Early-life chlamydial lung infection enhances allergic airways disease through age-dependent differences in immunopathology

Background

Asthma typically originates in early-life, and the impact of infection during immunologic maturation is a critical factor in disease pathogenesis. The progression of aberrant T_H2 cell responses and disease development has been attributed to a lack of infections. However, exposure to specific pathogens such as Chlamydia may alter immunologic programming and predispose to asthma.

Objective

To investigate the effects of chlamydial infection at different ages on allergic airways disease in later life.

Methods

Neonatal, infant, or adult BALB/c mice were infected and 6 weeks later were sensitized and subsequently challenged with ovalbumin. Hallmark features of allergic airways disease were compared with uninfected allergic and nonallergic controls.

Results

Early-life (neonatal and infant) but not adult chlamydial infection enhanced the development of hallmark features of asthma in ovalbumin-induced allergic airways disease. Notably early-life infection increased mucus-secreting cell numbers, IL-13 expression, and airway hyperresponsiveness. Neonatal infection attenuated eosinophil influx and ovalbumin-specific T_H2 cytokine release and numbers of activated myeloid dendritic cells (DCs) in lymph nodes. By contrast, infant infection augmented features of allergic inflammation with increased airway eosinophils, T_H2 cytokine, and DC responses. Both neonatal and infant infection increased systemic DC-induced IL-13 release from CD4⁺ T cells. The timing of infection had significant effects on lung structure because neonatal but not infant or adult infection induced increases in alveolar diameter.

Conclusion

Early-life respiratory chlamydial infections modulate immune responses, alter lung function and structure, and enhance the severity of allergic airways disease in later life.

Key words: Asthma, Chlamydia, immunologic programming, lung structure, dendritic cell, IL-13, infant, neonate, lung function

Abbreviations used: AHR, Airway hyperresponsiveness, DC, Dendritic cell, mDC, Myeloid dendritic cell, MLN, Mediastinal lymph node, Treg, Regulatory T