Limited Recognition of Highly Conserved Regions of SARS-CoV-2.

Understanding the immune response to severe acute respiratory syndrome coronavirus (SARS-CoV-2) is critical to overcome the current coronavirus disease (COVID-19) pandemic. Efforts are being made to understand the potential cross-protective immunity of memory T cells, induced by prior encounters with seasonal coronaviruses, in providing protection against severe COVID-19. In this study we assessed T-cell responses directed against highly conserved regions of SARS-CoV-2. Epitope mapping revealed 16 CD8+ T-cell epitopes across the nucleocapsid (N), spike (S), and open reading frame (ORF)3a proteins of SARS-CoV-2 and five CD8+ T-cell epitopes encoded within the highly conserved regions of the ORF1ab polyprotein of SARS-CoV-2. Comparative sequence analysis showed high conservation of SARS-CoV-2 ORF1ab T-cell epitopes in seasonal coronaviruses. Paradoxically, the immune responses directed against the conserved ORF1ab epitopes were infrequent and subdominant in both convalescent and unexposed participants. This subdominant immune response was consistent with a low abundance of ORF1ab encoded proteins in SARS-CoV-2 infected cells. Overall, these observations suggest that while cross-reactive CD8+ T cells likely exist in unexposed individuals, they are not common and therefore are unlikely to play a significant role in providing broad preexisting immunity in the community. IMPORTANCE T cells play a critical role in protection against SARS-CoV-2. Despite being highly topical, the protective role of preexisting memory CD8+ T cells, induced by prior exposure to circulating common coronavirus strains, remains less clear. In this study, we established a robust approach to specifically assess T cell responses to highly conserved regions within SARS-CoV-2. Consistent with recent observations we demonstrate that recognition of these highly conserved regions is associated with an increased likelihood of milder disease. However, extending these observations we observed that recognition of these conserved regions is rare in both exposed and unexposed volunteers, which we believe is associated with the low abundance of these proteins in SARS-CoV-2 infected cells. These observations have important implications for the likely role preexisting immunity plays in controlling severe disease, further emphasizing the importance of vaccination to generate the immunodominant T cells required for immune protection.

Selection and T-cell antigenicity of synthetic long peptides derived from SARS-CoV-2.

The pandemic caused by SARS-CoV-2 has led to the successful development of effective vaccines however the prospect of variants of SARS-CoV-2 and future coronavirus outbreaks necessitates the investigation of other vaccine strategies capable of broadening vaccine mediated T-cell responses and potentially providing cross-immunity. In this study the SARS-CoV-2 proteome was assessed for clusters of immunogenic epitopes restricted to diverse human leucocyte antigen. These regions were then assessed for their conservation amongst other coronaviruses representative of different alpha and beta coronavirus genera. Sixteen highly conserved peptides containing numerous HLA class I and II restricted epitopes were synthesized from these regions and assessed in vitro for their antigenicity against T-cells from individuals with previous SARS-CoV-2 infection. Monocyte derived dendritic cells were generated from these peripheral blood mononuclear cells (PBMC), loaded with SARS-CoV-2 peptides, and used to induce autologous CD4+ and CD8+ T cell activation. The SARS-CoV-2 peptides demonstrated antigenicity against the T-cells from individuals with previous SARS-CoV-2 infection indicating that this approach holds promise as a method to activate anti-SAR-CoV-2 T-cell responses from conserved regions of the virus which are not included in vaccines utilising the Spike protein.

Biology of COVID-19 and related viruses: Epidemiology, signs, symptoms, diagnosis, and treatment.

Coronaviruses belong to the family Coronaviridae order Nidovirales and are known causes of respiratory and intestinal disease in various mammalian and avian species. Species of coronaviruses known to infect humans are referred to as human coronaviruses (HCoVs). While traditionally, HCoVs have been a significant cause of the common cold, more recently, emergent viruses, including severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a global pandemic. Here, we discuss coronavirus disease (COVID-19) biology, pathology, epidemiology, signs and symptoms, diagnosis, treatment, and recent clinical trials involving promising treatments.

Pathogenesis of Coronaviruses Through Human Monocytes and Tissue Macrophages.

Coronaviruses (CoVs) contribute significantly to the burden of respiratory diseases, frequently as upper respiratory tract infections. Recent emergence of novel coronaviruses in the last few decades has highlighted the potential transmission, disease, and mortality related to these viruses. In this literature review, we shall explore the disease-causing mechanism of the virus through human monocytes and macrophages. Common strains will be discussed; however, this review will center around coronaviruses responsible for epidemics, namely severe acute respiratory syndrome coronavirus (SARS-CoV)-1 and -2 and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Macrophages are key players in the immune system and have been found to play a role in the pathogenesis of lethal coronaviruses. In physiology, they are white blood cells that engulf and digest cellular debris, foreign substances, and microbes. They play a critical role in innate immunity and help initiate adaptive immunity. Human coronaviruses utilize various mechanisms to undermine the innate immune response through its interaction with macrophages and monocytes. It is capable of entering immune cells through DPP4 (dipeptidyl-peptidase 4) receptors and antibody-dependent enhancement, delaying initial interferon response which supports robust viral replication. Pathogenesis includes triggering the production of overwhelming pro-inflammatory cytokines that attract other immune cells to the site of infection, which propagate prolonged pro-inflammatory response. The virus has also been found to suppress the release of anti-inflammatory mediators such as IL-10, leading to an aberrant inflammatory response. Elevated serum cytokines are also believed to contribute to pathological features seen in severe disease such as coagulopathy, acute lung injury, and multiorgan failure.

Epitope profiling reveals binding signatures of SARS-CoV-2 immune response in natural infection and cross-reactivity with endemic human CoVs.

A major goal of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine efforts is to elicit antibody responses that confer protection. Mapping the epitope targets of the SARS-CoV-2 antibody response is critical for vaccine design, diagnostics, and development of therapeutics. Here, we develop a pan-coronavirus phage display library to map antibody binding sites at high resolution within the complete viral proteomes of all known human-infecting coronaviruses in patients with mild or moderate/severe coronavirus disease 2019 (COVID-19). We find that the majority of immune responses to SARS-CoV-2 are targeted to the spike protein, nucleocapsid, and ORF1ab and include sites of mutation in current variants of concern. Some epitopes are identified in the majority of samples, while others are rare, and we find variation in the number of epitopes targeted between individuals. We find low levels of SARS-CoV-2 cross-reactivity in individuals with no exposure to the virus and significant cross-reactivity with endemic human coronaviruses (CoVs) in convalescent sera from patients with COVID-19.

CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope cross-react with selective seasonal coronaviruses.

Efforts are being made worldwide to understand the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, including the impact of T cell immunity and cross-recognition with seasonal coronaviruses. Screening of SARS-CoV-2 peptide pools revealed that the nucleocapsid (N) protein induced an immunodominant response in HLA-B7+ COVID-19-recovered individuals that was also detectable in unexposed donors. A single N-encoded epitope that was highly conserved across circulating coronaviruses drove this immunodominant response. In vitro peptide stimulation and crystal structure analyses revealed T cell-mediated cross-reactivity toward circulating OC43 and HKU-1 betacoronaviruses but not 229E or NL63 alphacoronaviruses because of different peptide conformations. T cell receptor (TCR) sequencing indicated that cross-reactivity was driven by private TCR repertoires with a bias for TRBV27 and a long CDR3ß loop. Our findings demonstrate the basis of selective T cell cross-reactivity for an immunodominant SARS-CoV-2 epitope and its homologs from seasonal coronaviruses, suggesting long-lasting protective immunity.

O impacto da covid - 19 na saúde de pessoas institucionalizadas / The impact of COVID-19 on the health of institutionalized persons / El impacto del COVID-19 em la salude de las personas institucionalizada

Introdução:A população idosa constitui um dos grupos mais vulneráveis à infecção pelo novo coronavírus. Tal fragilidade é ainda mais evidente naqueles que residem em Instituições para Idosos, por apresentar maior risco de contaminação e, ainda, de morbimortalidade. Objetivo: Identificar o impacto da COVID-19 na saúde de pessoas idosas residentes nas Instituições de Longa Permanência. Metodologia:Trata-se de estudo retrospectivo de revisão integrativa da literatura, entre os meses de novembro/2020 e março/2021, sintetizando estudos publicados sobre a temática. A partir do objetivo traçado para este estudo, determinamos quais seriam as questões norteadoras: 1. "Quais medidas estão sendo adotadas para minimizar os efeitos da COVID-19 nas Instituições de Longa Permanência para Idosos?" 2. "Quais os principais impactos causados por essas medidas?". Estes eixos colaboram para a compreensão dos acontecimentos de significativa relevância social. Resultados:As instituições para idosos, como ambientes coletivos, possuem residentes com elevada vulnerabilidade à infecção pelo novo coronavírus. Naqueles idosos acometidos por quadros de demência e outras doenças neurológicas, o isolamento social aprofunda a gravidade da infecção pela COVID-19, dificultando, assim, as atividades relacionadas à atenção e assistência realizadas pelos cuidadores. Ademais, caracteriza-se como medida fundamental a adoção do rastreamento laboratorial precoce para potencializar a prevenção de casos e promover o controle da infecção. Percebe-se ainda uma deficiência referente à construção de um protocolo com medidas de profilaxia e manejo adequado de modo mais direcionado dentro dessas instituições. Conclusão:Torna-se urgente um olhar mais atento às necessidades da população idosa, especialmente dogrupo institucionalizado, de modo a promover políticas de investimento em cuidados de saúde integrais e realizados por equipe multiprofissional (AU).

Introduction:The elderly population is one of the groups most vulnerable to infection by the new coronavirus. Such fragility is even more evident in those who live in Institutions for the Aged, as it presents a higher risk of contamination and, even, of morbidity and mortality. Objective: To identify the impact of COVID-19 on the health of elderly people residing in Long Term Institutions for the Aged. Methodology:This is a retrospective study of integrative literature review, between the months of November/2020 and March/2021, synthesizing published studies on the theme. Based on the objective outlined for this study, we determined what the guiding questions would be: 1. "What measures are being taken to minimize the effects of COVID-19 on Long Term Care Institutions for the Aged?" 2. "What are the main impacts caused by these measures?. These axes contribute to the understanding of events of significant social relevance. Results:Institutions for the aged, as collective environments, have residents with high vulnerability to infection with the new coronavirus. In those aged people affected by dementia and other neurological diseases, social isolation deepens the severity of the infection by COVID-19, thus hampering the activities related to the care and assistance performed by caregivers. In addition, the adoption of early laboratory screening is characterized as a fundamental measure to enhance the prevention of cases and promote infection control. It is also perceived a deficiency regarding the construction of a protocol with prophylaxis measures and adequate management in a more targeted way within these institutions.Conclusions:It is urgent to look more closely at the needs of the aged population, especially the institutionalized group, in order to promote investment policies in comprehensive health care carried out by a multidisciplinary team (AU).

Introducción: la población anciana es uno de los grupos más vulnerables a la infección por el nuevo coronavirus. Tal fragilidad es aún más evidente en quienes viven en Instituciones de Ancianos, ya que presenta un mayor riesgo de contaminación e, incluso, de morbilidad y mortalidad. Objetivo: Identificar el impacto del COVID-19 en la salud de los ancianos que residen en Instituciones de Atención de Larga Duración. Metodología: Se trata de un estudio retrospectivo de revisión integradora de la literatura, entre los meses de noviembre/2020 y marzo/2021, sintetizando los estudios publicados sobre el tema. Con base en el objetivo delineado para este estudio, determinamos cuáles serían las preguntas orientadoras: 1. "¿Qué medidas se están tomando para minimizar los efectos del COVID-19 en las Instituciones de Atención de Larga Duración para el Anciano?" 2. "¿Cuáles son los principales impactos provocados por estas medidas?". Estos ejes contribuyen a la comprensión de hechos de relevancia social significativa.Resultados:Las instituciones para los ancianos, como entornos colectivos, tienen residentes conalta vulnerabilidad a la infección por el nuevo coronavirus. Aquellos ancianos afectados por demencia y otras enfermedades neurológicas, el aislamiento social profundiza la gravedad de la infección por COVID-19, dificultando así las actividades relacionadas con el cuidado y asistencia que realizan los cuidadores. Además, la adopción del cribado precoz de laboratorio se caracteriza por ser una medida fundamental para potenciar la prevención de casos y promover el control de infecciones. También se percibe una deficiencia en la construcción de un protocolo con medidas de profilaxis y manejo adecuado de manera más focalizada dentro de estas instituciones. Conclusiones: Es urgente mirar más de cerca las necesidades de la población anciana, especialmente del grupo institucionalizado, para promover políticas de inversión en la atención integral de salud llevadas a cabo por un equipo multidisciplinario (AU).

Distinct SARS-CoV-2 antibody reactivity patterns in coronavirus convalescent plasma revealed by a coronavirus antigen microarray.

A coronavirus antigen microarray (COVAM) was constructed containing 11 SARS-CoV-2, 5 SARS-1, 5 MERS, and 12 seasonal coronavirus recombinant proteins. The array is designed to measure immunoglobulin isotype and subtype levels in serum or plasma samples against each of the individual antigens printed on the array. We probed the COVAM with COVID-19 convalescent plasma (CCP) collected from 99 donors who recovered from a PCR+ confirmed SARS-CoV-2 infection. The results were analyzed using two computational approaches, a generalized linear model (glm) and random forest (RF) prediction model, to classify individual specimens as either Reactive or non-reactive against the SARS-CoV-2 antigens. A training set of 88 pre-COVID-19 specimens (PreCoV) collected in August 2019 and102 positive specimens from SARS-CoV-2 PCR+ confirmed COVID-19 cases was used for these analyses. Results compared with an FDA emergency use authorized (EUA) SARS-CoV2 S1-based total Ig chemiluminescence immunoassay (Ortho Clinical Diagnostics VITROS Anti-SARS-CoV-2 Total, CoV2T) and with a SARS-CoV-2 S1-S2 spike-based pseudovirus micro neutralization assay (SARS-CoV-2 reporter viral particle neutralization titration (RVPNT) showed high concordance between the three assays. Three CCP specimens that were negative by the VITROS CoV2T immunoassay were also negative by both COVAM and the RVPNT assay. Concordance between VITROS CoV2T and COVAM was 96%, VITROS CoV2T and RVPNT 93%, and RVPNT and COVAM 91%. The discordances were all weakly reactive samples near the cutoff threshold of the VITROS CoV2T immunoassay. The multiplex COVAM allows CCP to be grouped according to antibody reactivity patterns against 11 SARS-CoV-2 antigens. Unsupervised K-means analysis, via the gap statistics, as well as hierarchical clustering analysis revealed three main clusters with distinct reactivity intensities and patterns. These patterns were not recapitulated by adjusting the VITROS CoV2T or RVPNT assay thresholds. Plasma classified by COVAM reactivity patterns offers potential to improve CCP therapeutic efficacy CoV2T alone. The use of a SARS-CoV-2 antigen array can qualify CCP for administration as a treatment for acute COVID-19, and interrogate vaccine immunogenicity and performance in preclinical, clinical studies, and routine vaccination to identify antibody responses predictive of protection from infection and disease.

Distinct antibody repertoires against endemic human coronaviruses in children and adults.

Four endemic human coronaviruses (HCoVs) are commonly associated with acute respiratory infection in humans. B cell responses to these "common cold" viruses remain incompletely understood. Here we report a comprehensive analysis of CoV-specific antibody repertoires in 231 children and 1168 adults using phage immunoprecipitation sequencing. Seroprevalence of antibodies against endemic HCoVs ranged between approximately 4% and 27% depending on the species and cohort. We identified at least 136 novel linear B cell epitopes. Antibody repertoires against endemic HCoVs were qualitatively different between children and adults in that anti-HCoV IgG specificities more frequently found among children targeted functionally important and structurally conserved regions of the spike, nucleocapsid, and matrix proteins. Moreover, antibody specificities targeting the highly conserved fusion peptide region and S2' cleavage site of the spike protein were broadly cross-reactive with peptides of epidemic human and nonhuman coronaviruses. In contrast, an acidic tandem repeat in the N-terminal region of the Nsp3 subdomain of the HCoV-HKU1 polyprotein was the predominant target of antibody responses in adult donors. Our findings shed light on the dominant species-specific and pan-CoV target sites of human antibody responses to coronavirus infection, thereby providing important insights for the development of prophylactic or therapeutic monoclonal antibodies and vaccine design.

Determine the Dentists' Practice in Compliance with General and Guidelines for Handling Coronavirus Disease 2019: A Systematic Review and Meta-analysis

ABSTRACT Objective: To determine the Dentists' practice in compliance with general and guidelines for handling Coronavirus Disease 2019. Material and Methods: PubMed, Embase, ISI, Scopus, Medicine have been used to search for articles until September 2020. EndNote X9 was used to manage electronic resources as a resource. Joanna Briggs Institute reviewer's manual (JBI) tools was used to assess the quality of studies included in the current systematic and meta-analysis review. The 95% confidence interval (CI) effect size, the random effect model, and the Restricted maximum-likelihood (REML) methods have all been calculated. I2 values of more than 50% indicated moderate-to-high heterogeneity. Stata/MP v.16 (the fastest version of Stata) statistical software was used to evaluate the Meta-analysis. Results: 39 articles were found in the initial keyword search. The full text of 16 studies was reviewed, and six studies were selected in the end. 72% of participants used a face mask during the dental procedure (72%, 95% CI; 40%-100%). 63% of participants measured fever when patients arrived during the COVID-19 pandemic (63%, 95% CI; 46%-79%). Moreover, 72% of participants used a face mask during the dental procedure (72%, 95% CI; 40%-100%). According to JBI tools, all studies had a moderate risk of bias. Conclusion: The results show that the performance of dental professionals in the conditions of the COVID-19 epidemic is not favorable. Training should be under the standards of treatment guidelines and further measures so that dental professionals can show proper practice by increasing their awareness of this virus and following up on its infection.

Unbiased Screens Show CD8+ T Cells of COVID-19 Patients Recognize Shared Epitopes in SARS-CoV-2 that Largely Reside outside the Spike Protein.

Developing effective strategies to prevent or treat coronavirus disease 2019 (COVID-19) requires understanding the natural immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We used an unbiased, genome-wide screening technology to determine the precise peptide sequences in SARS-CoV-2 that are recognized by the memory CD8+ T cells of COVID-19 patients. In total, we identified 3-8 epitopes for each of the 6 most prevalent human leukocyte antigen (HLA) types. These epitopes were broadly shared across patients and located in regions of the virus that are not subject to mutational variation. Notably, only 3 of the 29 shared epitopes were located in the spike protein, whereas most epitopes were located in ORF1ab or the nucleocapsid protein. We also found that CD8+ T cells generally do not cross-react with epitopes in the four seasonal coronaviruses that cause the common cold. Overall, these findings can inform development of next-generation vaccines that better recapitulate natural CD8+ T cell immunity to SARS-CoV-2.

Systemic innate and adaptive immune responses to SARS-CoV-2 as it relates to other coronaviruses.

The deadly pandemic caused by the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) represents one of the greatest threats humanity has faced in the last century. Infection with this easily transmissible virus can run the gamut from asymptomatic to fatal, and the disease caused by SARS-CoV-2 has been termed Coronavirus Disease 2019 (COVID-19). What little research that has already been conducted implicates pathological responses by the immune system as the leading culprit responsible for much of the morbidity and mortality caused by COVID-19. In this review we will summarize what is currently known about the systemic immune response to SARS-CoV-2 and potential immunotherapeutic approaches.

Coronavirus interactions with the cellular autophagy machinery.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is the most recent example of an emergent coronavirus that poses a significant threat to human health. Virus-host interactions play a major role in the viral life cycle and disease pathogenesis, and cellular pathways such as macroautophagy/autophagy prove to be either detrimental or beneficial to viral replication and maturation. Here, we describe the literature over the past twenty years describing autophagy-coronavirus interactions. There is evidence that many coronaviruses induce autophagy, although some of these viruses halt the progression of the pathway prior to autophagic degradation. In contrast, other coronaviruses usurp components of the autophagy pathway in a non-canonical fashion. Cataloging these virus-host interactions is crucial for understanding disease pathogenesis, especially with the global challenge of SARS-CoV-2 and COVID-19. With the recognition of autophagy inhibitors, including the controversial drug chloroquine, as possible treatments for COVID-19, understanding how autophagy affects the virus will be critical going forward. Abbreviations: 3-MA: 3-methyladenine (autophagy inhibitor); AKT/protein kinase B: AKT serine/threonine kinase; ATG: autophagy related; ATPase: adenosine triphosphatase; BMM: bone marrow macrophage; CGAS: cyclic GMP-AMP synthase; CHO: Chinese hamster ovary/cell line; CoV: coronaviruses; COVID-19: Coronavirus disease 2019; DMV: double-membrane vesicle; EAV: equine arteritis virus; EDEM1: ER degradation enhancing alpha-mannosidase like protein 1; ER: endoplasmic reticulum; ERAD: ER-associated degradation; GFP: green fluorescent protein; HCoV: human coronavirus; HIV: human immunodeficiency virus; HSV: herpes simplex virus; IBV: infectious bronchitis virus; IFN: interferon; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCoV: mouse coronavirus; MERS-CoV: Middle East respiratory syndrome coronavirus; MHV: mouse hepatitis virus; NBR1: NBR1 autophagy cargo receptor; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2 (autophagy receptor that directs cargo to phagophores); nsp: non-structural protein; OS9: OS9 endoplasmic reticulum lectin; PEDV: porcine epidemic diarrhea virus; PtdIns3K: class III phosphatidylinositol 3-kinase; PLP: papain-like protease; pMEF: primary mouse embryonic fibroblasts; SARS-CoV: severe acute respiratory syndrome coronavirus; SKP2: S-phase kinase associated protein 2; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; ULK1: unc-51 like autophagy activating kinase 1; Vps: vacuolar protein sorting.

Porcine Deltacoronavirus Accessory Protein NS7a Antagonizes IFN-ß Production by Competing With TRAF3 and IRF3 for Binding to IKKε.

As an emerging swine enteropathogenic coronavirus, porcine deltacoronavirus (PDCoV) not only causes serious diarrhea in suckling piglets but also possesses the potential for cross-species transmission, which has sparked growing interest when studying this emerging virus. We previously identified a novel accessory protein NS7a encoded by PDCoV; however, the function of NS7a was not resolved. In this study, we demonstrated that PDCoV NS7a is an interferon antagonist. Overexpression of NS7a notably inhibited Sendai virus (SeV)-induced interferon-ß (IFN-ß) production and the activation of IRF3 rather than NF-κB. NS7a also inhibited IFN-ß promoter activity induced by RIG-I, MDA5, MAVS, TBK1, and IKKε, which are key components of the RIG-I-like receptor (RLR) signaling pathway but not IRF3, the transcription factor downstream of TBK1/IKKε. Surprisingly, NS7a specifically interacts with IKKε but not with the closely related TBK1. Furthermore, NS7a interacts simultaneously with the kinase domain (KD) and the scaffold dimerization domain (SDD) of IKKε, competing with TRAF3, and IRF3 for binding to IKKε, leading to the reduction of RLR-mediated IFN-ß production. The interactions of TRAF3-IKKε and IKKε-IRF3 are also attenuated in PDCoV-infected cells. Taken together, our results demonstrate that PDCoV NS7a inhibits IFN-ß production by disrupting the association of IKKε with both TRAF3 and IRF3, revealing a new mechanism utilized by a PDCoV accessory protein to evade the host antiviral innate immune response.

Pangolins Lack IFIH1/MDA5, a Cytoplasmic RNA Sensor That Initiates Innate Immune Defense Upon Coronavirus Infection.

Zoonotic infections are an imminent threat to human health. Pangolins were recently identified as carriers and intermediate hosts of coronaviruses. Previous research has shown that infection with coronaviruses activates an innate immune response upon sensing of viral RNA by interferon-induced with helicase C domain 1 (IFIH1), also known as MDA5. Here, we performed a comparative genomics study of RNA sensor genes in three species of pangolins. DDX58/RIG-I, a sensor of cytoplasmic viral RNA and toll-like receptors (TLR) 3, 7, and 8, which bind RNA in endosomes, are conserved in pangolins. By contrast, IFIH1 a sensor of intracellular double-stranded RNA, has been inactivated by mutations in pangolins. Likewise, Z-DNA-binding protein (ZBP1), which senses both Z-DNA and Z-RNA, has been lost during the evolution of pangolins. These results suggest that the innate immune response to viruses differs significantly between pangolins and other mammals, including humans. We put forward the hypothesis that loss of IFIH1 and ZBP1 provided an evolutionary advantage by reducing inflammation-induced damage to host tissues and thereby contributed to a switch from resistance to tolerance of viral infections in pangolins.

Storm, typhoon, cyclone or hurricane in patients with COVID-19? Beware of the same storm that has a different origin.

Some of the articles being published during the severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 pandemic highlight a link between severe forms of coronavirus disease 2019 (COVID-19) and the so-called cytokine storm, also with increased ferritin levels. However, this scenario is more complex than initially thought due to the heterogeneity of hyperinflammation. Some patients with coronavirus 2019 disease (COVID-19) develop a fully blown secondary haemophagocytic lymphohistiocytosis (sHLH), whereas others, despite a consistent release of pro-inflammatory cytokines, do not fulfil sHLH criteria but still show some features resembling the phenotype of the hyperferritinemic syndrome. Despite the final event (the cytokine storm) is shared by various conditions leading to sHLH, the aetiology, either infectious, autoimmune or neoplastic, accounts for the differences in the various phases of this process. Moreover, the evidence of a hyperinflammatory microenvironment provided the rationale to employ immunomodulating agents for therapeutic purposes in severe COVID-19. This viewpoint aims at discussing the pitfalls and issues to be considered with regard to the use of immunomodulating agents in COVID-19, such as timing of treatment based on the viral load and the extent of cytokine/ferritin overexpression. Furthermore, it encompasses recent findings in the paediatric field about a novel multisystem inflammatory disease resembling toxic shock syndrome and atypical Kawasaki disease observed in children with proven SARS-CoV2 infection. Finally, it includes arguments in favour of adding COVID-19 to the spectrum of the recently defined 'hyperferritinemic syndrome', which already includes adult-onset Still's disease, macrophage activation syndrome, septic shock and catastrophic anti-phospholipid syndrome.

Serological and molecular findings during SARS-CoV-2 infection: the first case study in Finland, January to February 2020.

The first case of coronavirus disease (COVID-19) in Finland was confirmed on 29 January 2020. No secondary cases were detected. We describe the clinical picture and laboratory findings 3-23 days since the first symptoms. The SARS-CoV-2/Finland/1/2020 virus strain was isolated, the genome showing a single nucleotide substitution to the reference strain from Wuhan. Neutralising antibody response appeared within 9 days along with specific IgM and IgG response, targeting particularly nucleocapsid and spike proteins.

Gold nanoparticle-adjuvanted S protein induces a strong antigen-specific IgG response against severe acute respiratory syndrome-related coronavirus infection, but fails to induce protective antibodies and limit eosinophilic infiltration in lungs.

The spike (S) protein of coronavirus, which binds to cellular receptors and mediates membrane fusion for cell entry, is a candidate vaccine target for blocking coronavirus infection. However, some animal studies have suggested that inadequate immunization against severe acute respiratory syndrome coronavirus (SARS-CoV) induces a lung eosinophilic immunopathology upon infection. The present study evaluated two kinds of vaccine adjuvants for use with recombinant S protein: gold nanoparticles (AuNPs), which are expected to function as both an antigen carrier and an adjuvant in immunization; and Toll-like receptor (TLR) agonists, which have previously been shown to be an effective adjuvant in an ultraviolet-inactivated SARS-CoV vaccine. All the mice immunized with more than 0.5 µg S protein without adjuvant escaped from SARS after infection with mouse-adapted SARS-CoV; however, eosinophilic infiltrations were observed in the lungs of almost all the immunized mice. The AuNP-adjuvanted protein induced a strong IgG response but failed to improve vaccine efficacy or to reduce eosinophilic infiltration because of highly allergic inflammatory responses. Whereas similar virus titers were observed in the control animals and the animals immunized with S protein with or without AuNPs, Type 1 interferon and pro-inflammatory responses were moderate in the mice treated with S protein with and without AuNPs. On the other hand, the TLR agonist-adjuvanted vaccine induced highly protective antibodies without eosinophilic infiltrations, as well as Th1/17 cytokine responses. The findings of this study will support the development of vaccines against severe pneumonia-associated coronaviruses.