Early life RSV infection in neonatal mice leads to exacerbated allergic asthma due to persistent Th2 pulmonary responses that are abrogated by maternal supplementation with a L. johnsonii probiotic

Abstract

The development of immune responses in infants is central to establishing a balanced system that reacts appropriately to infectious stimuli but does not induce altered disease states with potential long term sequelae. Studies have linked severe RSV infection during early-life with an enhanced likelihood of developing childhood asthma. We have previously shown that supplementing adult mice with a probiotic species identified in allergen-protected animals, L. johnsonii, can attenuate pathologic responses in animals with viral and allergen induced disease. In these studies, we supplemented female mice with L. johnsonii by oral gavage prior to breeding and during pregnancy. The neonatal mice were infected with RSV at day 6 of age after 8 days of infection (day 14) some were evaluated. Subsequently, some of the neonatal miss were sensitized with allergen into the airway 4 or 12 weeks later and examined after a final challenge at 3 weeks post-sensitization. Our studies show that early-life RSV infection leads to long-term effects leaving mice prone to exacerbation upon secondary allergen exposure at 4 to 12 weeks post-infection. Offspring from the L. johnsonii supplemented mice were protected from an early life RSV infection and from the subsequent allergen-induced exacerbated responses. These early life protective responses reduced Th2 responses and mucus and were associated with an altered neonatal microbiome. Using cross-fostering studies we were able to demonstrate both in utero and post natal protective effects on the offspring that were dependent upon the supplementation of the mother with L. johnsonii. Assessment of the plasma and milk metabolic profiles identified an altered metabolite phenotype in the different cross-fostered neonates that may be useful in assessing allergen susceptible and/or protected early immune environments during early life. Thus, we have identified a maternal microbiome associated metabolomic effect associated with protective in offspring that is related to an altered immune phenotype in the lung during RSV infection and subsequent allergic asthma responses. These results identify that maternal environments on offspring have both in utero and post-natal effects and may help guide future clinical research toward evaluating the maternal impact on development of the infant's immune/allergic responses.