Hypercytokinemia and Pathogen-Host Interaction in COVID-19.
ABSTRACT: Severe acute respiratory syndrome (SARS) coronavirus (CoV)-2 (SARS-CoV-2) is a novel coronavirus identified as the cause of coronavirus disease-2019 (COVID-19) that began in Wuhan, China in late 2019 and spread now in 210 countries and territories around the world. Many people are asymptomatic or with mild symptoms. However, in some cases (usually the elderly and those with comorbidities) the disease may progress to pneumonia, acute respiratory distress syndrome and multi-organ dysfunction that can lead to death. Such wide interindividual differences in response to SARS-CoV-2 infection may relate to several pathogen- and host-related factors. These include the different levels of the ubiquitously present human angiotensin I converting enzyme 2 (ACE2) receptors gene expression and its variant alleles, the different binding affinities of ACE2 to the virus spike (S) protein given its L- and S-subtypes and the subsequent extent of innate immunity-related hypercytokinemia. The extensive synthesis of cytokines and chemokines in coronavirus diseases was suggested as a major factor in exacerbating lung damage and other fatal complications. The polymorphisms in genes coding for pro-inflammatory cytokines and chemokines have been associated with mediating the response and susceptibility to a wide range of infections and their severe outcomes. Understanding the nature of pathogen-host interaction in COVID-19 symptomatology together with the role of hypercytokinemia in disease severity may permit developing new avenues of approach for prevention and treatment and can delineate public health measures to control the spread of the disease.
Project description:The outbreaks of 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 infection have posed a severe threat to global public health. It is unclear how the human immune system responds to this infection. Here, we used metatranscriptomic sequencing to profile immune signatures in the bronchoalveolar lavage fluid of eight COVID-19 cases. The expression of proinflammatory genes, especially chemokines, was markedly elevated in COVID-19 cases compared to community-acquired pneumonia patients and healthy controls, suggesting that SARS-CoV-2 infection causes hypercytokinemia. Compared to SARS-CoV, which is thought to induce inadequate interferon (IFN) responses, SARS-CoV-2 robustly triggered expression of numerous IFN-stimulated genes (ISGs). These ISGs exhibit immunopathogenic potential, with overrepresentation of genes involved in inflammation. The transcriptome data was also used to estimate immune cell populations, revealing increases in activated dendritic cells and neutrophils. Collectively, these host responses to SARS-CoV-2 infection could further our understanding of disease pathogenesis and point toward antiviral strategies.
Project description:Coronavirus disease-2019 (COVID-19) has emerged as a pandemic affecting millions of adults. Severe acute respiratory syndrome coronavirus-2019 (SARS-CoV-2), the causative virus of COVID-19, infects host cells through angiotensin converting enzyme 2 (ACE2). Pre-clinical models suggest that ACE2 upregulation confers protective effects in acute lung injury. Additionally, renin-angiotensin aldosterone system inhibitors reduce adverse atherosclerotic cardiovascular disease, heart failure and chronic kidney disease outcomes, but may increase ACE2 levels. We review current knowledge of the role of ACE2 in cardiovascular physiology and SARS-CoV-2 virology as well as clinical data to inform the management of patients with or at risk for COVID-19 who require renin-angiotensin-aldosterone system inhibitor therapy.
Project description:The serious coronavirus disease-2019 (COVID-19) was first reported in December 2019 in Wuhan, China. COVID-19 is an infectious disease caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Angiotensin converting enzyme 2(ACE2) is the cellular receptor for SARS-CoV-2. Considering the critical roles of testicular cells for the transmission of genetic information between generations, we analyzed single-cell RNA-sequencing (scRNA-seq) data of adult human testis. The mRNA expression of ACE2 was expressed in both germ cells and somatic cells. Moreover, the positive rate of ACE2 in testes of infertile men was higher than normal, which indicates that SARS-CoV-2 may cause reproductive disorders through pathway activated by ACE2 and the men with reproductive disorder may easily to be infected by SARS-CoV-2. The expression level of ACE2 was related to the age, and the mid-aged with higher positive rate than young men testicular cells. Taken together, this research provides a biological background of the potential route for infection of SARS-CoV-2 and may enable rapid deciphering male-related reproductive disorders induced by COVID-19.
Project description:Coronavirus disease 2019 (COVID-19) is caused by novel coronavirus Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first time reported in December 2019 in Wuhan, China and thereafter quickly spread across the globe. Till September 19, 2020, COVID-19 has spread to 216 countries and territories. Severe infection of SARS-CoV-2 cause extreme increase in inflammatory chemokines and cytokines that may lead to multi-organ damage and respiratory failure. Currently, no specific treatment and authorized vaccines are available for its treatment. Renin angiotensin system holds a promising role in human physiological system specifically in regulation of blood pressure and electrolyte and fluid balance. SARS-CoV-2 interacts with Renin angiotensin system by utilizing angiotensin-converting enzyme 2 (ACE2) as a receptor for its cellular entry. This interaction hampers the protective action of ACE2 in the cells and causes injuries to organs due to persistent angiotensin II (Ang-II) level. Patients with certain comorbidities like hypertension, diabetes, and cardiovascular disease are under the high risk of COVID-19 infection and mortality. Moreover, evidence obtained from several reports also suggests higher susceptibility of male patients for COVID-19 mortality and other acute viral infections compared to females. Analysis of severe acute respiratory syndrome coronavirus (SARS) and Middle East respiratory syndrome coronavirus (MERS) epidemiological data also indicate a gender-based preference in disease consequences. The current review addresses the possible mechanisms responsible for higher COVID-19 mortality among male patients. The major underlying aspects that was looked into includes smoking, genetic factors, and the impact of reproductive hormones on immune systems and inflammatory responses. Detailed investigations of this gender disparity could provide insight into the development of patient tailored therapeutic approach which would be helpful in improving the poor outcomes of COVID-19. Graphical abstract.
Project description:The global outbreak of COVID-19 (Coronavirus Disease 2019) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome caused by Coronavirus 2) began in December 2019. Its closest relative, SARS-CoV-1, has a slightly mutated Spike (S) protein, which interacts with ACE2 receptor in human cells to start the infection. So far, there are no vaccines or drugs to treat COVID-19. So, research groups worldwide are seeking new molecules targeting the S protein to prevent infection by SARS-CoV-2 and COVID-19 establishment. We performed molecular docking analysis of eight synthetic peptides against SARS-CoV-2 S protein. All interacted with the protein, but Mo-CBP3-PepII and PepKAA had the highest affinity with it. By binding to the S protein, both peptides led to conformational alterations in the protein, resulting in incorrect interaction with ACE2. Therefore, given the importance of the S protein-ACE2 interaction for SARS-CoV-2 infection, synthetic peptides could block SARS-CoV-2 infection. Moreover, unlike other antiviral drugs, peptides have no toxicity to human cells. Thus, these peptides are potential molecules to be tested against SARS-CoV-2 and to develop new drugs to treat COVID-19.
Project description:Angiotensin-converting enzyme 2 (ACE2) is the receptor of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic. ACE2 has been shown to be down-regulated during coronaviral infection, with implications for circulatory homeostasis. In COVID-19, pulmonary vascular dysregulation has been observed resulting in ventilation perfusion mismatches in lung tissue, causing profound hypoxemia. Despite the loss of ACE2 and raised circulating vasoconstrictor angiotensin II (AngII), COVID-19 patients experience a vasodilative vasculopathy. This article discusses the interplay between the immune system and pulmonary vasculature and how SARS-CoV-2-mediated ACE2 disruption and AngII may contribute to the novel vascular pathophysiology of COVID-19.
Project description:Coronavirus disease 2019 (COVID-19) is a declared pandemic that is spreading all over the world at a dreadfully fast rate. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the pathogen of COVID-19, infects the human body using angiotensin-converting enzyme 2 (ACE2) as a receptor identical to the severe acute respiratory syndrome (SARS) pandemic that occurred in 2002-2003. SARS-CoV-2 has a higher binding affinity to human ACE2 than to that of other species. Animal models that mimic the human disease are highly essential to develop therapeutics and vaccines against COVID-19. Here, we review transgenic mice that express human ACE2 in the airway and other epithelia and have shown to develop a rapidly lethal infection after intranasal inoculation with SARS-CoV, the pathogen of SARS. This literature review aims to present the importance of utilizing the human ACE2 transgenic mouse model to better understand the pathogenesis of COVID-19 and develop both therapeutics and vaccines.
Project description:The ongoing coronavirus disease 2019 (COVID-19) pandemic has caused >20 million infections and >750,000 deaths. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, has been found closely related to the bat coronavirus strain RaTG13 (Bat-CoV RaTG13) and a recently identified pangolin coronavirus (Pangolin-CoV-2020). Here, we first investigated the ability of SARS-CoV-2 and three related coronaviruses to utilize animal orthologs of angiotensin-converting enzyme 2 (ACE2) for cell entry. We found that ACE2 orthologs of a wide range of domestic and wild mammals, including camels, cattle, horses, goats, sheep, cats, rabbits, and pangolins, were able to support cell entry of SARS-CoV-2, suggesting that these species might be able to harbor and spread this virus. In addition, the pangolin and bat coronaviruses, Pangolin-CoV-2020 and Bat-CoV RaTG13, were also found able to utilize human ACE2 and a number of animal-ACE2 orthologs for cell entry, indicating risks of spillover of these viruses into humans in the future. We then developed potently anticoronavirus ACE2-Ig proteins that are broadly effective against the four distinct coronaviruses. In particular, through truncating ACE2 at its residue 740 but not 615, introducing a D30E mutation, and adopting an antibody-like tetrameric-ACE2 configuration, we generated an ACE2-Ig variant that neutralizes SARS-CoV-2 at picomolar range. These data demonstrate that the improved ACE2-Ig variants developed in this study could potentially be developed to protect from SARS-CoV-2 and some other SARS-like viruses that might spillover into humans in the future.IMPORTANCE The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the currently uncontrolled coronavirus disease 2019 (COVID-19) pandemic. It is important to study the host range of SARS-CoV-2, because some domestic species might harbor the virus and transmit it back to humans. In addition, insight into the ability of SARS-CoV-2 and SARS-like viruses to utilize animal orthologs of the SARS-CoV-2 receptor ACE2 might provide structural insight into improving ACE2-based viral entry inhibitors. In this study, we found that ACE2 orthologs of a wide range of domestic and wild animals can support cell entry of SARS-CoV-2 and three related coronaviruses, providing insights into identifying animal hosts of these viruses. We also developed recombinant ACE2-Ig proteins that are able to potently block these viral infections, providing a promising approach to developing antiviral proteins broadly effective against these distinct coronaviruses.
Project description:The outbreak of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health, calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV). The CoV spike (S) protein plays the most important roles in viral attachment, fusion and entry, and serves as a target for development of antibodies, entry inhibitors and vaccines. Here, we identified the receptor-binding domain (RBD) in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2 (ACE2) receptors. SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and, hence, attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells, thus inhibiting their infection to host cells. SARS-CoV RBD-specific antibodies could cross-react with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2, suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.
Project description:Purpose:SARS-CoV-2 is a SARS-like novel coronavirus strain first identified in December 2019 in Wuhan, China. The virus has since spread globally, resulting in the current ongoing coronavirus disease 19 (COVID-19) pandemic. SARS-CoV-2 spike protein is a critical factor in the COVID-19 pathogenesis via interactions with the host cell angiotensin-converting enzyme 2 (ACE2) PD domain. Worldwide, numerous efforts are being made to combat COVID19. In the current study, we identified potential peptidomimetics against the SARS-CoV-2 spike protein. Methods:We utilized the information from ACE2-SARS-CoV-2 binary interactions, and based on crucial interacting interface residues, novel peptidomimetics were designed. Results:Top scoring peptidomimetics were found to bind at the ACE2 binding site of the receptor-binding domain (RBD) of SARS-CoV-2 spike protein. Conclusions:The current studies could pave the way for further investigations of these novel and potent compounds against the SARS-CoV-2.