Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases.

Macrophages are essential innate immune cells that contribute to host defense during infection. An important feature of macrophages is their ability to respond to extracellular cues and to adopt different phenotypes and functions in response to these stimuli. The evidence accumulated in the last decade has highlighted the crucial role of metabolic reprogramming during macrophage activation in infectious context. Thus, understanding and manipulation of macrophage immunometabolism during infection could be of interest to develop therapeutic strategies. In this review, we focus on 5 major metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis, tricarboxylic acid cycle and amino acid metabolism and discuss how they sustain and regulate macrophage immune function in response to parasitic, bacterial and viral infections as well as trained immunity. At the end, we assess whether some drugs including those used in clinic and in development can target macrophage immunometabolism for potential therapy during infection with an emphasis on SARS-CoV2 infection. 

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Modulation of Macrophage Immunometabolism: A New Approach to Fight Infections

Coronavirus disease 2019 (COVID-19) is currently a worldwide emergency caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). In observational clinical studies, statins have been identified as beneficial to hospitalized patients with COVID-19. However, experimental evidence of underlying statins protection against SARS-CoV-2 remains elusive. Here we reported for the first-time experimental evidence of the protective effects of simvastatin treatment both in vitro and in vivo. We found that treatment with simvastatin significantly reduced the viral replication and lung damage in vivo, delaying SARS-CoV-2-associated physiopathology and mortality in the K18-hACE2-transgenic mice model. Moreover, simvastatin also downregulated the inflammation triggered by SARS-CoV-2 infection in pulmonary tissue and in human neutrophils, peripheral blood monocytes, and lung epithelial Calu-3 cells in vitro, showing its potential to modulate the inflammatory response both at the site of infection and systemically. Additionally, we also observed that simvastatin affected the course of SARS-CoV-2 infection through displacing ACE2 on cell membrane lipid rafts. In conclusion, our results show that simvastatin exhibits early protective effects on SARS-CoV-2 infection by inhibiting virus cell entry and inflammatory cytokine production, through mechanisms at least in part dependent on lipid rafts disruption.

/pdf/simvastatin-downregulates-the-sars-cov-2-induced-1i6xk8uk.pdf

Simvastatin Downregulates the SARS-CoV-2-Induced Inflammatory Response and Impairs Viral Infection Through Disruption of Lipid Rafts

The transmissible respiratory disease COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected millions of people worldwide since its first reported outbreak in December of 2019 in Wuhan, China. Since then, multiple studies have shown an inverse correlation between the levels of high-density lipoprotein (HDL) particles and the severity of COVID-19, with low HDL levels being associated with an increased risk of severe outcomes. Some studies revealed that HDL binds to SARS-CoV-2 particles via the virus's spike protein and, under certain conditions, such as low HDL particle concentrations, it facilitates SARS-CoV-2 binding to angiotensin-converting enzyme 2 (ACE2) and infection of host cells. Other studies, however, reported that HDL suppressed SARS-CoV-2 infection. In both cases, the ability of HDL to enhance or suppress virus infection appears to be dependent on the expression of the HDL receptor, namely, the Scavenger Receptor Class B type 1 (SR-B1), in the target cells. SR-B1 and HDL represent crucial mediators of cholesterol metabolism. Herein, we review the complex role of HDL and SR-B1 in SARS-CoV-2-induced disease. We also review recent advances in our understanding of HDL structure, properties, and function during SARS-CoV-2 infection and the resulting COVID-19 disease.

Good Cholesterol Gone Bad? HDL and COVID-19.

Host cholesterol metabolism remodeling is significantly associated with the spread of human pathogenic coronaviruses, suggesting virus-host relationships could be affected by cholesterol-modifying drugs. Cholesterol has an important role in coronavirus entry, membrane fusion, and pathological syncytia formation, therefore cholesterol metabolic mechanisms may be promising drug targets for coronavirus infections. Moreover, cholesterol and its metabolizing enzymes or corresponding natural products exert antiviral effects which are closely associated with individual viral steps during coronavirus replication. Furthermore, the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 infections are associated with clinically significant low cholesterol levels, suggesting cholesterol could function as a potential marker for monitoring viral infection status. Therefore, weaponizing cholesterol dysregulation against viral infection could be an effective antiviral strategy. In this review, we comprehensively review the literature to clarify how coronaviruses exploit host cholesterol metabolism to accommodate viral replication requirements and interfere with host immune responses. We also focus on targeting cholesterol homeostasis to interfere with critical steps during coronavirus infection.

/pdf/coronavirus-infection-and-cholesterol-metabolism-2mua4r1w.pdf

Coronavirus Infection and Cholesterol Metabolism

Coronavirus disease 2019 is a kind of viral pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) However, the mechanism whereby SARS-CoV-2 invades host cells remains poorly understood Here we used SARS-CoV-2 pseudoviruses to infect human angiotensin-converting enzyme 2 (ACE2) expressing HEK293T cells and evaluated virus infection We confirmed that SARS-CoV-2 entry was dependent on ACE2 and sensitive to pH of endosome/lysosome in HEK293T cells The infection of SARS-CoV-2 pseudoviruses is independent of dynamin, clathrin, caveolin and endophilin A2, as well as macropinocytosis Instead, we found that the infection of SARS-CoV-2 pseudoviruses was cholesterol-rich lipid raft dependent Cholesterol depletion of cell membranes with methyl-β-cyclodextrin resulted in reduction of pseudovirus infection The infection of SARS-CoV-2 pseudoviruses resumed with cholesterol supplementation Together, cholesterol-rich lipid rafts, and endosomal acidification, are key steps of SARS-CoV-2 required for infection of host cells Therefore, our finding expands the understanding of SARS-CoV-2 entry mechanism and provides a new anti-SARS-CoV-2 strategy

Lei Zhang

Papers

Dependence of SARS-CoV-2 infection on cholesterol-rich lipid raft and endosomal acidification.