Host range and structural analysis of bat-origin RshSTT182/200 coronavirus binding to human ACE2 and its animal orthologs.

Bat-origin RshSTT182 and RshSTT200 coronaviruses (CoV) from Rhinolophus shameli in Southeast Asia (Cambodia) share 92.6% whole-genome identity with SARS-CoV-2 and show identical receptor-binding domains (RBDs). In this study, we determined the structure of the RshSTT182/200 receptor binding domain (RBD) in complex with human angiotensin-converting enzyme 2 (hACE2) and identified the key residues that influence receptor binding. The binding of the RshSTT182/200 RBD to ACE2 orthologs from 39 animal species, including 18 bat species, was used to evaluate its host range. The RshSTT182/200 RBD broadly recognized 21 of 39 ACE2 orthologs, although its binding affinities for the orthologs were weaker than those of the RBD of SARS-CoV-2. Furthermore, RshSTT182 pseudovirus could utilize human, fox, and Rhinolophus affinis ACE2 receptors for cell entry. Moreover, we found that SARS-CoV-2 induces cross-neutralizing antibodies against RshSTT182 pseudovirus. Taken together, these findings indicate that RshSTT182/200 can potentially infect susceptible animals, but requires further evolution to obtain strong interspecies transmission abilities like SARS-CoV-2.

A comparative review of pathogenesis and host innate immunity evasion strategies among the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV).

COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has put the global public health at its highest threat around the world. Previous epidemic caused by the acute respiratory syndrome coronavirus (SARS-CoV) in 2002 is also considered since both the coronaviruses resulted in the similar clinical complications. The outbreak caused by the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 had a low rate of disease transmission and death cases. Modes of entry by MERS and SARS coronaviruses are similar to that of SARS-CoV-2, except MERS-CoV utilize different receptor. They all belong to the lineage C of ß-coronavirus. Based on the information from the previous reports, the present review is mainly focused on the mechanisms of disease progression by each of these viruses in association to their strategies to escape the host immunity. The viral entry is the first step of pathogenesis associated with attachment of viral spike protein with host receptor help releasing the viral RNA into the host cell. Models of molecular pathogenesis are outlined with virus strategies escaping the host immunity along with the role of various inflammatory cytokines and chemokines in the process. The molecular aspects of pathogenesis have also been discussed.

Mechanisms of Coronavirus Nsp1-Mediated Control of Host and Viral Gene Expression.

Many viruses disrupt host gene expression by degrading host mRNAs and/or manipulating translation activities to create a cellular environment favorable for viral replication. Often, virus-induced suppression of host gene expression, including those involved in antiviral responses, contributes to viral pathogenicity. Accordingly, clarifying the mechanisms of virus-induced disruption of host gene expression is important for understanding virus-host cell interactions and virus pathogenesis. Three highly pathogenic human coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2, have emerged in the past two decades. All of them encode nonstructural protein 1 (nsp1) in their genomes. Nsp1 of SARS-CoV and MERS-CoV exhibit common biological functions for inducing endonucleolytic cleavage of host mRNAs and inhibition of host translation, while viral mRNAs evade the nsp1-induced mRNA cleavage. SARS-CoV nsp1 is a major pathogenic determinant for this virus, supporting the notion that a viral protein that suppresses host gene expression can be a virulence factor, and further suggesting the possibility that SARS-CoV-2 nsp1, which has high amino acid identity with SARS-CoV nsp1, may serve as a major virulence factor. This review summarizes the gene expression suppression functions of nsp1 of CoVs, with a primary focus on SARS-CoV nsp1 and MERS-CoV nsp1.

La COVID-19: comunicado conjunto sobre el nuevo coronavirus y los perros y gatos / COVID-19. Joint statement on the new coronavirus and cats and dogs

El Centro Panamericano de Fiebre Aftosa y Salud Pública Veterinaria de la Organización Panamericana de la Salud / Organización Mundial de la Salud (PANAFTOSA-OPS/OMS) y la Protección Animal Mundial (PAM) comunican al público en general los aspectos referentes al COVID-19 y la relación con las mascotas (perros y gatos).

Genotype and phenotype of COVID-19: Their roles in pathogenesis.

COVID-19 is a novel coronavirus with an outbreak of unusual viral pneumonia in Wuhan, China, and then pandemic. Based on its phylogenetic relationships and genomic structures the COVID-19 belongs to genera Betacoronavirus. Human Betacoronaviruses (SARS-CoV-2, SARS-CoV, and MERS-CoV) have many similarities, but also have differences in their genomic and phenotypic structure that can influence their pathogenesis. COVID-19 is containing single-stranded (positive-sense) RNA associated with a nucleoprotein within a capsid comprised of matrix protein. A typical CoV contains at least six ORFs in its genome. All the structural and accessory proteins are translated from the sgRNAs of CoVs. Four main structural proteins are encoded by ORFs 10, 11 on the one-third of the genome near the 3'-terminus. The genetic and phenotypic structure of COVID-19 in pathogenesis is important. This article highlights the most important of these features compared to other Betacoronaviruses.

Competências e regras / Coleção COVID-19 / Skills and rules / COVID-19 Collection

No Brasil, as competências e regras a que se submetem os entes federados e as diferentes instituições afetas ao direito à saúde, conformaram-se no conteúdo desse livro. As Comissões Intergestores do SUS, o Congresso Nacional e o Tribunal de Contas da União (TCU), os conselhos nacionais de Justiça (CNJ) e do Ministério Público (CNMP), agências reguladoras (Anvisa) e o Conselho Nacional de Saúde (CNS) exararam manifestações por estratégias e instrumentação diversa, descritas e analisadas. As estratégias de saúde digital e da comunicação em saúde estiveram sob avaliação, assim como o desempenho do Conass e das Secretarias Estaduais de Saúde (SES), em especial no quesito transparência das informações. Ainda nessa seara, os textos aqui compilados trouxeram ao debate questões relacionadas às transferências de recursos federais aos cofres estaduais, às requisições administrativas e aos dilemas que circundam o âmbito fiscal do SUS. Numa tentativa de agrupar os principais comandos, estão apresentados o rol de leis e atos administrativos, a normativa regulatória sanitária e a interpretação do poder judiciário acerca da legislação, especialmente sob o crivo da responsabilização dos gestores públicos. Quando iniciada a organização da Coleção COVID-19, a principal expectativa era que a disponibilização de seu conteúdo ocorresse num cenário em que as medidas de prevenção, controle e até mesmo mitigação tivessem apresentado as melhores respostas, no Brasil e no mundo. Mas, o recrudescimento do número de infectados e dos óbitos já é um fato. Novas medidas, não farmacológicas, dessa vez acompanhadas das campanhas de vacinação em vários países, já são realidade no âmbito dos territórios. Portanto, o tempo permitirá perceber outros tantos comandos normativos afetos à saúde pública no Brasil e no mundo, o que requererá atenção do leitor quanto à necessidade de pesquisa e atualização. Conforme já asseverado, os textos revelam as opiniões de seus autores, ainda que porventura divirjam das posições do Conass. Que os diferentes posicionamentos compilados no Volume 3 ­ Competências e Regras ­ sejam capazes de denotar limites e potencialidades para a gestão, bem como possam contribuir com aprendizados para o futuro!

Reflexões e futuro / Coleção COVID-19 / Reflections and future / COVID-19 Collection

A partir dos desafios para a efetivação do direito à saúde, o Volume 6 ­ Reflexões e Futuro ­ apresenta debates relacionados às questões ambientais, urbanas, das relações humano-natureza, das arboviroses ­ que juntos contribuem para a análise da conformação do futuro pós-pandemia. Nessa esteira seguem análises relacionadas à saúde pública, à sociedade brasileira, à infoestrutura como apoio às decisões estratégicas e a avaliação, como dispositivo potente para a gestão. Ainda em sede de desafios, o livro aborda a Vigilância Sanitária como elemento primordial para o enfrentamento das emergências em saúde pública e nesse escopo se insere o Programa Nacional de Imunizações (PNI), do Brasil. À títulos comparativos, há narrativas acerca do enfrentamento da pandemia nos países de língua portuguesa, especialmente Portugal, bem como no Canadá e no Quebec possibilitando aprendizados com as experiências de outros sistemas universais. A abordagem acerca das políticas governamentais de compras públicas, da imagem do SUS nos contextos, nas narrativas e para as pessoas são encerradas com reflexões sobre a cobertura sanitária enquanto valor e a reforma sanitária brasileira como necessidade atual. Ainda que esse levante editorial se encerre, por ora, no volume 6 da Coleção COVID-19, a pandemia continua e outros tantos elementos poderão ser percebidos, contextualizados e merecerão registro. O Conass envida agradecimentos aos que estiveram empenhados em registrar seus diferentes campos de observação: gestores, auditores, ministros, médicos, pesquisadores, farmacêuticos, cientistas sociais, juízes, antropólogos, promotores, advogados, cientistas de dados, administradores, professores, comunicadores e todos que contribuíram com a análise e possíveis aperfeiçoamentos da gestão estadual do SUS no enfrentamento das emergências sanitárias.

Los Aerosoles Dentales a Propósito de la Pandemia por COVID-19 / Dental Aerosols in the Context of COVID-19 Pandemic

RESUMEN: La pandemia por COVID-19 ha hecho que la atención odontológica de rutina se suspenda. La causa principal es el pobre control del aerosol en la consulta dental. Los aerosoles liberados por el instrumental odontológico son esenciales para la remoción de los tejidos bucales enfermos. Sin embargo, al mezclarse con saliva o sangre contaminada, los aerosoles pueden diseminar microorganismos infectivos fuera de la boca del paciente. Existe evidencia de que el SARS-CoV-2 se encuentra en la saliva del 91,7 % de los sujetos enfermos. Este artículo presenta evidencias y reflexiones para el control del aerosol odontológico, las que podrían permitir aumentar la seguridad del ejercicio de la odontología durante la pandemia y pospandemia.

ABSTRACT: The COVID-19 pandemic has caused routine dental check-ups to be cancelled. The main cause is poor aerosol control in the dental office. Aerosols released by dental instruments are essential for the removal of diseased oral tissues. However, when mixed with saliva or contaminated blood, aerosols can spread infectious microorganisms out of the patient's mouth. In addition, SARS-CoV-2 has been detected in the self-collected saliva of 91.7 % of patients. This article presents evidence and reflections for the control of dental aerosol, which could allow increasing the safety of dental practice during the pandemic and post-pandemic.

COVID-19: the trends of conspiracy theories vs facts.

Coronavirus disease (COVID-19) caused by SARS-CoV-2-a new single-stranded RNA virus with respiratory system proclivity and epithelial cell- is a novel infectious disease that originated in Wuhan, China in December, 2019 and has spread to many countries with the total number of confirmed cases put at 20,259,579 cases as of 12th August, 2020. It is transmitted from human-to-human via droplets. When an infected person coughs or sneezes, these droplets find their way into the mouth or nostrils of another person that is within a close range. Alternatively it can be contracted by touching infected hard surfaces and using the same hands to touch the mouth, nose and eye(s). COVID-19 has been declared a global pandemic by the World Health Organization (WHO) on 11th March, 2020. There is currently no therapeutic substance accepted as a panacea for the prophylaxis of this infectious disease. As a result of this back drop, many nations have instituted fourteen (14) days quarantine for suspected cases, social distancing and border closure in an attempt to curb the spread of COVID-19. There has been several conspirary theories that emanated since the disease was declared a pandemic. This paper provides useful information to serve as reference to those who seek proper understanding of COVID-19 and its deleterious effects in the body, by distiguishing between the factsand the conspiracy theoriesof coronavirus disease.

Acute Guillain-Barré polyradiculoneuritis indicative of COVID-19 infection: a case report.

The new coronavirus 2019 epidemic declared in China on December 31, 2019 soon spread to the rest of the world, becoming the subject of an unprecedented health pandemic according to the World Health Organization's declaration of March 11, 2020. It is a disease that has the potential to cause multiple systemic infections. We report here the case of an acute polyradiculoneuritis of the Guillain-Barré type (GBS) indicative of a COVID-19 infection. This is a 41 year old patient seen for ascending, symmetrical and bilateral, progressive and acute tetraparesis with in a context of influenza syndrome and digestive infections treated 2 weeks earlier. During a COVID-19 infection, certain inflammatory cells stimulated by the virus produce inflammatory cytokines creating immune-mediated processes. The same mechanism is observed in GBS being also an immune-mediated disorder. The management of this disease in COVID-19 positive patients does not differ from that of patients who do not carry the virus. The risk of respiratory distress in COVID-19 positive patients becomes twice as great in patients with GBS who test positive for COVID-19 at the same time. Monitoring for hemodynamic disorders and respiratory distress in a neuro-intensive care unit may be fruitful.

Conserved Genomic Terminals of SARS-CoV-2 as Coevolving Functional Elements and Potential Therapeutic Targets.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 40 million people worldwide, with over 1 million deaths as of October 2020 and with multiple efforts in the development and testing of antiviral drugs and vaccines under way. In order to gain insights into SARS-CoV-2 evolution and drug targets, we investigated how and to what extent the SARS-CoV-2 genome sequence differs from those of other well-characterized human and animal coronavirus genomes, as well as how polymorphic SARS-CoV-2 genomes are generally. We ultimately sought to identify features in the SARS-CoV-2 genome that may contribute to its viral replication, host pathogenicity, and vulnerabilities. Our analyses suggest the presence of unique sequence signatures in the 3' untranslated region (3'-UTR) of betacoronavirus lineage B, which phylogenetically encompasses SARS-CoV-2 and SARS-CoV as well as multiple groups of bat and animal coronaviruses. In addition, we identified genome-wide patterns of variation across different SARS-CoV-2 strains that likely reflect the effects of selection. Finally, we provide evidence for a possible host-microRNA-mediated interaction between the 3'-UTR and human microRNA hsa-miR-1307-3p based on the results of multiple computational target prediction analyses and an assessment of similar interactions involving the influenza A H1N1 virus. This interaction also suggests a possible survival mechanism, whereby a mutation in the SARS-CoV-2 3'-UTR leads to a weakened host immune response. The potential roles of host microRNAs in SARS-CoV-2 replication and infection and the exploitation of conserved features in the 3'-UTR as therapeutic targets warrant further investigation.IMPORTANCE The coronavirus disease 2019 (COVID-19) outbreak is having a dramatic global effect on public health and the economy. As of October 2020, SARS-CoV-2 has been detected in over 189 countries, has infected over 40 million people, and is responsible for more than 1 million deaths. The genome of SARS-CoV-2 is small but complex, and its functions and interactions with human host factors are being studied extensively. The significance of our study is that, using extensive SARS-CoV-2 genome analysis techniques, we identified potential interacting human host microRNA targets that share similarity with those of influenza A virus H1N1. Our study results will allow the development of virus-host interaction models that will enhance our understanding of SARS-CoV-2 pathogenesis and motivate the exploitation of both the interacting viral and host factors as therapeutic targets.

Correcting the imbalanced protective RAS in COVID-19 with angiotensin AT2-receptor agonists.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is responsible for the global corona virus disease 2019 (COVID-19) pandemic enters host cells via a mechanism that includes binding to angiotensin converting enzyme (ACE) 2 (ACE2). Membrane-bound ACE2 is depleted as a result of this entry mechanism. The consequence is that the protective renin-angiotensin system (RAS), of which ACE2 is an essential component, is compromised through lack of production of the protective peptides angiotensin-(1-7) and angiotensin-(1-9), and therefore decreased stimulation of Mas (receptor Mas) and angiotensin AT2-receptors (AT2Rs), while angiotensin AT1-receptors (AT1Rs) are overstimulated due to less degradation of angiotensin II (Ang II) by ACE2. The protective RAS has numerous beneficial actions, including anti-inflammatory, anti-coagulative, anti-fibrotic effects along with endothelial and neural protection; opposite to the deleterious effects caused by heightened stimulation of angiotensin AT1R. Given that patients with severe COVID-19 exhibit an excessive immune response, endothelial dysfunction, increased clotting, thromboses and stroke, enhancing the activity of the protective RAS is likely beneficial. In this article, we discuss the evidence for a dysfunctional protective RAS in COVID and develop a rationale that the protective RAS imbalance in COVID-19 may be corrected by using AT2R agonists. We further review preclinical studies with AT2R agonists which suggest that AT2R stimulation may be therapeutically effective to treat COVID-19-induced disorders of various organ systems such as lung, vasculature, or the brain. Finally, we provide information on the design of a clinical trial in which patients with COVID-19 were treated with the AT2R agonist Compound 21 (C21). This trial has been completed, but results have not yet been reported.

Clinical characteristics and longitudinal chest CT features of healthcare workers hospitalized with coronavirus disease 2019 (COVID-19).

Rationale: The clinical data and corresponding dynamic CT findings were investigated in detail to describe the clinical and imaging profiles of COVID-19 pneumonia disease progression. Methods: Forty HCWs with COVID-19 were included in this study and 30 enrolled for imaging assessment. Disease was divided into four stages based on time from onset: stage 1 (1-6 days), stage 2 (7-13 days), stage 3 (14-22 days), and stage 4 (> 22 days). Clinical wand imaging data were analyzed retrospectively. Results: The cohort included 33 female and 7 male cases, with a median age of 40 years. Six had underlying comorbidities. More than half of the cases were nurses (22, 55%). Each stage included 39, 37, 34 and 32 CTs, respectively. Bilateral lesions, multifocal lesions and lesions with GGO pattern occurred in both lower lobes at all stages. The crazy-paving pattern (20, 54%), air bronchogram (13, 35%), and pleural effusion (2, 5%) were the most common CT features in stage 2. Consolidation score peaked in stage 2 whereas total lesions score peaked in stage 3. Conclusions: COVID-19 pneumonia in HCWs has a potential predilection for younger female workers. Stage 2 of COVID-19 pneumonia may be the key period for controlling progression of the disease, and consolidation scores may be an objective reflection of the severity of lung involvement.

Temporal changes of CT findings between non-severe and severe cases of COVID-19 pneumonia: a multi-center, retrospective, longitudinal Study.

Background and aim: To perform a longitudinal analysis of serial CT findings over time in patients with COVID-19 pneumonia. Methods: From February 5 to March 8, 2020, 73 patients (male to female, ratio of 43:30; mean age, 51 years) with COVID-19 pneumonia were retrospectively enrolled and followed up until discharge from three institutions in China. The patients were divided into the severe and non-severe groups according to treatment option. The patterns and distribution of lung abnormalities, total CT scores, single ground-glass opacity (GGO) CT scores, single consolidation CT scores, single reticular CT scores and the amounts of zones involved were reviewed by 2 radiologists. These features were analyzed for temporal changes. Results: In non-severe group, total CT scores (median, 9.5) and the amounts of zones involved were slowly increased and peaked in disease week 2. In the severe group, the increase was faster, with scores also peaking at 2 weeks (median, 20). In both groups, the later parameters began to decrease in week 4 (median values of 9 and 19 in the non-severe and severe groups, respectively). In the severe group, the dominant residual lung lesions were reticular (median single reticular CT score, 10) and consolidation (median single consolidation CT score, 7). In the non-severe group, the dominant residual lung lesions were GGO (median single GGO CT score, 7) and reticular (median single reticular CT score, 4). In both non-severe and severe groups, the GGO pattern was dominant in week 1, with a higher proportion in the severe group compared with the non-severe group (72% vs. 65%). The consolidation pattern peaked in week 2, with 9 (32%) and 19 (73%) in the non-severe and severe groups, respectively; the reticular pattern became dominant from week 4 (both group >40%). Conclusion: The extent of CT abnormalities in the severe and non-severe groups peaked in disease week 2. The temporal changes of CT manifestations followed a specific pattern, which might indicate disease progression and recovery.

Classical Drug Digitoxin Inhibits Influenza Cytokine Storm, With Implications for Covid-19 Therapy.

BACKGROUND/AIM: Influenza viruses, corona viruses and related pneumotropic viruses cause sickness and death partly by inducing cytokine storm, a hyper-proinflammatory host response by immune cells and cytokines in the host airway. Based on our in vivo experience with digitoxin as an inhibitor of TNFα-driven NFĸB signaling for cytokine expression in prostate cancer in rats and in cystic fibrosis in humans, we hypothesize that this drug will also block a virally-activated cytokine storm. Materials Methods: Digitoxin was administered intraperitoneally to cotton rats, followed by intranasal infection with 107TCID50/100 g of cotton rat with influenza strain A/Wuhan/H3N2/359/95. Daily digitoxin treatment continued until harvest on day 4 of the experiment. RESULTS: The cardiac glycoside digitoxin significantly and differentially suppressed levels of the cytokines TNFα, GRO/KC, MIP2, MCP1, and IFNγ, in the cotton rat lung in the presence of influenza virus. CONCLUSION: Since cytokine storm is a host response, we suggest that digitoxin may have a therapeutic potential not only for influenza and but also for coronavirus infections.

Radiotherapy in the COVID-19 Pandemic Era.

BACKGROUND/AIM: In 2020, because of coronavirus pandemic, medical activities changed. The aim of this report is to compare the volumes of Pisa radiotherapy activities from March 9th to May 31st, 2020, with the same period in 2019. PATIENTS AND METHODS: We analyzed the activity of our Unit to evaluate how logistics changes, related to the COVID-19 epidemic, impacted on volumes of radiotherapy (RT) activity and on the number of cases of COVID-19 infections observed in healthcare professionals and patients. RESULTS: The total number of first-time visits between March-May 2020 was reduced by 18%, probably due to delays in diagnosis and histological tests as well as the temporary closure of the operating rooms. None of the healthcare professionals and only two patients contracted the infection. CONCLUSION: We were able to treat all patients referred to our hospital and we were able to reduce risk of infection for both our patients and healthcare staff, guaranteeing continuum of care for our oncological patients.