respiratory Syncytial Virus (RSV) Infection: A Case Study

Background/Objective: Respiratory syncytial virus (RSV) causes acute respiratory infections in children and adults. RSV has many non-specific symptoms such as cough and dyspnea. RSV is associated with high mortality in children, the elderly, and immunocompromised individuals. Although rare, RSV has been reported to cause extrapulmonary complications such as arrhythmias and myocarditis. This case focuses on a patient infected with RSV who presents with acute sustained monomorphic ventricular tachycardia (SMVT). Case Overview: An 83 year-old patient with a history of type 2 diabetes mellitus, hypertension, persistent atrial fibrillation, and asthma presented to the emergency department with concerns of cough, malaise, and a syncopal episode. Upon admission, the patient tested positive for RSV and was diagnosed with acute bronchitis exacerbated by history of asthma. The patient soon developed SMVT with heart rates as high as 235 beats per minute. After consultation with an electrophysiologist, the VT was attributed to myocarditis as a result of the RSV infection. Oral amiodarone was prescribed, and the patient was discharged two weeks later. In a follow-up visit, no SMVT was reported, and the dosage of amiodarone was decreased. Discussion: With the onset of the SARS-CoV2 pandemic in early 2020, myocarditis associated with viral infection has been of interest in recent literature. Many cases of cardiovascular complications have been reported in patients infected with SARS-CoV2. Consequently, it is important to discuss cases of other respiratory viruses also presenting with arrhythmia and myocarditis. In the current case, a patient with RSV developed new onset VT. VT can be life-threatening and can cause further cardiovascular complications. Conclusion: RSV can cause new onset cardiovascular complications, albeit rare. It is important for clinicians to be aware of such complications especially in cases in which patients have preexisting cardiovascular conditions. Patients infected with RSV should be closely monitored for new onset complications.

Evaluation of the ImmuView RSV Test for Rapid Detection of Respiratory Syncytial Virus in Adult Patients with Influenza-Like Symptoms

By timely RSV diagnosis among patients with influenza-like symptoms, especially when influenza diagnostics turn negative, it is possible to prevent unnecessary antibiotic usage as well as reduce diagnostic testing, nosocomial transmission, and hospital stay. Previous rapid RSV tests have demonstrated poor sensitivity in adults, and we could demonstrate that the novel ImmuView RSV test similarly showed limited value for diagnosing RSV infection in adult patients.