Molecular and Cellular Mechanisms of Respiratory Syncytial Viral Infection: Using Murine Models to Understand Human Pathology

Abstract

Respiratory syncytial virus (RSV) causes severe pathology of the lower respiratory tract in infants, immunocompromised people, and elderly. Despite decades of research, there is no licensed vaccine against RSV, and many therapeutic drugs are still under development. Detailed understanding of molecular and cellular mechanisms of the RSV infection pathology can accelerate the development of efficacious treatment. Current studies on the RSV pathogenesis are based on the analysis of biopsies from the infected patients; however deeper understanding of molecular and cellular mechanisms of the RSV pathology could be achieved using animal models. Mice are the most often used model for RSV infection because they exhibit manifestations similar to those observed in humans (bronchial obstruction, mucous hypersecretion, and pulmonary inflammation mediated by lymphocytes, macrophages, and neutrophils). Additionally, the use of mice is economically feasible, and many molecular tools are available for studying RSV infection pathogenesis at the molecular and cellular levels. This review summarizes new data on the pathogenesis of RSV infection obtained in mouse models, which demonstrated the role of T cells in both the antiviral defense and the development of lung immunopathology. T cells not only eliminate the infected cells, but also produce significant amounts of the proinflammatory cytokines TNFα and IFNγ. Recently, a new subset of tissue-resident memory T cells (T RM ) was identified that provide a strong antiviral defense without induction of lung immunopathology. These cells accumulate in the lungs after local rather than systemic administration of RSV antigens, which suggests new approaches to vaccination. The studies in mouse models have revealed a minor role of interferons in the anti-RSV protection, as RSV possesses mechanisms to escape the antiviral action of type I and III interferons, which may explain the low efficacy of interferon-containing drugs. Using knockout mice, a significant breakthrough has been achieved in understanding the role of many pro-inflammatory cytokines in lung immunopathology. It was found that in addition to TNFα and IFNγ, the cytokines IL-4, IL-5, IL-13, IL-17A, IL-33, and TSLP mediate the major manifestations of the RSV pathogenesis, such as bronchial obstruction, mucus hyperproduction, and lung infiltration by pro-inflammatory cells, while IL-6, IL-10, and IL-27 exhibit the anti-inflammatory effect. Despite significant differences between the mouse and human immune systems, mouse models have made a significant contribution to the understanding of molecular and cellular mechanisms of the pathology of human RSV infection.

Analysis of temporal metabolic rewiring for human respiratory syncytial virus infection by integrating metabolomics and proteomics

“…Inflammatory cytokines and chemokines are secreted by the infected epithelial and immune cells during HRSV infection (Shilovskiy et al, 2021 ). The in vitro results demonstrated an increased level of IL-1β, IL-6, and tumor necrosis factor α (TNF-α) in two epithelial cells, and similar results were obtained in the infected BALB/c mice (Fig.…”

miRNA‐34b/c regulates mucus secretion in RSV‐infected airway epithelial cells by targeting FGFR1

“…Respiratory syncytial virus infection is the most common respiratory system infection in the period of infants and young children. The severity of RSV infection varies from mild symptoms of the common cold to airway obstruction, even hypoxia and pneumonia 24 . Mucus hypersecretion is one of the main hallmarks of RSV infection.…”

“…The severity of RSV infection varies from mild symptoms of the common cold to airway obstruction, even hypoxia and pneumonia. 24 Mucus hypersecretion is one of the main hallmarks of RSV infection. Excessive mucus secretion with cell debris will obstruct the bronchioles which is a critical reason for the aggravation of RSV infection.…”

Prevention and Treatment Strategies for Respiratory Syncytial Virus (RSV)

“…Several groups have examined infants with RSV infection who did not have significant comorbidities (e.g., prematurity, bronchopulmonary dysplasia, congenital heart disease) and identified genes associated with inflammatory pathways implicated in severe disease [ 28 ]. This complex interplay between the viral genome and host immune system can result in a type-2 immune response and the release of pro-inflammatory cytokines that, in turn, activate mucus metaplasia and mucin secretion, further exaggerating airway obstruction [ 29 , 30 , 31 ]. An understanding of these potential mechanisms has led to various therapeutic approaches that can be applied to reverse airway obstruction, most notably mucolytics [ 32 ], bronchodilators [ 33 ], and anti-inflammatory agents [ 34 ], and they are summarized in Table 1 .…”