Lipid droplet density alters the early innate immune response to viral infection

Abstract

The cellular localisation of many innate signalling events following viral infection has yet to be elucidated, however there has been a few cases in which membranes of certain cellular organelles have acted as platforms to these events. Of these, lipid droplets (LDs) have recently been identified as signalling platforms for innate TLR7 and 9 signalling. Despite their wide range of similar roles in various metabolic pathways, LDs have been overlooked as potential platforms for antiviral innate signalling events. This study established an in vitro model to evaluate the efficiency of the early innate immune response in cells with reduced LD content to the viral mimics, dsDNA and dsRNA, and Sendai viral infection. Using RT-qPCR, the expression of IFN-β and IFN-λ was quantified following stimulation along with the expression of specific ISGs. Luciferase based assays evaluated the combined expression of ISRE-promoter driven ISGs under IFN-β stimulation. Cellular LD content did not alter the entry of fluorescently labelled viral mimics into cells, but significantly decreased the ability of both Huh-7 and HeLa cells to produce type I and III IFN, as well as downstream ISG expression, indicative of an impeded innate immune response. This observation was also seen during Sendai virus infection of HeLa cells, where both control and LD reduced cells replicated the virus to the same level, but a significantly impaired type I and III IFN response was observed in the LD reduced cells. In addition to altered IFN production, cells with reduced LD content exhibited decreased expression of specific antiviral ISGs: Viperin, IFIT-1 and OAS-1 under IFN-β stimulation; However the overall induction of the ISRE-promoter was not effected. This study implicates a role for LDs in an efficient early innate host response to viral infection and future work will endeavour to determine the precise role these important organelles play in induction of an antiviral response.

C6orf106 is a novel inhibitor of the interferon-regulatory factor 3–dependent innate antiviral response

“…To confirm C6orf106 as a negative regulator of antiviral cytokine transcription, cells were infected with Sendai virus (SeV), an RNA virus (genus Respirovirus, family Paramyxoviridae) that induces type I IFN cytokine transcription in HeLa cells (47). In agreement with poly(I:C) stimulation studies, C6orf106 inhibited IFN-␣, IFN-␤, and TNF␣ transcription induced by Sendai virus infection as demonstrated by both siRNA ( Fig.…”

Fat, fight, and beyond: The multiple roles of lipid droplets in infections and inflammation

“…LDs are not always unfavorable to the host during viral infections. The presence of LDs could be required for an effective early innate response to viral infection, mainly related to type I and III IFN responses . In response to viral infection by HCV, viperin was the first protective protein reported to be loaded onto LDs .…”

“…The presence of LDs could be required for an effective early innate response to viral infection, mainly related to type I and III IFN responses. 164 In response to viral infection by HCV, viperin was the first protective protein reported to be loaded onto LDs. 31 The antiviral protein viperin is one of the hundreds of genes regulated by the cell-signaling proteins and master regulators IFNs in response to viral infection.…”

ssRNA Virus and Host Lipid Rearrangements: Is There a Role for Lipid Droplets in SARS-CoV-2 Infection?

“…In this regard, although LDs are supposed to be a platform for viral replication, they might also contribute in antiviral signaling events, suggesting a double role for these organelles, which makes the scenario more complex and less trivial than anticipated ( Monson et al, 2018 ). In fact, LD biogenesis is a well-established event occurring in cells of the immune system following pathogen infections and inflammation.…”