An ACAT inhibitor suppresses SARS-CoV-2 replication and boosts antiviral T cell activity.

The severity of disease following infection with SARS-CoV-2 is determined by viral replication kinetics and host immunity, with early T cell responses and/or suppression of viraemia driving a favourable outcome. Recent studies uncovered a role for cholesterol metabolism in the SARS-CoV-2 life cycle and in T cell function. Here we show that blockade of the enzyme Acyl-CoA:cholesterol acyltransferase (ACAT) with Avasimibe inhibits SARS-CoV-2 pseudoparticle infection and disrupts the association of ACE2 and GM1 lipid rafts on the cell membrane, perturbing viral attachment. Imaging SARS-CoV-2 RNAs at the single cell level using a viral replicon model identifies the capacity of Avasimibe to limit the establishment of replication complexes required for RNA replication. Genetic studies to transiently silence or overexpress ACAT isoforms confirmed a role for ACAT in SARS-CoV-2 infection. Furthermore, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells from the blood of patients sampled during the acute phase of infection. Thus, re-purposing of ACAT inhibitors provides a compelling therapeutic strategy for the treatment of COVID-19 to achieve both antiviral and immunomodulatory effects. Trial registration: NCT04318314.

Long-term observations of the persistence of olfactory disorders after COVID-19 infection

Background An olfactory disorder is often described as a characteristic initial symptom in patients with COVID-19 infection. The long-term olfactory disorders after a COVID-19 infection have not yet been described in detail. The aim of the study was to investigate the long-term effects of COVID-19 infections on smelling. Methods Patients with persistent, subjective smell &/ taste disorders were examined by means of questionnaires, endoscopic examinations, as well as side-separated olfactory testing using sniffin- sticks (TDI) and taste testing. After initial presentation and initiation of olfactory training, structured controls were performed for 72 patients six, 12 and 18 weeks after initial consultation. Results On average, the patient presented seven months after the onset of symptoms. 70 % of the patients were female and in average patients were 40 years old. Parosmia was reported by 64 % of the patients at this point. An at least unilateral functional anosmia was observed in 24 % and at least unilateral hyposmia in 71 % of the patients. A difference of ≥ 5 points in TDI between the respective sides could be identified in 35 %. During the first (six weeks), second (12 weeks) and third (18 weeks) control 32 %, 9 % and 14 % of the patients showed an improvement in smell of ≥ 5 points in the TDI test using sniffing sticks, respectively. Discussion Persistence of an olfactory disorder in the sense of hyp-/anosmia and parosmia can occur in young, female patients after COVID-19 infection. A side difference in smell can occur due to certain individual anatomy and the entry of the virus. A small proportion of patients with persistent olfactory disorders show regeneration.

Olfactory and gustatory disorder after COVID-19 vaccination

Background Olfactory and gustatory disorders after COVID-19 vaccination have been described in the literature in case reports. These are mainly described after the Comirnaty vaccination. In this case report, the olfactory and gustatory disorders of two patients after Comirnaty vaccination are described. Methods The two affected patients with persistent subjective olfactory and/ or gustatory dysfunction after COVID-19 vaccination were evaluated using olfactory testing with Sniffin Sticks (TDI) and taste testing. Therapy was subsequently initiated and patients were followed up at regular intervals. Results 2 Patients (1 male and 1 female) with an average age of 80 years, who developed olfactory and/or gustatory disorders after the first and second vaccination respectively, were examined and tested. One case exhibited in the subjective and objective tests a functional anosmia (TDI: right 14.3, left 12.8) whilst the second case displayed hyposmia (TDI: right 18.75, left 21.75) and hypogeusia (right 4/16, left 6/16). Antibody testing showed the presence of IgG(S) but no IgG(Nc) was detected. Discussion Olfactory dysfunction in terms of hyp- or anosmia, as well as parosmia, may occur in patients after COVID-19 vaccination without previous COVID- 19-infection and should always be tested objectively. One case even exhibited hypogeusia. Despite laboratory diagnostics, previous COVID-19 infections cannot be ruled out with certainty. Age-related pre-existing disorders cannot be evaluated. Whether the course of olfactory dysfunction is comparable to that of patients after COVID-19 infection needs to be investigated in further studies.

eHealth in Self-Managing at a Distance Patients with COPD.

Worldwide, healthcare delivery for chronic diseases has been challenging due to the current SARS-COV-2 pandemic. The growing use of information and communication technologies via telehealth has gained popularity in all fields of medicine. In chronic respiratory diseases, self-management, defined as a structured but personalized multi-component intervention with the main goal of achieving healthy behavioral change, is an essential element of long-term care. Iterative interventions delivered by a well-trained health coach in order to empower and provide the patient with the tools and skills needed to adopt sustained healthy behaviors have proven to be effective in chronic obstructive pulmonary disease (COPD). Benefits have been shown to both improve patient quality of life and reduce acute exacerbation events and acute healthcare utilization. In COPD, the evidence so far has shown us that remote technologies such as telemonitoring or remote management may improve patient-reported outcomes and healthcare utilization. However, clear limitations are still present and questions remain unanswered. More and better designed studies are therefore necessary to define the place of eHealth in self-managing at a distance in patients with COPD.

An ACAT inhibitor regulates SARS-CoV-2 replication and antiviral T cell activity (preprint)

The severity of disease following infection with SARS-CoV-2 is determined by viral replication kinetics and host immunity, with early T cell responses and/or suppression of viraemia driving a favourable outcome. Recent studies have uncovered a role for cholesterol metabolism in the SARS-CoV-2 life cycle and in T cell function. Here we show that blockade of the enzyme Acyl-CoA:cholesterol acyltransferase (ACAT) with Avasimibe inhibits SARS-CoV-2 entry and fusion independent of transmembrane protease serine 2 expression in multiple cell types. We also demonstrate a role for ACAT in regulating SARS-CoV-2 RNA replication in primary bronchial epithelial cells. Furthermore, Avasimibe boosts the expansion of functional SARS-CoV-2-specific T cells from the blood of patients sampled in the acute phase of infection. Thus, re-purposing of available ACAT inhibitors provides a compelling therapeutic strategy for the treatment of COVID-19 to achieve both antiviral and immunomodulatory effects.

The circadian clock component BMAL1 regulates SARS-CoV-2 entry and replication in lung epithelial cells.

The coronavirus disease 2019 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract via spike glycoprotein binding to angiotensin-converting enzyme (ACE2). Circadian rhythms coordinate an organism's response to its environment and can regulate host susceptibility to virus infection. We demonstrate that silencing the circadian regulator Bmal1 or treating lung epithelial cells with the REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry and replication. Importantly, treating infected cells with SR9009 limits SARS-CoV-2 replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system. Transcriptome analysis revealed that Bmal1 silencing induced interferon-stimulated gene transcripts in Calu-3 lung epithelial cells, providing a mechanism for the circadian pathway to limit SARS-CoV-2 infection. Our study highlights alternative approaches to understand and improve therapeutic targeting of SARS-CoV-2.

Adverse Life Trajectories Are a Risk Factor for SARS-CoV-2 IgA Seropositivity.

Asymptomatic individuals, called "silent spreaders" spread SARS-CoV-2 efficiently and have complicated control of the ongoing COVID-19 pandemic. As seen in previous influenza pandemics, socioeconomic and life-trajectory factors are important in disease progression and outcome. The demographics of the asymptomatic SARS-CoV-2 carriers are unknown. We used the CON-VINCE cohort of healthy, asymptomatic, and oligosymptomatic individuals that is statistically representative of the overall population of Luxembourg for age, gender, and residency to characterise this population. Gender (male), not smoking, and exposure to early-life or adult traumatic experiences increased the risk of IgA seropositivity, and the risk associated with early-life exposure was a dose-dependent metric, while some other known comorbidities of active COVID-19 do not impact it. As prior exposure to adversity is associated with negative psychobiological reactions to external stressors, we recorded psychological wellbeing during the study period. Exposure to traumatic events or concurrent autoimmune or rheumatic disease were associated with a worse evolution of anxiety and depressive symptoms throughout the lockdown period. The unique demographic profile of the "silent spreaders" highlights the role that the early-life period plays in determining our lifelong health trajectory and provides evidence that the developmental origins of health and disease is applicable to infectious diseases.

A randomised clinical trial of azithromycin versus standard care in ambulatory COVID-19 - the ATOMIC2 trial (preprint)

Background The antibacterial, anti-inflammatory and antiviral properties of azithromycin suggest therapeutic potential against COVID-19. Randomised data in mild-moderate disease are lacking. We assessed whether azithromycin is effective in reducing hospitalisation in patients with mild-moderate COVID-19. Methods This open-label, randomised superiority clinical trial at 19 centres in the United Kingdom enrolled adults, [≥]18 years, presenting to hospitals with clinically-diagnosed highly-probable or confirmed COVID-19 infection, with <14 days symptoms, considered suitable for initial ambulatory management. Patients were randomised (1:1) to azithromycin (500 mg daily orally for 14 days) or to standard care without macrolides. The primary outcome was the difference in proportion of participants with death or hospital admission from any cause over the 28 days from randomisation, assessed according to intention-to-treat (ITT). Trial registration: ClinicalTrials.gov, NCT04381962, Study closed. Findings 298 participants were enrolled from 3rd June 2020 to 29th January 2021. The primary outcome was assessed in 292 participants. The primary endpoint was not significantly different between the azithromycin and control groups (Adjusted OR 0.91 [95% CI 0.43-1.92], p=0.80). Rates of respiratory failure, progression to pneumonia, all-cause mortality, and adverse events, including serious cardiovascular events, were not significantly different between groups. Interpretation In patients with mild-moderate COVID-19 managed without hospital admission, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospitalisation or death. Our findings do not support the use of azithromycin in patients with mild-moderate COVID-19. Funding NIHR Oxford BRC, University of Oxford and Pfizer Inc.

Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells.

COVID-19, caused by the novel coronavirus SARS-CoV-2, is a global health issue with more than 2 million fatalities to date. Viral replication is shaped by the cellular microenvironment, and one important factor to consider is oxygen tension, in which hypoxia inducible factor (HIF) regulates transcriptional responses to hypoxia. SARS-CoV-2 primarily infects cells of the respiratory tract, entering via its spike glycoprotein binding to angiotensin-converting enzyme 2 (ACE2). We demonstrate that hypoxia and the HIF prolyl hydroxylase inhibitor Roxadustat reduce ACE2 expression and inhibit SARS-CoV-2 entry and replication in lung epithelial cells via an HIF-1α-dependent pathway. Hypoxia and Roxadustat inhibit SARS-CoV-2 RNA replication, showing that post-entry steps in the viral life cycle are oxygen sensitive. This study highlights the importance of HIF signaling in regulating multiple aspects of SARS-CoV-2 infection and raises the potential use of HIF prolyl hydroxylase inhibitors in the prevention or treatment of COVID-19.

Circadian regulation of SARS-CoV-2 infection in lung epithelial cells (preprint)

The COVID-19 pandemic, caused by SARS-CoV-2 coronavirus, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract, via binding human angiotensin-converting enzyme (ACE2), and infection can result in pneumonia and acute respiratory distress syndrome. Circadian rhythms coordinate an organisms response to its environment and recent studies report a role for the circadian clock to regulate host susceptibility to virus infection. Influenza A infection of arhythmic mice, lacking the circadian component BMAL1, results in higher viral replication and elevated inflammatory responses leading to more severe bronchitis, highlighting the impact of circadian pathways in respiratory function. We demonstrate circadian regulation of ACE2 in lung epithelial cells and show that silencing BMAL1 or treatment with the synthetic REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry and RNA replication. Treating infected cells with SR9009 limits viral replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system. Our study suggests new approaches to understand and improve therapeutic targeting of COVID-19.

MAIT cell activation augments adenovirus vector vaccine immunogenicity.

Mucosal-associated invariant T (MAIT) cells are innate sensors of viruses and can augment early immune responses and contribute to protection. We hypothesized that MAIT cells may have inherent adjuvant activity in vaccine platforms that use replication-incompetent adenovirus vectors. In mice and humans, ChAdOx1 (chimpanzee adenovirus Ox1) immunization robustly activated MAIT cells. Activation required plasmacytoid dendritic cell (pDC)-derived interferon (IFN)-α and monocyte-derived interleukin-18. IFN-α-induced, monocyte-derived tumor necrosis factor was also identified as a key secondary signal. All three cytokines were required in vitro and in vivo. Activation of MAIT cells positively correlated with vaccine-induced T cell responses in human volunteers and MAIT cell-deficient mice displayed impaired CD8+ T cell responses to multiple vaccine-encoded antigens. Thus, MAIT cells contribute to the immunogenicity of adenovirus vectors, with implications for vaccine design.

Changing body norms in the context of increasing body size: Samoa in 1995 and 2018.

OBJECTIVE: To understand how body size preferences changed in Samoa between 1995 and 2017 to 2019. METHODS: Data were from adults aged from 31 to 59 years, who participated in two separate cross-sectional studies of obesity and cardiometabolic risk conducted in Samoa in 1995 and 2017 to 2019. Participants nominated line drawings representing their current size, ideal size, the most attractive and healthiest size, and the lower/upper limits of "normal" size. RESULTS: In both sexes, body size preferences and perceived current average body size have increased, yet preference for bodies smaller than one's perceived current size has persisted. Furthermore, the range of body sizes that people considered "normal" has narrowed, suggesting decreased tolerance for extremes of body size. CONCLUSIONS: These findings may have implications for mental and physical health outcomes, inform development of future health initiatives, and contribute to a deeper understanding of how body norms and weight-related public health efforts interface.