Preexposure to CpG Protects against the Delayed Effects of Neonatal Respiratory Syncytial Virus Infection

Abstract

Severe respiratory viral infection in early life is associated with recurrent wheeze and asthma in later childhood. Neonatal immune responses tend to be skewed toward T helper 2 (Th2) responses, which may contribute to the development of a pathogenic recall response to respiratory infection. Since neonatal Th2 skewing can be modified by stimulation with Toll-like receptor (TLR) ligands, we investigated the effect of exposure to CpG oligodeoxynucleotides (TLR9 ligands) prior to neonatal respiratory syncytial virus (RSV) infection in mice. CpG preexposure was protective against enhanced disease during secondary adult RSV challenge, with a reduction in viral load and an increase in Th1 responses. A similar Th1 switch and reduction in disease were observed if CpG was administered in the interval between neonatal infection and challenge. In neonates, CpG pretreatment led to a transient increase in expression of major histocompatibility complex class II (MHCII) and CD80 on CD11c-positive cells and gamma interferon (IFN-γ) production by NK cells after RSV infection, suggesting that the protective effects may be mediated by antigen-presenting cells (APC) and NK cells. We conclude that the adverse effects of early-life respiratory viral infection on later lung health might be mitigated by conditions that promote TLR activation in the infant lung.

Respiratory syncytial virus infection of newborn CX3CR1-deficent mice induces a pathogenic pulmonary innate immune response

“…IFN-γ is considered to be a protective cytokine in the context of RSV infection. Pretreatment with CpG oligodeoxynucleotide in newborn mice induces a protective Th1 (IFN-γ) response with reduced disease upon subsequent RSV infection (48). Thus, the combined effect of enhanced IL-17 response and reduced IFN-γ production from immune cells would be expected to promote disease severity in the absence of functional CX3CR1, as observed in our analyses.…”

Flt3 ligand improves the innate response to respiratory syncytial virus and limits lung disease upon RSV reexposure in neonate mice

“…Other studies have attempted to modulate the consequences of early life RSV infection on later lung health. Thus, exposure to CpG prior to a neonatal RSV infection increases MHC II and CD80 expression on CD11c + cells, IFN‐γ production by NK cells and is protective against enhanced disease upon adult reexposure, leading to the conclusion that the protective effects of CpG are mediated by DCs and NK cells . However, in our hands, Flt3‐L treatment did not significantly increase NK cells in neonatal lung (data not shown).…”

Attenuated Bordetella pertussis Vaccine Protects against Respiratory Syncytial Virus Disease via an IL-17–Dependent Mechanism

“…We therefore analyzed the effects of immunizing neonatal mice with BPZE1 on the outcome of RSV challenge in adulthood; even after this long interval, BPZE1 continued to protect against RSV disease. Part of this effect could be a result of innate sensing of bacteria (with BPZE1 as source of TLR ligands) leading to mucosal imprinting, analogous to the effects of CpG in neonatal mice (17). However, recent studies with influenza A show the need of live BPZE1 because heat-killed bacteria did not provide protection (7) thus indicating a combination of effects.…”