The postnatal maturation of human innate immunity against influenza infections and the associated risk for severe influenza diseases in dependence on the developing gut microbiome

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Compared to older children and adults the incidence of influenza-associated deaths among children below 5 years of age is low. Comorbidities do not fully explain this particularity. It largely remains unclear what reprogramming of immunity aggravates the severity of influenza diseases with increasing age. For the influenza A virus (IAV) we found no differences between neonates and adults with respect to infectibility and replication in human primary airway epithelial cells (AECs), macrophages and monocytes. However, our data suggest that the protection of newborn infants from severe courses of influenza is linked to a specifically blunted inflammatory response in a cell-type-independent manner. Global transcriptome analyses in human neonatal and adult monocytes revealed that the differential response to IAV mainly traces back to a specific differential programming at baseline. We identified candidate genes whose individual reprogramming during environmental adaptation obviously changes the character of the anti-IAV response of monocytes later in life. Whether human AECs from newborn infants differ transcriptionally and epigenetically from adults is not known. In mice, it has been repeatedly shown that the postnatally colonizing microbiota has strong imprinting effects on resident and non-resident immune cells. In humans, clear evidences for such relationships are still pending, specifically with respect to anti-IAV immunity.Here we propose to explore the postnatal plasticity of respiratory and innate immune responses toward influenza infections and linkages with the developing gut microbiome. We will profile for the first time the transcriptional and epigenetic programming of neonatal compared to adult primary AECs and their response patterns to IAV infection. Postnatal reprogramming of anti-IAV immunity will be investigated within a prospective single-center birth cohort of healthy term babies that are examined and sampled at defined time points during the first year of life. AECs and monocytes will be infected ex vivo with IAV. In this project we will first focus on the monocytes in terms of tracking age-dependent IAV-relevant transcriptional and epigenetic changes. In parallel, nasal swabs and stool samples are collected from the cohort. Here, we restrict to the analysis of gut microbiomes using 16S rRNA sequencing and metagenomics of DNA extracted from the stool samples. Finally, data on the overall progression of immune programming and microbiota composition will be integrated using modern state-of-the art pipelines. Aim is to identify what microbiota at what extent very likely impacts on the later responsivity of non-resident monocytes toward IAV. Understanding the molecular mechanisms how individual immunity towards the influenza virus is shaped during early life will open new avenues to counter an increased susceptibility to severe influenza infections at the earliest conceivable moment in life.