Proteomic analysis of SARS-CoV-2 responsible for COVID-19 in Algeria (in silico study)
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Background and aim: Abnormal liver function tests (LFTs) and gastrointestinal (GI) symptoms have been reported up to 50% in patients with COVID-19, and in 5% they can precede respiratory symptoms The objective of this work is to describe the LFTs and GI symptoms of patients with COVID-19 and their association with admission to the intensive care unit (ICU) and mortality Material and Methods We conducted a retrospective, cross sectional, descriptive study, using files from patients with a positive Gen Finder COVID-19 test, admitted to Medica Sur Clinic and Foundation between March 13th through May 14th, 2020 We performed descriptive analysis of data and its association with clinical outcomes Results: A total of 108 patients with COVID-19 were identified;68 5% (n = 74) were men, the mean age was 53 ± 14 years and the body mass index was 28 6 ± 5 8 kg/m2 The most frequent comorbidity was hypertension with 24% (n = 26) The presence of comorbidities was associated with risk of ICU admission (OR 3 9 [95% CI 1 6-9 9], p = 0 002) The most frequent symptoms were cough (72 2%, n = 78), fever (69 4%, n = 75) and dyspnea (48 1%, n = 52) At least one abnormal LFT was present in 94% (n = 103) of patients at admission, the most frequent was LDH (88 9%, n = 96), AST and GGT (63%, n = 65), which are summarized in Table 1 Patients presented abnormal LFTs and respiratory symptoms in 48 1% (n = 52), while 16 6% (n = 18) presented abnormal LFTs without respiratory symptoms Among GI symptoms, 37% (n = 4) reported at least one, including diarrhea (28 7%, n = 31), hyporexia (9 3%, n = 10), nausea (8 3%, n = 9) or vomiting (4 6%, n = 5) Of patients admitted to the ICU (n = 39), 27 5% (n = 10) presented at least one GI symptom Mortality was 7 4% (n = 8) No associations were found between abnormal LFTs, GI symptoms, and outcomes of mortality and ICU admission Conclusions: In patients with COVID 19, the presence of metabolic comorbidities confers a higher risk of ICU admission, in contrast to abnormal LFTs and GI symptoms that were not associated with clinical outcomes Conflicts of interest: The authors have no conflicts of interest to declare
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The coronavirus disease 2019 (COVID-19) pandemic provided a unique opportunity to activate and mobilize a new approach to aligning and accelerating research activities across the Mayo Clinic enterprise. Just days after the state-wide lockdown in Minnesota, the executive deans of research and practice activated a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/COVID-19 Research Task Force led by medical, scientific, and administrative leaders from across Mayo Clinic. This task force was created even before molecular testing was offered to the communities in which Mayo Clinic operates. The SARS-CoV-2/COVID-19 Research Task Force responded to vigorous efforts by the Mayo Clinic research community across the following domains:•Conducting basic laboratory research on SARS-CoV-2/COVID-19 as well as host responses•Developing a vaccine•Launching studies on the immune response and on how and whether certain immune responses protect against reinfection•Investigating the body's innate response to COVID-19 and ways to block the inflammatory response that contributes to severity of the disease•Designing epidemiologic and artificial intelligence research to predict disease spread and aid in allocation of community resources, such as testing capabilities•Evaluating factors to help predict the risk of complications and disease severity•Engaging communities to understand the pandemic's impact and community priorities for research•Adopting novel strategies to monitor patients with COVID-19 before and after they leave the hospital by using remote monitoring and wearable devices•Developing processes for reducing environmental risk, such as novel approaches to decontaminating personal protective equipment•Working with regulatory bodies to create new and nimble processes for study review, approval, and implementation Besides the above, the SARS-CoV-2/COVID-19 Research Task Force was responsible for other challenges occurring in an accelerating research environment in the new SARS-CoV-2/COVID-19 field, including concerns that pockets of COVID-19 research could exist across Mayo Clinic that were not part of a unified plan or that duplicative clinical trials could be competing for the same patients. The task force leadership quickly established a structure with a design and culture that enabled a unique and very effective operational model within the rapidly evolving landscape of the COVID-19 pandemic, that is•An overall task force structure with a physician-scientist chair and an administrative co-chair•Establishment of 16 function-specific work streams, aligned to strategies of the SARS-CoV-2/COVID-19 Research Task Force and led by experts in those areas (eg, clinical trials, data science, artificial intelligence, pediatrics, and community-engaged research) (Figure)•Steering groups at each major site (Arizona, Florida, Rochester, Mayo Clinic Health System) to ensure that site-specific needs were met and that opportunities for research can be quickly shared from one campus to another•An overall culture of trust, autonomy, rapid communication, and nearly immediate access to thought leaders and scientific experts As the task force was launching and establishing its structure, the urgency was underscored by the sheer magnitude of patient lives at stake. At the time of task force development, no current COVID-19 treatments were shown to improve health and save lives; therefore, activating interventional trials became a top priority. The SARS-CoV-2/COVID-19 Research Task Force examined the safety and efficacy of very strategically selected experimental therapies that were not yet approved by the US Food and Drug Administration (FDA). Hundreds of clinical trials related to COVID-19 are registered on ClinicalTrials.gov from a broad range of subject areas, for example, basic science investigating the immunology and virology of SARS-CoV-2, early vaccine development, registries, health disparities research, epidemiologic studies, chemoprophylaxis, and numerous treatment trials. The investigational treatments span a spectrum of existing antiviral agents, antimicrobial agents, convalescent plasma, and immune-modulatory and cellular therapies. Within this landscape, Mayo Clinic took a specific, values-driven, scientific approach to therapies included in their investigational portfolio. The therapies needed to show an acceptable human safety profile; biologic plausibility; in vitro anti–SARS-CoV-2 activity, where appropriate; a sufficient, secure drug supply that was compliant with FDA Good Manufacturing Practice; a funding source that covered costs; and an investigational new drug approval from the FDA. In addition to the scientific rigor invoked during this crisis, Mayo Clinic called upon its rich heritage of values-driven care and teamwork to support the needs of patients. This culture spans all Mayo Clinic locations and all three shields: practice, research, and education. Key experienced clinical investigators serve as leads for the practice at each Mayo Clinic campus. The clinical leaders provide support for the practice shield with guidance on off-label drug use and available trials. The education shield ensured that trainees rotated through the inpatient COVID-19 clinical services in a virtual manner, which minimized their contact with infected patients while giving them unique experiences in the operation of clinical trials and in treating COVID-19 patients as discoveries were unfolding. The physician leaders served the research shield by reviewing all research proposals, with a sharp focus on evaluating clinical interventional trials to determine appropriateness for Mayo Clinic. Clinical trials that were applicable across Mayo Clinic's diverse geographic sites were sought, and trials with the highest scientific merit and feasibility were prioritized for review by the Mayo Clinic Institutional Review Board. Trials that were of lesser merit, duplicative, or otherwise inappropriate for Mayo Clinic were not pursued. Management of the COVID-19 research portfolio at sites outside of Rochester required some flexibility in tailoring trials to different populations and differences in regional practice and disease incidence. After the treatment trials began, Mayo Clinic initiated a new process to evaluate hospitalized patients real-time for eligibility in one or more clinical trials, which was a departure from the normal process of clinical trial enrollment. We created the approach, which is consensus-driven, because we recognized that, at the onset, no one had experience in treating COVID-19. Therefore, a consensus-driven approach would maximize the equipoise around treatment recommendations. Treatment review teams evaluated each hospitalized patient once or twice daily to determine trial eligibility, decide on appropriateness of the treatment, recommend investigative therapies, and monitor outcomes. Recommendations were shared and discussed with primary treating physicians and a decision was made regarding if and when a drug trial would be offered to each patient. This model allowed a small group to gain experience in treating and managing COVID-19, which was leveraged for the benefit of subsequent patients. As with any new process, challenges were encountered and lessons were learned. Therapeutics showed the most promise early on, and we aligned trials to sites based on drug availability and patient need, then mobilized operational teams to create accelerated pathways to approval. Research leaders identified staff with deep expertise in clinical trials to serve as project managers along with a dedicated team to shepherd clinical trials through the regulatory and approval processes. The team spanned Code & Coverage Analysis, the Office of Sponsored Projects Administration, Legal Contract Administration, Office of Research Regulatory Support, Office of Research Finance, and the Mayo Clinic Institutional Review Board, as well as important ancillary services such as research pharmacy, biospecimen accessioning and processing, budgets and contracts, and data collection. Bidirectional communication channels were created, reviewed, and iteratively improved to maintain information flow among principal investigators for the individual trials, the treatment review group, and the treating physicians. The treatment review teams, described above in Patient Selection, are an example of this type of bidirectional communication. Besides team evaluations and recommendations, patients and providers have opportunities to ask for clarifications or updates, and during hospitalization, the patient's course is monitored and discussed daily with the primary care teams. This approach has enabled timely and transparent discussions to address any trial-related issues, ultimately for the betterment of patient care. With a rich history and breadth of research excellence, Mayo Clinic was well positioned to respond to the COVID-19 pandemic and leveraged its deep resources across multiple disciplines to create an effective, efficient SARS-CoV-2/COVID-19 Research Task Force that spanned all research domains and all Mayo Clinic sites.
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In the American biographical crime film Catch Me If You Can, FBI agent Carl Hanratty goes all out to catch the notorious impostor and cheque counterfeiter Frank Abagnale Jr. Hanratty's dogged pursuit of the culprit bears striking resemblance to current COVID-19 research efforts to find evidence of changes that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection might leave in the brain. In The Lancet Neurology, Jakob Matschke and colleagues1Matschke J Lütgehetmann M Hagel C et al.Neuropathology of patients with COVID-19 in Germany: a post-mortem case series.Lancet Neurol. 2020; (published online Oct 5.)https://doi.org/10.1016/S1474-4422(20)30308-2Summary Full Text Full Text PDF PubMed Scopus (849) Google Scholar give a detailed account of the histological alterations related to COVID-19 in the CNS. Through meticulous detective work, they mapped the brain's immunoinflammatory response to viral infection and detected SARS-CoV-2 protein expression in a substantial percentage of autoptic brains of patients with COVID-19. Matschke and colleagues analysed 43 brains from a large cohort of patients who died with COVID-19,2Edler C Schröder AS Aepfelbacher M et al.Dying with SARS-CoV-2 infection—an autopsy study of the first consecutive 80 cases in Hamburg, Germany.Int J Legal Med. 2020; 134: 1275-1284Crossref PubMed Scopus (329) Google Scholar focusing on inflammatory changes and detection of SARS-CoV-2. To find out which CNS cell types are prone to SARS-CoV-2 infection, the authors screened gene expression datasets for signatures related to viral entry and persistence. Their in-silico analysis showed high expression of angiotensin-converting enzyme 2 (ACE2) in oligodendrocytes and of transmembrane serine proteases 2 and 4 (TMPRSS2 and TMPRSS4) in neurons—genes that code for proteins crucially implicated in SARS-CoV-2 host-cell entry (ACE2) and proteolytic priming of the virus-decorating spikes (TMPRSS2).3Hoffmann M Kleine-Weber H Schroeder S et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280Summary Full Text Full Text PDF PubMed Scopus (13431) Google Scholar Interestingly, a study using human brain organoids, published in September, 2020,4Ramani A Müller L Ostermann PN et al.SARS-CoV-2 targets neurons of 3D human brain organoids.EMBO J. 2020; (published online Sept 2.)DOI: 10.15252/embj.2020106230Crossref PubMed Scopus (330) Google Scholar showed that SARS-CoV-2 can readily infect and kill neurons. The neuronal cell death upon viral infection was preceded by aberrant intraneuronal localisation and hyperphosphorylation of Tau protein,4Ramani A Müller L Ostermann PN et al.SARS-CoV-2 targets neurons of 3D human brain organoids.EMBO J. 2020; (published online Sept 2.)DOI: 10.15252/embj.2020106230Crossref PubMed Scopus (330) Google Scholar similar to the pathogenesis of Alzheimer's disease and other neurodegenerative diseases. Matschke and colleagues used quantitative RT-PCR (qRT-PCR) and immunohistochemistry with antibodies against nucleocapsid and spike proteins to detect SARS-CoV-2. Whereas viral RNA was detected in 48% of cases, viral protein detection was positive in 40%. Overall, the authors found SARS-CoV-2, either viral RNA or viral protein (or both), in 51% of the brains investigated. Remarkably, SARS-CoV-2 presence did not correlate with the severity of neuropathological alterations. While the replicative and infective potential of the viral RNA remains unclear, the in-situ detection of SARS-CoV-2 proteins is an important finding, as it confirms the presence of the virus in the brain. In this context, concerns5Deigendesch N Sironi L Kutza M et al.Correlates of critical illness-related encephalopathy predominate postmortem COVID-19 neuropathology.Acta Neuropathol. 2020; 140: 583-586Crossref PubMed Scopus (102) Google Scholar, 6Solomon IH Normandin E Bhattacharyya S et al.Neuropathological features of COVID-19.N Engl J Med. 2020; 383: 989-992Crossref PubMed Scopus (595) Google Scholar that the comparably low viral genome levels detectable by qRT-PCR in brain tissue might be blood-derived deserve mention. Of note, the authors found virus protein expression to be confined to the medulla oblongata and to cranial nerves originating from the lower brainstem (most likely glossopharyngeal or vagal nerve). Considering the capability of SARS-CoV-2 to infect human gut enterocytes as well as pneumocytes,7Lamers MM Beumer J van der Vaart J et al.SARS-CoV-2 productively infects human gut enterocytes.Science. 2020; 369: 50-54Crossref PubMed Scopus (1159) Google Scholar, 8Schaefer IM Padera RF Solomon IH et al.In situ detection of SARS-CoV-2 in lungs and airways of patients with COVID-19.Mod Pathol. 2020; (published online June 19.)https://doi.org/10.1038/s41379-020-0595-zCrossref Scopus (218) Google Scholar this finding is of particular interest, warranting future investigations of vagal nerve tissue as a potential viral CNS access route in COVID-19. The study also identified pronounced, brainstem-accentuated microglia activation, confirming previous work.5Deigendesch N Sironi L Kutza M et al.Correlates of critical illness-related encephalopathy predominate postmortem COVID-19 neuropathology.Acta Neuropathol. 2020; 140: 583-586Crossref PubMed Scopus (102) Google Scholar As these brain-resident macrophage-like innate immune cells are highly heterogeneous with regard to gene expression, regional abundance, and perhaps functions,9Masuda T Sankowski R Staszewski O Prinz M Microglia Heterogeneity in the Single-Cell Era.Cell Rep. 2020; 30: 1271-1281Summary Full Text Full Text PDF PubMed Scopus (365) Google Scholar it seems worth testing whether microglia activated in a COVID-19 context correspond to a specific subtype,10Böttcher C Schlickeiser S Sneeboer MAM et al.Human microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometry.Nat Neurosci. 2019; 22: 78-90Crossref PubMed Scopus (258) Google Scholar expressing sets of genes reflective of particular functional states. Given the complex pathophysiology of COVID-19, any autopsy study is bound to have limitations (varying post-mortem intervals, incomplete or lacking clinical data, etc) and the present study is no exception in that regard. Confounding factors, such as the multiple comorbidities present among older patients with COVID-19 and, equally important, common COVID-19 treatment modalities, such as invasive ventilation (which might promote cerebral microbleeds) or dexamethasone medication (known to modulate immune responses), have to be considered when interpreting neuropathological findings. In the context of dexamethasone, it is unfortunate that no data on steroid medication were used to investigate correlations between some of the findings. Likewise, in the absence of appropriate control cohorts, it remains unclear to what extent microglia activation and brain infiltration by cytotoxic T-lymphocytes represent COVID-19-specific findings. Both sparse lymphocytic infiltrates and microglia activation were recently documented in the brains of individuals without COVID-19, and they appeared to be particularly pronounced in septic cases.5Deigendesch N Sironi L Kutza M et al.Correlates of critical illness-related encephalopathy predominate postmortem COVID-19 neuropathology.Acta Neuropathol. 2020; 140: 583-586Crossref PubMed Scopus (102) Google Scholar At a time when a potential second wave of infections is increasingly becoming of global concern, the question of whether the neuropathological alterations in COVID-19 directly result from SARS-CoV-2 brain infection as opposed to reflecting sequelae of an overstimulated systemic immune response is of high clinical importance. Whereas the first scenario would support the use of remdesevir or other antivirals, anti-inflammatory modalities appear to be the treatment of choice once damaging immunoinflammatory mechanisms take over. Teasing apart these fundamentally different scenarios is an ongoing task for neuropathology experts. The work by Matschke and colleagues1Matschke J Lütgehetmann M Hagel C et al.Neuropathology of patients with COVID-19 in Germany: a post-mortem case series.Lancet Neurol. 2020; (published online Oct 5.)https://doi.org/10.1016/S1474-4422(20)30308-2Summary Full Text Full Text PDF PubMed Scopus (849) Google Scholar represents an important step towards navigating the complex pathophysiology of COVID-19 in the brain. Just like agent Hanratty, the authors have done a superb job closing in on the culprit. SF reports grants from the Botnar Research Centre for Child Health. Neuropathology of patients with COVID-19 in Germany: a post-mortem case seriesIn general, neuropathological changes in patients with COVID-19 seem to be mild, with pronounced neuroinflammatory changes in the brainstem being the most common finding. There was no evidence for CNS damage directly caused by SARS-CoV-2. The generalisability of these findings needs to be validated in future studies as the number of cases and availability of clinical data were low and no age-matched and sex-matched controls were included. Full-Text PDF
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Although SARS-CoV-2 may primarily enter the cells of the lungs, the small bowel may also be an important entry or interaction site, as the enterocytes are rich in angiotensin converting enzyme (ACE)-2 receptors. The initial gastrointestinal symptoms that appear early during the course of Covid-19 support this hypothesis. Furthermore, SARS-CoV virions are preferentially released apically and not at the basement of the airway cells. Thus, in the setting of a productive infection of conducting airway epithelia, the apically released SARS-CoV may be removed by mucociliary clearance and gain access to the GI tract via a luminal exposure. In addition, post-mortem studies of mice infected by SARS-CoV have demonstrated diffuse damage to the GI tract, with the small bowel showing signs of enterocyte desquamation, edema, small vessel dilation and lymphocyte infiltration, as well as mesenteric nodes with severe hemorrhage and necrosis. Finally, the small bowel is rich in furin, a serine protease which can separate the S-spike of the coronavirus into two "pinchers" (S1 and 2). The separation of the S-spike into S1 and S2 is essential for the attachment of the virion to both the ACE receptor and the cell membrane. In this special review, we describe the interaction of SARS-CoV-2 with the cell and enterocyte and its potential clinical implications.
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