Immune responses to SARS-CoV-2 infection in Humans and ACE2 humanized mice
01 Mar 2021-Vol. 1, Iss: 2, pp 124-130
TL;DR: In this article, the authors review the present literature describing the innate and adaptive immune responses including innate immune cells, cytokine responses, antibody responses and T cell responses against SARS-CoV-2 in human infection, as well as in AEC2-humanized mouse infection.
Abstract: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a major public health threat worldwide. Insight into protective and pathogenic aspects of SARS-CoV-2 immune responses is critical to work out effective therapeutics and develop vaccines for controlling the disease. Here, we review the present literature describing the innate and adaptive immune responses including innate immune cells, cytokine responses, antibody responses and T cell responses against SARS-CoV-2 in human infection, as well as in AEC2-humanized mouse infection. We also summarize the now known and unknown about the role of the SARS-CoV-2 immune responses. By better understanding the mechanisms that drive the immune responses, we can tailor treatment strategies at specific disease stages and improve our response to this worldwide public health threat.
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TL;DR: In this paper, the authors established an animal model highly susceptible to SARS-CoV-2 via the intratracheal tract infection in CAG promoter-driven human angiotensin-converting enzyme 2-transgenic (CAG-hACE2) mice.
Abstract: COVID-19, caused by SARS-CoV-2, has spread worldwide with dire consequences. To urgently investigate the pathogenicity of COVID-19 and develop vaccines and therapeutics, animal models that are highly susceptible to SARS-CoV-2 infection are needed. In the present study, we established an animal model highly susceptible to SARS-CoV-2 via the intratracheal tract infection in CAG promoter-driven human angiotensin-converting enzyme 2-transgenic (CAG-hACE2) mice. The CAG-hACE2 mice showed several severe symptoms of SARS-CoV-2 infection, with definitive weight loss and subsequent death. Acute lung injury with elevated cytokine and chemokine levels was observed at an early stage of infection in CAG-hACE2 mice infected with SARS-CoV-2. Analysis of the hACE2 gene in CAG-hACE2 mice revealed that more than 15 copies of hACE2 genes were integrated in tandem into the mouse genome, supporting the high susceptibility to SARS-CoV-2. In the developed model, immunization with viral antigen or injection of plasma from immunized mice prevented body weight loss and lethality due to infection with SARS-CoV-2. These results indicate that a highly susceptible model of SARS-CoV-2 infection in CAG-hACE2 mice via the intratracheal tract is suitable for evaluating vaccines and therapeutic medicines.
17 citations
TL;DR: In this paper , a hierarchical cognize framework (HCF) is proposed for multi-fault diagnosis in an interconnected system (ICS), which covers the cognition of sensors, data patterns in single sensors and data climates.
Abstract: An interconnected system (ICS) is a complex industry system with multiple sensors, multiple tasks, and massive interaction. It is also of great importance for conducting the fault diagnosis technology research. Multi-fault diagnosis (MFD) is an urgent problem in engineering, while the complex mapping relationships among the system sensors, data patterns in single sensors, and fault modes in ICSs bringing severe challenges. The faults of ICS are similar to human disease in multiple dimensions. Enlightening the understanding of diseases in medicine guides us: hierarchical cognition and knowledge-data-fusion are important systematic ideas. Inspired by these, we propose a hierarchical cognize framework (HCF), which covers the cognition of sensors, data patterns in single sensors, and data climates. Subsequently, we propose a fuzzy neighbourhood three-way decision (FN3WD), experience fused self-adaptation Gaussian-mixture-model (EFSA-GMM), and coding-with-knowledge-discrimination (CWKD) to construct an HCF. To comprehensively verify the HCF, we successfully apply the HCF to the MFD of a satellite power system. Classic models of two-mainstream strategies are introduced as comparisons, specifically, MC-DCNN, MC-SVM, ML-DCNN, and ML-SVM. Compared to the comparative models, the HCF performs an increase of 12.35%, 7.72%, 6.90%, and 8.10% at least in accuracy, precision, recall, and F1-score, respectively, in 10 times cross-validation. Benefitting from the fusion of knowledge, the HCF has cognitive advantages in obtaining a high accuracy and precision diagnosis results. Meanwhile, the time consumption of the HCF is approximately 130 s, which is considerably reduced by as much as 50% compared with the deep learning models.
7 citations
TL;DR: In this paper , the effects and potential mechanisms of several compounds from Lianqiao leaves on the bioactivities of some key proteins of COVID-19 and its variants, as well as diabetic endothelial dysfunctions were illuminated through in vitro and in silico analyses.
7 citations
TL;DR: A review of animal models for in vivo tests with SARS-CoV-2 as well as the challenges involved in the safety and efficacy trials can be found in this article.
Abstract: INTRODUCTION: The search for an animal model capable of reproducing the physiopathology of the COVID-19, and also suitable for evaluating the efficacy and safety of new drugs has become a challenge for many researchers. AREAS COVERED: This work reviews the current animal models for in vivo tests with SARS-CoV-2 as well as the challenges involved in the safety and efficacy trials. EXPERT OPINION: Studies have reported the use of nonhuman primates, ferrets, mice, Syrian hamsters, lagomorphs, mink, and zebrafish in experiments that aimed to understand the course of COVID-19 or test vaccines and other drugs. In contrast, the assays with animal hyperimmune sera have only been used in in vitro assays. Finding an animal that faithfully reproduces all the characteristics of the disease in humans is difficult. Some models may be more complex to work with, such as monkeys, or require genetic manipulation so that they can express the human ACE2 receptor, as in the case of mice. Although some models are more promising, possibly the use of more than one animal model represents the best scenario. Therefore, further studies are needed to establish an ideal animal model to help in the development of other treatment strategies besides vaccines.
3 citations
TL;DR: The use of genetically diverse mouse models, such as the collaborative cross (CC) or the diversity outbred (DO) models, has been a useful tool to overcome the translatability of the results found in mice to humans as mentioned in this paper.
Abstract: Mouse models are an essential tool in different areas of research, including nutrition and phytochemical research. Traditional inbred mouse models have allowed the discovery of therapeutical targets and mechanisms of action and expanded our knowledge of health and disease. However, these models lack the genetic variability typically found in human populations, which hinders the translatability of the results found in mice to humans. The development of genetically diverse mouse models, such as the collaborative cross (CC) or the diversity outbred (DO) models, has been a useful tool to overcome this obstacle in many fields, such as cancer, immunology and toxicology. However, these tools have not yet been widely adopted in the field of phytochemical research. As demonstrated in other disciplines, use of CC and DO models has the potential to provide invaluable insights for translation of phytochemicals from rodents to humans, which are desperately needed given the challenges and numerous failed clinical trials in this field. These models may prove informative for personalized use of phytochemicals in humans, including: predicting interindividual variability in phytochemical bioavailability and efficacy, identifying genetic loci or genes governing response to phytochemicals, identifying phytochemical mechanisms of action and therapeutic targets, and understanding the impact of genetic variability on individual response to phytochemicals. Such insights would prove invaluable for personalized implementation of phytochemicals in humans. This review will focus on the current work performed with genetically diverse mouse populations, and the research opportunities and advantages that these models can offer to phytochemical research.
2 citations
References
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TL;DR: During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness, and patients often presented without fever, and many did not have abnormal radiologic findings.
Abstract: Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of...
22,622 citations
TL;DR: O surto do novo coronavÃrus (COVID-19) em Wuhan, China, iniciado em dezembro de 2019, evoluiu para se tornar uma pandemia global A.
6,850 citations
TL;DR: Investigation of NLR and lymphocyte subsets is helpful in the early screening of critical illness, diagnosis and treatment of COVID-19 and shows the novel coronavirus might mainly act on lymphocytes, especially T lymphocytes.
Abstract: BACKGROUND: In December 2019, coronavirus 2019 (COVID-19) emerged in Wuhan and rapidly spread throughout China. METHODS: Demographic and clinical data of all confirmed cases with COVID-19 on admission at Tongji Hospital from 10 January to 12 February 2020 were collected and analyzed. The data on laboratory examinations, including peripheral lymphocyte subsets, were analyzed and compared between patients with severe and nonsevere infection. RESULTS: Of the 452 patients with COVID-19 recruited, 286 were diagnosed as having severe infection. The median age was 58 years and 235 were male. The most common symptoms were fever, shortness of breath, expectoration, fatigue, dry cough, and myalgia. Severe cases tend to have lower lymphocyte counts, higher leukocyte counts and neutrophil-lymphocyte ratio (NLR), as well as lower percentages of monocytes, eosinophils, and basophils. Most severe cases demonstrated elevated levels of infection-related biomarkers and inflammatory cytokines. The number of T cells significantly decreased, and were more impaired in severe cases. Both helper T (Th) cells and suppressor T cells in patients with COVID-19 were below normal levels, with lower levels of Th cells in the severe group. The percentage of naive Th cells increased and memory Th cells decreased in severe cases. Patients with COVID-19 also have lower levels of regulatory T cells, which are more obviously decreased in severe cases. CONCLUSIONS: The novel coronavirus might mainly act on lymphocytes, especially T lymphocytes. Surveillance of NLR and lymphocyte subsets is helpful in the early screening of critical illness, diagnosis, and treatment of COVID-19.
3,532 citations
TL;DR: The SARS-CoV-2 infection may affect primarily T lymphocytes particularly CD4+T and CD8+ T cells, resulting in decrease in numbers as well as IFN-γ production, which may be of importance due to their correlation with disease severity in COVID-19.
Abstract: BACKGROUNDSince December 2019, an outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, and is now becoming a global threat. We aimed to delineate and compare the immunological features of severe and moderate COVID-19.METHODSIn this retrospective study, the clinical and immunological characteristics of 21 patients (17 male and 4 female) with COVID-19 were analyzed. These patients were classified as severe (11 cases) and moderate (10 cases) according to the guidelines released by the National Health Commission of China.RESULTSThe median age of severe and moderate cases was 61.0 and 52.0 years, respectively. Common clinical manifestations included fever, cough, and fatigue. Compared with moderate cases, severe cases more frequently had dyspnea, lymphopenia, and hypoalbuminemia, with higher levels of alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin, and D-dimer as well as markedly higher levels of IL-2R, IL-6, IL-10, and TNF-α. Absolute numbers of T lymphocytes, CD4+ T cells, and CD8+ T cells decreased in nearly all the patients, and were markedly lower in severe cases (294.0, 177.5, and 89.0 × 106/L, respectively) than moderate cases (640.5, 381.5, and 254.0 × 106/L, respectively). The expression of IFN-γ by CD4+ T cells tended to be lower in severe cases (14.1%) than in moderate cases (22.8%).CONCLUSIONThe SARS-CoV-2 infection may affect primarily T lymphocytes, particularly CD4+ and CD8+ T cells, resulting in a decrease in numbers as well as IFN-γ production by CD4+ T cells. These potential immunological markers may be of importance because of their correlation with disease severity in COVID-19.TRIAL REGISTRATIONThis is a retrospective observational study without a trial registration number.FUNDINGThis work is funded by grants from Tongji Hospital for the Pilot Scheme Project, and partly supported by the Chinese National Thirteenth Five Years Project in Science and Technology for Infectious Disease (2017ZX10202201).
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