Lung Development, Tobacco Smoke and Sensitivity to Infection
Initial Award Abstract
Environmental tobacco smoke (ETS), also known as second-hand smoke, is a common indoor air pollutant. There is substantial epidemiologic evidence that maternal smoking during pregnancy as well as exposure of infants to ETS is associated with a number of adverse health effects in childhood, including increased frequency of asthma and lower respiratory tract and middle ear infections. Influenza A virus infection is one of the most prevalent causes for respiratory tract diseases worldwide, with infants and the elderly showing the highest hospitalization and mortality rates. Pediatric mortality from influenza has been recognized nationally for several years. Although influenza viral infection alone can lead to death, most influenza-related deaths are the result of either exacerbation of underlying medical conditions or invasive co-infection with another infectious pathogen, such as Staphylococcus aureus, which is one of the most common pathogens involved in influenza-associated bacterial pneumonia. Although the influenza virus has been studied extensively, there is limited research to investigate the role of perinatal exposure to ETS in early childhood influenza infection and even fewer studies to examine the role of perinatal ETS exposure in subsequent illness and death from secondary bacterial infection following influenza infection. It is clear that there is a close relationship between cigarette smoking and the risk of influenza infections and that viral infections in humans can result in increased sensitivity to challenges with bacteria and bacterial products. However, little is known regarding the potential mechanisms of how exposure to ETS during the perinatal period increases the incidence and severity of respiratory influenza virus infection in infants and young children. In a similar fashion, it is unknown how early exposure to ETS increases the frequency of illness and death due to secondary bacterial infection following influenza infection.
In this grant proposal, we will address the hypothesis that ETS exposure during the perinatal period enhances pulmonary innate immunity to overwhelm protective anti-inflammatory defenses to influenza virus infection, thereby increasing susceptibility and mortality to secondary bacterial infection. Two specific aims will define: 1) the influence of ETS on pulmonary innate immunity in response to primary influenza virus infection in neonatal mice and compare the response to that in adult mice and 2) the effects of ETS on secondary bacterial infection after influenza infection in neonatal mice. The proposed studies will address the impact of ETS exposure on adverse childhood lung health by using neonatal mice exposed to ETS before and after birth, which are then infected with influenza virus followed by exposure to Staphylococcus aureus bacteria. The proposed research is important to advance human health because it will define how ETS affects immune maturation to alter the response of children to influenza virus infection during early life development. Due to the continued high prevalence of both childhood respiratory virus infections and exposure to tobacco combustion products, this work has the potential to substantially advance our understanding of the interplay among lung and immune development, influenza virus infection and maternal/neonatal ETS exposures. The findings of this work will also provide important information for better prevention strategies to reduce the incidence of respiratory influenza virus infection and to decrease mortality due to secondary bacterial infections following primary viral infection in infants exposed to ETS during the perinatal period. |