Holtzman, D. | Search bioRxiv

bioRxiv2022

Virus-like particle displaying SARS-CoV-2 receptor binding domain elicits neutralizing antibodies and is protective in a challenge model

While the effort to vaccinate people against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has largely been successful, particularly in the developed world, the rise of new variants as well as waning immunity illustrate the need for a new generation of vaccines that provide broader and/or more durable protection against infection and severe disease. Here we describe the generation and characterization of IVX-411, a computationally designed, two-component virus-like particle (VLP) displaying the ancestral SARS-CoV-2 receptor binding domain (RBD) on its surface. Immunization of mice with IVX-411 generates neutralizing antibodies against the ancestral strain as well as three variants of concern. Neutralizing antibody titers elicited by IVX-411 are durable and significantly higher than those elicited by immunization with soluble RBD and spike antigens. Furthermore, immunization with IVX-411 is shown to be protective in a Syrian Golden hamster challenge model using two different strains of SARS-CoV-2. Overall, these studies demonstrate that IVX-411 is highly immunogenic and capable of eliciting broad, protective immunity.

immunology↗

bioRxiv2022

Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol

Neuroinflammation is a major hallmark of Alzheimers disease and several other neurological and psychiatric disorders and is often associated with dysregulated cholesterol metabolism. Relative to homeostatic microglia, activated microglia express higher levels of Ch25h, an enzyme that hydroxylates cholesterol to produce 25-hydroxycholesterol (25HC). 25HC is an oxysterol with interesting immune roles stemming from its ability to regulate cholesterol biosynthesis. Since astrocytes synthesize cholesterol in the brain and transport it to other cells via apolipoprotein E (ApoE)-containing lipoproteins, we hypothesized that secreted 25HC from microglia may influence lipid metabolism as well as extracellular ApoE derived from astrocytes. Here we show that astrocytes take up externally added 25HC and respond with altered lipid metabolism. 25HC increased extracellular levels of ApoE lipoprotein particles without altering Apoe mRNA expression, due to elevated Abca1 expression via activation of LXRs and decreased ApoE reuptake due to suppressed Ldlr expression via inhibition of SREBP. Astrocytes metabolized 25HC to limit its effects on lipid metabolism via Cyp7b1, an enzyme responsible for 7-hydroxylation of 25HC. Knockdown of Cyp7b1 expression with siRNA prolonged the effects of 25HC on astrocyte lipid metabolism. 25HC also suppressed Srebf2 expression to reduce cholesterol synthesis in astrocytes but did not affect fatty acid levels or the genes required for fatty acid synthesis. We further show that 25HC led to a doubling of the amount of cholesterol esters and their concomitant storage in lipid droplets. Our results suggest an important role for 25HC in regulating astrocyte lipid metabolism.

cell biology↗