Human dendritic cells in blood and airways during respiratory viral infection

Detta är en avhandling från Stockholm : Karolinska Institutet, Dept of Medicine, Solna

Sammanfattning: The air we inhale contains oxygen necessary for life, but also potentially harmful microorganisms, toxins and allergens. This presents an important immunological dilemma: how can our lungs quickly and selectively eliminate harmful agents without inflicting damage on the delicate tissues of the lungs? We have thus evolved a network of cells involved in immune surveillance, made up of dendritic cells (DCs), monocytes and macrophages. Together, these mononuclear phagocytes sample the lungs and airways for presence of foreign pathogens such as viruses or bacteria. Recognition of pathogenic patterns – for instance the genetic material of viruses or the lipid membrane of bacteria – triggers a cascade of events in these immune cells. They produce inflammatory mediators to signal that a source of danger has been detected, and to contain the infection while awaiting the arrival of other immune cells. DCs migrate to lymphoid organs where they present antigens to naïve T cells, thus shaping the generation of protective and adaptive immunity. Much of what we know of how our immune system functions come from studies in murine models. In this thesis, we focus our attention on human DCs. Using super resolution microscopy, we assessed the early trafficking events that take place upon internalisation of influenza A virus (IAV) by human DCs. We report that IAV trafficked via early and late endosomes in DCs, similar to epithelial cells, but with more delayed kinetics. Next, we investigated whether maturation of monocyte-derived versus bona fide DCs affects their susceptibility to IAV infection. Indeed, the two subsets of DCs are inherently different in their ability to respond to pathogenic signals by producing antiviral mediators, which protect them from IAV infection. The accessibility of human blood has improved our understanding of human DCs. However, immune cells residing at mucosal barriers are our first line of defence against respiratory viruses. Increasing data suggest that there is tissue-specific regulation of immune cells due to factors present in the local microenvironment. Hence, we performed bronchoscopies on healthy subjects and hantavirus-infected patients to characterise DCs residing in the airways and bronchial mucosal tissue. We identified several subsets of respiratory DCs at steady state, alongside alveolar macrophages and monocyte-derived cells. During acute hantavirus disease, DCs and monocytes were depleted from circulation, whereas the lungs were infiltrated with monocytes and DCs. Collectively, our findings reveal the heterogeneity of human DCs in their response to respiratory viruses, depending on their origin and anatomical location. A deeper understanding of the complex interplay between respiratory viruses and human DCs reveals how DCs contribute to immunity or pathogenesis. This knowledge may help us develop better preventive and therapeutic strategies by targeting or modulating DCs to achieve favourable immune responses.

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