Study of lipid droplets role on the function of dendritic cells infected with herpes simplex virus type 1

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Herpes simplex virus type 1 (HSV-1) infection is highly prevalent in the human population and infections are lifelong, with sporadic reactivations that may elicit recurrent symptomatic disease. HSV-1 can evade the host immune response at multiple levels, by interfering with innate and adaptive immunity. Dendritic cells (DCs) are key immune cells that activate and regulate antiviral immune responses. DCs can activate CD4+ and CD8+ T cells, which can modulate the host antiviral immune response and elicit immunity. HSV- 1 infects DCs and alters their function by hampering their maturation, antigen-processing capacity, and migration to lymph nodes which alter their capacity to activate naïve T cells and mount an effective antiviral response. On the other hand, lipid droplets (LDs) are neutral lipid-rich organelles reported to negatively modulate DC function, decreasing the capacity of these cells to present antigens T cells and activate these cells. Here, we sought to assess whether HSV-1 alters lipid metabolism in DCs and induces LDs within these cells. Interestingly, we found that HSV-1 induces LDs in DCs, as well as significant changes in lipid metabolism processes, altering lipid accumulation and the expression of lipid metabolism-related genes. Importantly, we found that the pharmacological inhibition of lipid metabolism-related enzymes associated with fatty acid uptake and cholesterol ester synthesis inhibited LD accumulation in HSV-1-infected DCs, decreased virus yield. Furthermore, HSV-1-infected DCs treated with such drugs improved the viability of DCs and their capacity to activate virus-specific CD8+ T cells in vitro and migrate to lymph nodes to promote the activation of virus-specific CD8+ T cells in vivo. These findings indicate that HSV-1 infection significantly alters lipid metabolism in DCs, seemingly playing a significant role in the deterioration of the function of these cells upon infection with this virus.
Tesis (Doctor in Biological Sciences with specialization in Molecular Genetics and Microbiology)--Pontificia Universidad Católica de Chile, 2023