The role of high cholesterol in SARS-CoV-2 infectivity

Coronavirus disease 2019 (COVID19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus binds to angiotensinogen converting enzyme 2 (ACE2) which mediates viral entry into mammalian cells. COVID19 is notably severe in elderly and those with underlying chronic conditions. The cause of selective severity is not well understood. Here we show cholesterol and the signaling lipid phosphatidyl-inositol 4,5 bisphosphate (PIP2) regulate viral infectivity through the localization of ACE2's into nanoscopic (<200 nm) lipid clusters. Uptake of cholesterol into cell membranes (a condition common to chronic disease) causes ACE2 to move from PIP2 lipids to endocytic ganglioside (GM1) lipids, where the virus is optimally located for viral entry. In mice, age, and high fat diet increase lung tissue cholesterol by up to 40%. And in smokers with chronic disease, cholesterol is elevated two-fold, a magnitude of change that dramatically increases infectivity of virus in cell culture. We conclude increasing the ACE2 location near endocytic lipids increases viral infectivity and may help explain the selective severity of COVID-19 in aged and diseased populations.

Utilization of Telehealth Solutions for Patients with Opioid Use Disorder Using Buprenorphine: A Scoping Review

Objectives: A scoping review was conducted to examine the breadth of evidence related to telehealth innovations being utilized in the treatment of Opioid Use Disorder (OUD) with buprenorphine and its effect on patient outcomes and healthcare delivery. Background(s): With the opioid epidemic worsening from year to year, there is a critical need to connect with this growing population and get them access to life-saving interventions. Buprenorphine is shown to be associated with lower overdose rates and a decrease in opioid-related acute care, but has historically been underutilized in treatment for OUD. Previous studies have determined that geographical barriers and lack of access to DEA-waivered providers are common obstacles towards starting MAT. Telehealth presents itself as a solution to this discrepancy and is becoming more feasible to integrate into clinical practice. Method(s): The authors systematically searched seven databases and websites for peer-reviewed and gray literature related to telehealth solutions for buprenorphine treatment published between 2008 and March 18, 2021. There were 69 articles which met inclusion criteria. Result(s): According to the reviewed literature, incorporation of telehealth technology with Medication Assisted Treatment (MAT) for OUD is associated with higher patient satisfaction, comparable rates of retention, and an overall reduction in health care costs. Conclusion(s): Utilization of synchronous videoconferencing has reportedly been effective in increasing access to and usage of buprenorphine by overcoming both geographical and logistical barriers. This has been made possible through the expansion of telehealth technologies and a substantial push towards relaxed federal guidelines, both of which were quickly escalated in response to the COVID-19 pandemic. Future research is needed to fully quantify the effect of these factors;however, the results appear promising thus far and should urge policymakers to consider making these temporary policy changes permanent. (Figure Presented) .

Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture.

Hydroxychloroquine (HCQ), a drug used to treat lupus and malaria, was proposed as a treatment for SARS-coronavirus-2 (SARS-CoV-2) infection, albeit with controversy. In vitro, HCQ effectively inhibits viral entry, but its use in the clinic has been hampered by conflicting results. A better understanding of HCQ's mechanism of actions in vitro is needed. Recently, anesthetics were shown to disrupt ordered clusters of monosialotetrahexosylganglioside1 (GM1) lipid. These same lipid clusters recruit the SARS-CoV-2 surface receptor angiotensin converting enzyme 2 (ACE2) to endocytic lipids, away from phosphatidylinositol 4,5 bisphosphate (PIP2) clusters. Here we employed super-resolution imaging of cultured mammalian cells (VeroE6, A549, H1793, and HEK293T) to show HCQ directly perturbs clustering of ACE2 receptor with both endocytic lipids and PIP2 clusters. In elevated (high) cholesterol, HCQ moves ACE2 nanoscopic distances away from endocytic lipids. In cells with resting (low) cholesterol, ACE2 primarily associates with PIP2 clusters, and HCQ moves ACE2 away from PIP2 clusters-erythromycin has a similar effect. We conclude HCQ inhibits viral entry through two distinct mechanisms in high and low tissue cholesterol and does so prior to inhibiting cathepsin-L. HCQ clinical trials and animal studies will need to account for tissue cholesterol levels when evaluating dosing and efficacy.