The role of high cholesterol in age-related COVID19 lethality

Wang, Hao; Yuan, Zixuan; Pavel, Mahmud Arif; Jablonski, Sonia Mediouni; Jablonski, Joseph; Hobson, Robert J.; Valente, Susana T.; Reddy, Chakravarthy; Hansen, Scott B.

doi:10.1101/2020.05.09.086249

Cited by 132 publications

(192 citation statements)

References 84 publications

(134 reference statements)

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“…To construct the vectors for pseudovirus packaging, the full-length spike gene was PCR-amplified from Sfull or Sdel strain and cloned into the pcDNA3.1 vector. The Sfull spike gene with two mutations (R682S, R685S) (Wang et al, 2020a) in the furin cleavage site was generated by PCR. The full-length SARS-CoV or MERS-CoV spike gene was cloned similarly.…”

Section: Discussionmentioning

confidence: 99%

The S1/S2 boundary of SARS-CoV-2 spike protein modulates cell entry pathways and transmission

Zhu

Feng

et al. 2020

Preprint

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The global spread of SARS-CoV-2 is posing major public health challenges. One unique feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site, the function of which remains uncertain. We found that the virus with intact spike (Sfull) preferentially enters cells via fusion at the plasma membrane, whereas a clone (Sdel) with deletion disrupting the multi-basic S1/S2 site instead utilizes a less efficient endosomal entry pathway. This idea was supported by the identification of a suite of endosomal entry factors specific to Sdel virus by a genome-wide CRISPR-Cas9 screen. A panel of host factors regulating the surface expression of ACE2 was identified for both viruses. Using a hamster model, animal-to-animal transmission with the Sdel virus was almost completely abrogated, unlike with Sfull. These findings highlight the critical role of the S1/S2 boundary of the SARS-CoV-2 spike protein in modulating virus entry and transmission.

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Section: Discussionmentioning

confidence: 99%

The S1/S2 boundary of SARS-CoV-2 spike protein modulates cell entry pathways and transmission

Zhu

Feng

et al. 2020

Preprint

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“…Rather than targeting a receptor, it targets GM1 domains and sets the threshold for APP processing by altering GM1 domain function. This concept is likely important to other biological systems 61 given the profound effect of cholesterol on human health.…”

Section: Discussionmentioning

confidence: 99%

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Wang

Kulas

Ferris

et al. 2020

Preprint

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Alzheimer's Disease (AD), a common and burdensome neurodegenerative disorder, is characterized by the presence of β-Amyloid (Aβ) plaques, inflammation, and loss of cognitive function. A cholesteroldependent process sorts Aβ-producing enzymes into nanoscale lipid compartments (also called lipid rafts). Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic marker for sporadic AD. Evidence suggests apoE links to Aβ production through lipid rafts, but so far there has been little scientific validation of this link in vivo. Here we use super-resolution imaging to show apoE utilizes astrocyte-derived cholesterol to specifically traffic amyloid precursor protein (APP) into lipid rafts where it interacts with β-and g-secretases to generate Aβ-peptide. We find that targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid rafts where it interacts with αsecretase and gives rise to soluble APPα (sAPPα), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and g-secretase trafficking, suggesting the ratio of Aβ to sAPPα is regulated by the trafficking of the substrate, not the enzymes. Treatment of astrocytes with inflammatory cytokines IL-1β, IL-6 and TNF-α upregulates the synthesis of cholesterol in the astrocytes. We conclude that cholesterol is a signaling molecule kept low in neurons to inhibit raft function, decrease Aβ formation, and enable astrocyte regulation of APP by cholesterol control of substrate presentation. Highlights:ApoE regulates amyloid precursor protein localization to rafts and its exposure to α-vs. β-secretase. α-, β-, and g-Secretases are activated by substrate presentation. ApoE specifically transports astrocyte cholesterol to neurons. Astrocyte cholesterol synthesis disruption prevents Alzheimer's-associated amyloid pathology in mice.

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“…Indeed, lipid rafts have previously been implicated as important cell surface domains for the entry of other viruses (114,115). An increase in cholesterol increases the availability of SARS-CoV-2 viral entry points (111). As cholesterol levels increase with aging and with metabolic disorders this could contribute to their associations with the severity of COVID-19.…”

Section: Lipid Raftsmentioning

confidence: 99%

Obesity, Diabetes and COVID-19: An Infectious Disease Spreading From the East Collides With the Consequences of an Unhealthy Western Lifestyle

et al. 2020

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The pandemic of COVID-19, caused by the coronavirus, SARS-CoV-2, has had a global impact not seen for an infectious disease for over a century. This acute pandemic has spread from the East and has been overlaid onto a slow pandemic of metabolic diseases of obesity and diabetes consequent from the increasing adoption of a Western-lifestyle characterized by excess calorie consumption with limited physical activity. It has become clear that these conditions predispose individuals to a more severe COVID-19 with increased morbidity and mortality. There are many features of diabetes and obesity that may accentuate the clinical response to SARS-CoV-2 infection: including an impaired immune response, an atherothrombotic state, accumulation of advanced glycation end products and a chronic inflammatory state. These could prime an exaggerated cytokine response to viral infection, predisposing to the cytokine storm that triggers progression to septic shock, acute respiratory distress syndrome, and multi-organ failure. Infection leads to an inflammatory response and tissue damage resulting in increased metabolic activity and an associated increase in the mechanisms by which cells ingest and degrade tissue debris and foreign materials. It is becoming clear that viruses have acquired an ability to exploit these mechanisms to invade cells and facilitate their own life-cycle. In obesity and diabetes these mechanisms are chronically activated due to the deteriorating metabolic state and this may provide an increased opportunity for a more profound and sustained viral infection.

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The role of high cholesterol in age-related COVID19 lethality

Cited by 132 publications

References 84 publications

The S1/S2 boundary of SARS-CoV-2 spike protein modulates cell entry pathways and transmission

The S1/S2 boundary of SARS-CoV-2 spike protein modulates cell entry pathways and transmission

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Obesity, Diabetes and COVID-19: An Infectious Disease Spreading From the East Collides With the Consequences of an Unhealthy Western Lifestyle

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