Abstract: Premature infants are highly susceptible to viral infections in early life, which is associated with higher morbidity and mortality. Although established preventive measures such as passive and active immunization are available, the majority of respiratory illnesses in premature infants are caused by viruses (e.g. rhinovirus, metapneumovirus) with non-existing preventive strategies. Recently, the nasal microbiome of healthy term-newborns has been linked to the severity of viral respiratory illnesses, accompanied by heightened risk for asthma development. However, systemic data from premature infants is currently missing, but novel prophylactic and therapeutic options are urgently needed in this high-risk patient cohort. Establishing the NOSE cohort study (Nasal Cross-Omics Signatures to Decipher Viral Susceptibility in Early Childhood), the overarching aim of this study is to decipher host-virus-microbiome-interactions in the nasal airway of premature infants unraveling so-far unknown mechanisms of viral susceptibility leading to novel treatment options. These goals will be achieved via holistic and integrative systems-biology-based approaches incorporating state-of-the-art cross-omics and modern cell culture techniques. Therefore, combating viral susceptibility with this precision medicine approach opens up the opportunity to improve the long-term outcome and quality of life of premature infants.