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.

FIG. 1.

RSV binding and triggering of cellular responses. RSV is bound by surface glycosaminoglycans, and the F protein binds to TLR4, while G glycoprotein (virus associated or secreted) binds fractalkine receptor CX3CR1. The interaction with TLR4 leads to upregulation of NF-κB via MyD88. RSV upregulates NF-κB via IκB and STAT1 and -3 via reactive oxygen species (ROS), and RSV RNA activates protein kinase R. Viral NS proteins inhibit the interferon response factor (IRF3) pathway.

FIG. 2.

Cells involved in the immune response to RSV. Cellular infection triggers the release of early inflammatory mediators, e.g., TNF and IFN-α/β. NK cells and PMN are recruited in the first 3 days of infection, at which time DC carry viral antigen to local lymph nodes and present it to CD4⁺ T cells. Once primed, these cells migrate back to the infected epithelium, release further mediators, and recruit additional inflammatory cells, including mononuclear cells (including CD8⁺ T cells and B cells) and granulocytes (e.g., neutrophils [PMN] and eosinophils [Eo]). Ab, antibody.

FIG. 3.

Immunopathology to RSV surface proteins. In the BALB/c mouse, different RSV proteins expressed by recombinant vaccinia viruses after infection by scarification of the skin cause markedly different effects on subsequent RSV challenge intranasally. The F protein primes CD4 and CD8 T cells and leads to intense inflammation characterized by efflux of PMN. The G attachment glycoprotein primes for CD4 T cells and no CD8 response and is associated with a relatively weak NK cell response; this leads to eosinophilia. The transcription antiterminator (M2) protein primes only CD8 T cells and induces almost no CD4 T-cell response and virtually no antibody. This is often the most illness inducing of the sensitizing protocols, but the effect is not as durable and that induced by G or F. Ab, antibody.

FIG. 4.

Interactions of T cells and cytokines. Normal mild or asymptomatic infections are cleared with a predominantly Th1 response, with IFN-γ being generated from NK cells and CD4 and CD8 T cells (left). This inhibits the Th2 cytokine pathways, which are generally inactive. In disease enhanced by prior immunity or in some otherwise predisposed individuals, there is a rapid and strong Th2-type system (right). This Th2-type response may be caused by reduced levels of key cytokines (e.g., IL-12) at an early stage of infection or by vaccination (e.g., with FI-RSV) leading to preferential production of cells that make IL-4 and IL-5. IL-4 suppresses Th1 cytokines and upregulates Th2 cytokines, most importantly IL-5 and IL-13, which leads to eosinophilia and airway narrowing. However, the Th1 response can also be pathogenic if it exceeds that necessary for simple viral clearance, and it may be associated not with eosinophilia but with PMN efflux (see also Fig. 3). IgE, immunoglobulin E.

FIG. 5.

Overview of the sequence of immune events in viral clearance and disease. In primary infection of nonvaccinated individuals (A), virus peaks on about day 4, associated with recruitment of NK cells, which make IFN-γ. Virus is eliminated between days 5 and 8, during which time activated CD4 and CD8 T cells are recruited and produce local cytokines. The peak of disease coincides with this phase. Anti-RSV serum antibody appears relatively late. In previously vaccinated or sensitized individuals (B), the virus titer is typically 100- to 1,000-fold less than in primary infection and peaks earlier (e.g., day 2). However, the rapid and potent cellular response enhances disease severity, which is usually much greater than in primary infection. Notably, high levels of preexisting specific antibody can prevent infection completely and do not cause disease enhancement.