The aim of this thesis was to provide further insight into the role of the innate immune response against RSV. First, I studied the transcriptomic profile of local and systemic neutrophils during severe bronchiolitis in children admitted to the pediatric intensive care unit (Chapter 2). Using low input RNA sequencing on freshly isolated neutrophils from the blood and airways of 16 infants with RSV, I identified an interferon response in airway neutrophils during severe RSV infection. These data indicate that neutrophils alter their transcription in response to virus induced interferons. The fact that this interferon response is present late during infection in severe disease might indicate that this response is insufficient in protecting the host from severe infection, and at least coincides with immune-induced pathology. Second, in Chapter 3, in order to therapeutically modulate the neutrophil immune response, the potential of two inhibitory receptors: SIRL-1 and LAIR-1 as immune modulators, was evaluated. Targeting these receptors with specific agonistic antibodies moderately inhibited oxidative burst and neutrophil extracellular trap formation by airway neutrophils from RSV patients ex vivo. Third, in Chapter 4 I aimed to develop a model to study epithelial and neutrophil interaction during RSV infection in vitro. Culturing and differentiating bronchial epithelial cells at an air liquid interface mimicked in vivo features of the airway epithelium. Infection with RSV in co-culture with neutrophils offered the potential to study neutrophil induced epithelial injury. When this model will be further optimized this will provide an additional and highly warranted tool to better understand the harmful versus protective role of neutrophils during RSV infection. Fourth, we presented an overview of the mechanisms by which neutrophil function could be targeted to prevent tissue injury and preserve homeostasis (Chapter 5). This review can be used as a guideline for future studies regarding neutrophil modulation. Finally, I identified a novel monogenetic disease as a possible cause of recurrent severe RSV bronchiolitis (Chapter 6). The chapter contains a description of the first patient with inherited CD14 deficiency and I identified a link with recurrent RSV disease. My work shows that CD14 mediates the immune response against RSV, and that the clinical phenotype of CD14 deficiency is characterized by, but not limited to, recurrent severe RSV infection. Implications of the main findings of this thesis will be further discussed in the general discussion.