Characterization of the respiratory disease sequelae resulting from pulmonary chlamydial infection as neonates
Chlamydia trachomatis is the cause of neonatal morbidity in 16--24% cases of all reported cases of pneumonia in U.S. following perinatal transmission from infected mothers during delivery. The infection is primarily asymptomatic and often goes undetected until 6 weeks after birth. Despite antimicrobial treatment, Chlamydia infected neonates have been reported to develop altered lung function characterized by asthma and obstructive expiratory airflow with greater retentions of trapped in the lungs 7--8 years later in life. These reports not only suggest an early life origin for development of abnormal lung function, but also underscore the need to understand the basis of such chronic respiratory sequelae to devise effective preventive strategies. As a first attempt towards understanding the changes induced in the lung compartment; both structural and functional, we have established a neonatal mouse model of pulmonary chlamydial infection. One-day old pups challenged intranasally with C. muridarum (C. trachomatis mouse pneumonitis) exhibited significantly greater inflammatory responses primarily involving polymorphonuclear leukocytes from day 4 through day 14 post-challenge. This cellular recruitment was paralleled with greater induction of inflammatory cytokines such as IL-1beta, IL-6, IL-12, IFN-gamma and TNF-gamma throughout the course of infection and subsequent bacterial clearance. To this end, mice deficient in IL-12p35 or IFN-gamma or IFN-gammaR not only demonstrated 100% susceptibility within 2 weeks, but also exhibited minimal cellular recruitment into the lung following chlamydial challenge suggesting that endogenous IL-12/IFN-gamma axis plays a pivotal role not only in protection but also in recruitment of inflammatory cells into the lung compartment. Lung function analyses in these challenged (on day 1 or 7 after birth) mice at 5 or 8 weeks after bacterial clearance exhibited greater airway resistance and lung compliance associated with reduced lung elastance compared to age matched mock (PBS) treated mice. The altered lung function in these mice correlated with reduced alveolar numbers at all of the observed time points. Furthermore, the altered structural/functional observations paralleled reduced surfactant protein C expression at 5 weeks after challenge suggesting that early chlamydial infection may down regulate expression of crucial proteins that are important for normal lung development. Importantly, intraperitoneal administration of antimicrobials in these animals early after birth not only reduced bacterial burden in these tissues but ameliorated Chlamydia induced altered lung function such as compliance and elastance. In summary, we have established a viable chronic model of neonatal pulmonary chlamydial infection and demonstrated that bacterial exposure at birth is sufficient to cause altered lung structure/function as adults. Moreover, our study for the first time provides greater understanding of lung physiology, growth and development in the context of chlamydial infection at birth.