Age at First Viral Infection Determines the Pattern of T Cell–mediated Disease during Reinfection in Adulthood

Abstract

Infants experiencing severe respiratory syncytial virus (RSV) bronchiolitis have an increased frequency of wheeze and asthma in later childhood. Since most severe RSV infections occur between the 8th and 24th postnatal week, we examined whether age at first infection determines the balance of cytokine production and lung pathology during subsequent rechallenge. Primary RSV infection in newborn mice followed the same viral kinetics as in adults but was associated with reduced and delayed IFN-γ responses. To study rechallenge, mice were infected at 1 day or 1, 4, or 8 weeks of age and reinfected at 12 weeks. Neonatal priming produced more severe weight loss and increased inflammatory cell recruitment (including T helper 2 cells and eosinophils) during reinfection, whereas delayed priming led to enhanced interferon γ production and less severe disease during reinfection. These results show the crucial importance of age at first infection in determining the outcome of reinfection and suggest that the environment of the neonatal lung is a major determinant of cytokine production and disease patterns in later life. Thus, simply delaying RSV infection beyond infancy might reduce subsequent respiratory morbidity in later childhood.

Siglec‐1 inhibits RSV‐induced interferon gamma production by adult T cells in contrast to newborn T cells

“…We show that newborn CD4 + T cells are capable of producing comparable levels of IFN‐γ compared to adults but in a delayed fashion compared to adults. The formation of IFN‐γ‐producing cells upon RSV infection in newborn mice is also delayed and may underlie the susceptibility of young infants to severe RSV infections in vivo 3. We propose that RSV‐specific IFN‐γ‐producing memory T cells in adults rapidly produce IFN‐γ In vitro, whereas IFN‐γ production by newborn naïve T cells newborns is delayed.…”

“…The high rate of reinfections by RSV results in a significant burden on health care in infants and elderly 2. Interferon gamma (IFN‐γ) and T cells are essential to mount an adequate immune response during RSV infections in newborn and adult mice 3, 4, 5. This suggests an important role for IFN‐γ in the clearance of primary infections as well as in reinfections 4, 6.…”

Bystander suppression of allergic airway inflammation by lung resident memory CD8+ T cells

“…It was recently reported that the timing of respiratory syncytial virus infection during development has distinct effects on subsequent immune responses in mice (26). Indeed, experimental and epidemiological observations lead to the hypothesis that sites of infection, genetic predisposition, and the timing, type, and severity of infections are key factors in determining the development of asthma.…”

Genetic Susceptibility to the Delayed Sequelae of Neonatal Respiratory Syncytial Virus Infection Is MHC Dependent

“…The genetic interactions between host, virus, and environment that contribute to postbronchiolitic wheeze are likely to be complex (11), which makes it very difficult to uncover the genetic architecture through analysis of human cohorts. We previously developed a murine model to study the delayed consequences of neonatal RSV infection (12). Using this model, we and others have demonstrated that CD8 cells (13), IL-13 (14), IgE (15), and IFN-g (16,17) are all important determinants of disease severity after RSV infection.…”