Immune Responses and Disease Enhancement during Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is one of the commonest and most troublesome viruses of infancy. It causes most cases of bronchiolitis, which is associated with wheezing in later childhood. In primary infection, the peak of disease typically coincides with the development of specific T- and B-cell responses, which seem, in large part, to be responsible for disease. Animal models clearly show that a range of immune responses can enhance disease severity, particularly after vaccination with formalin-inactivated RSV. Prior immune sensitization leads to exuberant chemokine production, an excessive cellular influx, and an overabundance of cytokines during RSV challenge. Under different circumstances, specific mediators and T-cell subsets and antibody-antigen immune complex deposition are incriminated as major factors in disease. Animal models of immune enhancement permit a deep understanding of the role of specific immune responses in RSV disease, assist in vaccine design, and indicate which immunomodulatory therapy might be beneficial to children with bronchiolitis

Human metapneumovirus: Enhanced pulmonary disease in cotton rats immunized with formalin-inactivated virus vaccine and challenged

“…The enhanced expression of IL-4 may be indication of a shift from a Th-1 to Th-2 response when vaccinated animals are challenged. Although the lesions of the hRSV enhancement are not fully replicated in the mouse model, analysis of that model suggests that an imbalanced immune response is involved in the enhancement [15]. We believe that the Paramyxoviridae vaccine-induced enhancement is not related to the antibodydependent enhancement (ADE) of infectivity seen with dengue, Ebola, and some other viruses [8,24].…”

Intranasal treatment with a novel immunomodulator mediates innate immune protection against lethal pneumonia virus of mice

“…[40]. In individuals predisposed to enhanced RSV disease, a reduction in virus replication and rapid viral clearance is observed [40].…”

“…In individuals predisposed to enhanced RSV disease, a reduction in virus replication and rapid viral clearance is observed [40]. However, inflammatory responses tend to be exacerbated and often lead to immunopathology [40].…”

“…In the lower respiratory tract, RSV primarily targets ciliated cells of the small bronchioles and pneumocytes of the alveoli [42]. Severe RSV bronchiolitis shares similar pathology to influenza virus-, PIV-, and adenovirus-mediated bronchiolitis [40]. RSV replication in the LRT leads to edema by inducing necrosis of epithelial cells (ECs), high mucous production, and increased accumulation of leukocytes into the site of infection [35,40,42].…”

Contribution of cytokines to pathology and protection in virus infection

“…This lack of requirement for IFNγ for protection against most acute viral infections, could Although primary RSV infection is normally dominated by IFNγ rather than Th2 cytokines, severe bronchiolitis may be accompanied by evidence of Th2 activation [116]. However, compared to the case for other severe respiratory viral infections leading to lower respiratory tract infections, IFN--γ production by peripheral blood mononuclear cells appears to be decreased in RSV disease, perhaps pointing to its role in pathogenesis [114]. STAT1 activation by both type I and type II IFNs has been shown to play an important role in establishing a protective, Th1 Ag--specific immune response to RSV infection, however, with an accompanying preferential IL--4, IL--5, and IL--13 induction [117].…”