Enhanced Viral Replication and Modulated Innate Immune Responses in Infant Airway Epithelium following H1N1 Infection

Abstract

Influenza is the cause of significant morbidity and mortality in pediatric populations. The contribution of pulmonary host defense mechanisms to viral respiratory infection susceptibility in very young children is poorly understood. As a surrogate to compare mucosal immune responses of infant and adult lungs, rhesus monkey primary airway epithelial cell cultures were infected with pandemic influenza A/H1N1 virus in vitro. Virus replication, cytokine secretion, cell viability, and type I interferon (IFN) pathway PCR array profiles were evaluated for both infant and adult cultures. In comparison with adult cultures, infant cultures showed significantly increased levels of H1N1 replication, reduced alpha interferon (IFN-␣) protein synthesis, and no difference in cell death following infection. Age-dependent differences in expression levels of multiple genes associated with the type I IFN pathway were observed in H1N1-infected cultures. To investigate the pulmonary and systemic responses to H1N1 infection in early life, infant monkeys were inoculated with H1N1 by upper airway administration. Animals were monitored for virus and parameters of inflammation over a 14-day period. High H1N1 titers were recovered from airways at day 1, with viral RNA remaining detectable until day 9 postinfection. Despite viral clearance, bronchiolitis and alveolitis persisted at day 14 postinfection; histopathological analysis revealed alveolar septal thickening and intermittent type II pneumocyte hyperplasia. Our overall findings are consistent with the known susceptibility of pediatric populations to respiratory virus infection and suggest that intrinsic developmental differences in airway epithelial cell immune function may contribute to the limited efficacy of host defense during early childhood. IMPORTANCETo the best of our knowledge, this study represents the first report of intrinsic developmental differences in infant airway epithelial cells that may contribute to the increased susceptibility of the host to respiratory virus infections. Despite the global burden of influenza, there are currently no vaccine formulations approved for children <6 months of age. Given the challenges of conducting experimental studies involving pediatric patients, rhesus monkeys are an ideal laboratory animal model to investigate the maturation of pulmonary mucosal immune mechanisms during early life because they are most similar to those of humans with regard to postnatal maturation of the lung structure and the immune system. Thus, our findings are highly relevant to translational medicine, and these data may ultimately lead to novel approaches that enhance airway immunity in very young children.

Innate Immunity to Respiratory Infection in Early Life

“…Furthermore, epithelial cells from juveniles housed in filtered air produced higher cytokine responses than those in conventional housing suggesting the microbial richness of the environment may influence epithelial responsiveness. The same group demonstrated that infant Rhesus monkey primary epithelial cell cultures are more permissive for the H1N1 influenza virus than those from adult airways, while producing less IL-1α (85). In humans, type I IFNs are detected at only low levels in the airways of RSV-bronchiolitic infants.…”

Human Bocavirus 1 Infection: Clinical Cases

“…The group of incidence is similar to other significant respiratory pathogens in infants, such as RSV and PI viruses [32]. Accordingly, HBoV1 infection in very young children can relate to the immaturity of the innate immune response, which renders them more susceptible to respiratory infections during the first months of life [33,34]. The event of infection in newborns and young infants has been reported previously and raises questions concerning the presence of maternal antibodies with effective protection in this age group [10,24,35].…”

The use of nonhuman primates in research on seasonal, pandemic and avian influenza, 1893–2014

“…In an interesting study, Clay and colleagues modeled the susceptibility of human infants to severe influenza by experimentally infecting infant and adult rhesus macaques with the 2009 virus (Clay et al, 2014). Primary airway epithelial cultures from infant macaques supported higher levels of viral replication than cells from adults and displayed weaker innate immune responses.…”