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1.
Front Immunol ; 13: 858256, 2022.
Article in English | MEDLINE | ID: covidwho-1760238

ABSTRACT

To determine whether aorta becomes immune organ in pathologies, we performed transcriptomic analyses of six types of secretomic genes (SGs) in aorta and vascular cells and made the following findings: 1) 53.7% out of 21,306 human protein genes are classified into six secretomes, namely, canonical, caspase 1, caspase 4, exosome, Weibel-Palade body, and autophagy; 2) Atherosclerosis (AS), chronic kidney disease (CKD) and abdominal aortic aneurysm (AAA) modulate six secretomes in aortas; and Middle East Respiratory Syndrome Coronavirus (MERS-CoV, COVID-19 homologous) infected endothelial cells (ECs) and angiotensin-II (Ang-II) treated vascular smooth muscle cells (VSMCs) modulate six secretomes; 3) AS aortas upregulate T and B cell immune SGs; CKD aortas upregulate SGs for cardiac hypertrophy, and hepatic fibrosis; and AAA aorta upregulate SGs for neuromuscular signaling and protein catabolism; 4) Ang-II induced AAA, canonical, caspase 4, and exosome SGs have two expression peaks of high (day 7)-low (day 14)-high (day 28) patterns; 5) Elastase induced AAA aortas have more inflammatory/immune pathways than that of Ang-II induced AAA aortas; 6) Most disease-upregulated cytokines in aorta may be secreted via canonical and exosome secretomes; 7) Canonical and caspase 1 SGs play roles at early MERS-CoV infected ECs whereas caspase 4 and exosome SGs play roles in late/chronic phases; and the early upregulated canonical and caspase 1 SGs may function as drivers for trained immunity (innate immune memory); 8) Venous ECs from arteriovenous fistula (AVF) upregulate SGs in five secretomes; and 9) Increased some of 101 trained immunity genes and decreased trained tolerance regulator IRG1 participate in upregulations of SGs in atherosclerotic, Ang-II induced AAA and CKD aortas, and MERS-CoV infected ECs, but less in SGs upregulated in AVF ECs. IL-1 family cytokines, HIF1α, SET7 and mTOR, ROS regulators NRF2 and NOX2 partially regulate trained immunity genes; and NRF2 plays roles in downregulating SGs more than that of NOX2 in upregulating SGs. These results provide novel insights on the roles of aorta as immune organ in upregulating secretomes and driving immune and vascular cell differentiations in COVID-19, cardiovascular diseases, inflammations, transplantations, autoimmune diseases and cancers.


Subject(s)
COVID-19 , Middle East Respiratory Syndrome Coronavirus , Renal Insufficiency, Chronic , Angiotensin II , Aorta , COVID-19/genetics , Caspase 1 , Cell Differentiation , Cell Transdifferentiation , Cytokines , Endothelial Cells , Humans , NF-E2-Related Factor 2
2.
Stem Cell Res Ther ; 13(1): 71, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1759775

ABSTRACT

Pulmonary fibrosis is a devastating disease that eventually leads to death and respiratory failure. Despite the wide range of drugs, including corticosteroids, endothelin antagonist, and pirfenidone, there is no effective treatment, and the only main goal of treatment is to alleviate the symptoms as much as possible to slow down the progression of the disease and improve the quality of life. Lung transplantation may be a treatment option for a few people if pulmonary fibrosis develops and there is no established treatment. Pulmonary fibrosis caused by the COVID19 virus is another problem that we face in most patients despite the efforts of the international medical communities. Therefore, achieving alternative treatment for patients is a great success. Today, basic research using stem cells on pulmonary fibrosis has published promising results. New stem cell-based therapies can be helpful in patients with pulmonary fibrosis. Wharton jelly-derived mesenchymal stem cells are easily isolated in large quantities and made available for clinical trials without causing ethical problems. These cells have higher flexibility and proliferation potential than other cells isolated from different sources and differentiated into various cells in laboratory environments. More clinical trials are needed to determine the safety and efficacy of these cells. This study will investigate the cellular and molecular mechanisms and possible effects of Wharton jelly-derived mesenchymal stem cells in pulmonary fibrosis.


Subject(s)
COVID-19 , Mesenchymal Stem Cells , Pulmonary Fibrosis , Wharton Jelly , Cell Differentiation , Humans , Pulmonary Fibrosis/therapy , Quality of Life
4.
Eur Respir Rev ; 30(161)2021 Sep 30.
Article in English | MEDLINE | ID: covidwho-1736334

ABSTRACT

Respiratory diseases are among the leading causes of morbidity and mortality worldwide, representing a major unmet medical need. New chemical entities rarely make it into the clinic to treat respiratory diseases, which is partially due to a lack of adequate predictive disease models and the limited availability of human lung tissues to model respiratory disease. Human pluripotent stem cells (hPSCs) may help fill this gap by serving as a scalable human in vitro model. In addition, human in vitro models of rare genetic mutations can be generated using hPSCs. hPSC-derived epithelial cells and organoids have already shown great potential for the understanding of disease mechanisms, for finding new potential targets by using high-throughput screening platforms, and for personalised treatments. These potentials can also be applied to other hPSC-derived lung cell types in the future. In this review, we will discuss how hPSCs have brought, and may continue to bring, major changes to the field of respiratory diseases by understanding the molecular mechanisms of the pathology and by finding efficient therapeutics.


Subject(s)
Pluripotent Stem Cells , Cell Differentiation , Epithelial Cells , Humans , Lung , Organoids
5.
Am J Physiol Cell Physiol ; 322(4): C591-C604, 2022 04 01.
Article in English | MEDLINE | ID: covidwho-1701350

ABSTRACT

Primary airway epithelial cells (pAECs) cultivated at air-liquid interface (ALI) conditions are widely used as surrogates for human in vivo epithelia. To extend the proliferative capacity and to enable serially passaging of pAECs, conditional reprogramming (cr) has been employed in recent years. However, ALI epithelia derived from cr cells often display functional changes with increasing passages. This highlights the need for thorough validation of the ALI cultures for the respective application. In our study, we evaluated the use of serially passaged cr nasal epithelial cells (crNECs) as a model to study SARS-CoV-2 infection and effects on ion and water transport. NECs were obtained from healthy individuals and cultivated as ALI epithelia derived from passages 1, 2, 3, and 5. We compared epithelial differentiation, ion and water transport, and infection with SARS-CoV-2 between passages. Our results show that epithelia maintained major differentiation characteristics and physiological ion and water transport properties through all passages. However, the frequency of ciliated cells, short circuit currents reflecting epithelial Na+ channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR) activity and expression of aquaporin 3 and 5 decreased gradually over passages. crNECs also expressed SARS-CoV-2 receptors angiotensin converting enzyme 2 (ACE2) and transmembrane serin2 protease 2 (TMPRSS2) across all passages and allowed SARS-CoV-2 replication in all passages. In summary, we provide evidence that passaged crNECs provide an appropriate model to study SARS-CoV-2 infection and also epithelial transport function when considering some limitations that we defined herein.


Subject(s)
COVID-19 , Cell Differentiation , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Epithelial Cells/metabolism , Humans , Infant, Newborn , SARS-CoV-2
6.
Cells ; 11(3)2022 01 28.
Article in English | MEDLINE | ID: covidwho-1690348

ABSTRACT

Advances in human pluripotent stem cell (hPSC) technology allow one to deconstruct the human body into specific disease-relevant cell types or create functional units representing various organs. hPSC-based models present a unique opportunity for the study of co-occurring disorders where "cause and effect" can be addressed. Poor neurodevelopmental outcomes have been reported in children with congenital heart diseases (CHD). Intuitively, abnormal cardiac function or surgical intervention may stunt the developing brain, leading to neurodevelopmental disorders (NDD). However, recent work has uncovered several genetic variants within genes associated with the development of both the heart and brain that could also explain this co-occurrence. Given the scalability of hPSCs, straightforward genetic modification, and established differentiation strategies, it is now possible to investigate both CHD and NDD as independent events. We will first overview the potential for shared genetics in both heart and brain development. We will then summarize methods to differentiate both cardiac & neural cells and organoids from hPSCs that represent the developmental process of the heart and forebrain. Finally, we will highlight strategies to rapidly screen several genetic variants together to uncover potential phenotypes and how therapeutic advances could be achieved by hPSC-based models.


Subject(s)
Heart Defects, Congenital , Neurodevelopmental Disorders , Pluripotent Stem Cells , Cell Differentiation/genetics , Heart Defects, Congenital/genetics , Heart Defects, Congenital/metabolism , Humans , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/metabolism , Organoids/metabolism , Pluripotent Stem Cells/metabolism
7.
Sci Adv ; 8(6): eabk2691, 2022 02 11.
Article in English | MEDLINE | ID: covidwho-1685473

ABSTRACT

Upon virus infection, CD8+ T cell accumulation is tightly controlled by simultaneous proliferation and apoptosis. However, it remains unclear how TCR signal coordinates these events to achieve expansion and effector cell differentiation. We found that T cell-specific deletion of nuclear helicase Dhx9 led to impaired CD8+ T cell survival, effector differentiation, and viral clearance. Mechanistically, Dhx9 acts as the key regulator to ensure LCK- and CD3ε-mediated ZAP70 phosphorylation and ERK activation to protect CD8+ T cells from apoptosis before proliferative burst. Dhx9 directly regulates Id2 transcription to control effector CD8+ T cell differentiation. The DSRM and OB_Fold domains are required for LCK binding and Id2 transcription, respectively. Dhx9 expression is predominantly increased in effector CD8+ T cells of COVID-19 patients. Therefore, we revealed a previously unknown regulatory mechanism that Dhx9 protects activated CD8+ T cells from apoptosis and ensures effector differentiation to promote antiviral immunity independent of nuclear sensor function.


Subject(s)
Antiviral Agents/pharmacology , Arenaviridae Infections/prevention & control , CD8-Positive T-Lymphocytes/immunology , COVID-19/prevention & control , DEAD-box RNA Helicases/metabolism , Immunity, Innate , Neoplasm Proteins/metabolism , Animals , Arenaviridae Infections/immunology , Arenaviridae Infections/metabolism , Arenaviridae Infections/pathology , COVID-19/immunology , COVID-19/metabolism , COVID-19/pathology , Cell Differentiation , DEAD-box RNA Helicases/genetics , Humans , Lymphocyte Activation , Lymphocytic choriomeningitis virus/physiology , Mice , Neoplasm Proteins/genetics , SARS-CoV-2/physiology , Virus Replication
8.
Front Immunol ; 12: 780900, 2021.
Article in English | MEDLINE | ID: covidwho-1662580

ABSTRACT

Mesenchymal stem cells (MSCs) are multipotent adult stem cells present in virtually all tissues; they have potent self-renewal capacity and differentiate into multiple cell types. For many reasons, these cells are a promising therapeutic alternative to treat patients with severe COVID-19 and pulmonary post-COVID sequelae. These cells are not only essential for tissue regeneration; they can also alter the pulmonary environment through the paracrine secretion of several mediators. They can control or promote inflammation, induce other stem cells differentiation, restrain the virus load, and much more. In this work, we performed single-cell RNA-seq data analysis of MSCs in bronchoalveolar lavage samples from control individuals and COVID-19 patients with mild and severe clinical conditions. When we compared samples from mild cases with control individuals, most genes transcriptionally upregulated in COVID-19 were involved in cell proliferation. However, a new set of genes with distinct biological functions was upregulated when we compared severely affected with mild COVID-19 patients. In this analysis, the cells upregulated genes related to cell dispersion/migration and induced the γ-activated sequence (GAS) genes, probably triggered by IFNGR1 and IFNGR2. Then, IRF-1 was upregulated, one of the GAS target genes, leading to the interferon-stimulated response (ISR) and the overexpression of many signature target genes. The MSCs also upregulated genes involved in the mesenchymal-epithelial transition, virus control, cell chemotaxis, and used the cytoplasmic RNA danger sensors RIG-1, MDA5, and PKR. In a non-comparative analysis, we observed that MSCs from severe cases do not express many NF-κB upstream receptors, such as Toll-like (TLRs) TLR-3, -7, and -8; tumor necrosis factor (TNFR1 or TNFR2), RANK, CD40, and IL-1R1. Indeed, many NF-κB inhibitors were upregulated, including PPP2CB, OPTN, NFKBIA, and FHL2, suggesting that MSCs do not play a role in the "cytokine storm" observed. Therefore, lung MSCs in COVID-19 sense immune danger and act protectively in concert with the pulmonary environment, confirming their therapeutic potential in cell-based therapy for COVID-19. The transcription of MSCs senescence markers is discussed.


Subject(s)
COVID-19/immunology , Cell Proliferation/physiology , Inflammation/immunology , Lung/immunology , Mesenchymal Stem Cells/immunology , Regeneration/immunology , Adult , COVID-19/metabolism , Cell Differentiation/immunology , Cell Movement/immunology , Cytoplasm/immunology , Epithelial-Mesenchymal Transition/immunology , Humans , Inflammation/metabolism , Mesenchymal Stem Cells/metabolism , SARS-CoV-2/immunology , Up-Regulation/immunology , Young Adult
9.
Biotechnol Lett ; 44(2): 159-177, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1633325

ABSTRACT

It only took 8 months for the pneumonia caused by a previously unknown coronavirus to turn into a global pandemic of unprecedentedly far-reaching implications. Failure of the already discovered treatment measures opened up a new opportunity to evaluate the potentials of mesenchymal stem cells and their extracellular vesicles (EVs), exosomes in particular. Eventually, the initial success experienced after the use of MSCs in treating the new pneumonia by Lnge and his team backed up the idea of MSC-based therapies and pushed them closer to becoming a reality. However, MSC-related concerns regarding safety such as abnormal differentiation, spontaneous malignant and the formation of ectopic tissues have triggered the replacement of MSCs by their secreted exosomes. The issue has been further strengthened by the fact that the exosomes leave similar treatment impacts when compared to their parental cells. In recent years, much attention has been paid to the use of MSC-derived exosomes in the treatment of a variety of diseases. With a primary focus on COVID-19 and its current treatment methods, the present review looks into the potentials of MSCs and MSC-derived exosomes in battling the ongoing pandemic. Finally, the research will draw an analogy between exosomes and their parental cells, when it comes to the progresses and challenges in using exosomes as a large-scale treatment method.


Subject(s)
COVID-19 , Exosomes , Mesenchymal Stem Cells , COVID-19/drug therapy , COVID-19/therapy , Cell Differentiation , Humans
10.
Int J Mol Sci ; 23(2)2022 Jan 13.
Article in English | MEDLINE | ID: covidwho-1625839

ABSTRACT

The global urgency to uncover medical countermeasures to combat the COVID-19 pandemic caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has revealed an unmet need for robust tissue culture models that faithfully recapitulate key features of human tissues and disease. Infection of the nose is considered the dominant initial site for SARS-CoV-2 infection and models that replicate this entry portal offer the greatest potential for examining and demonstrating the effectiveness of countermeasures designed to prevent or manage this highly communicable disease. Here, we test an air-liquid-interface (ALI) differentiated human nasal epithelium (HNE) culture system as a model of authentic SARS-CoV-2 infection. Progenitor cells (basal cells) were isolated from nasal turbinate brushings, expanded under conditionally reprogrammed cell (CRC) culture conditions and differentiated at ALI. Differentiated cells were inoculated with different SARS-CoV-2 clinical isolates. Infectious virus release into apical washes was determined by TCID50, while infected cells were visualized by immunofluorescence and confocal microscopy. We demonstrate robust, reproducible SARS-CoV-2 infection of ALI-HNE established from different donors. Viral entry and release occurred from the apical surface, and infection was primarily observed in ciliated cells. In contrast to the ancestral clinical isolate, the Delta variant caused considerable cell damage. Successful establishment of ALI-HNE is donor dependent. ALI-HNE recapitulate key features of human SARS-CoV-2 infection of the nose and can serve as a pre-clinical model without the need for invasive collection of human respiratory tissue samples.


Subject(s)
COVID-19/virology , Nasal Mucosa/cytology , Nasal Mucosa/virology , Tissue Culture Techniques/methods , Adolescent , Adult , Angiotensin-Converting Enzyme 2/metabolism , Cell Culture Techniques , Cell Differentiation , Epithelial Cells/cytology , Epithelial Cells/virology , Female , Humans , Male , Middle Aged , Models, Biological , SARS-CoV-2 , Virus Internalization
11.
Ann N Y Acad Sci ; 1506(1): 74-97, 2021 12.
Article in English | MEDLINE | ID: covidwho-1612914

ABSTRACT

Single cell biology has the potential to elucidate many critical biological processes and diseases, from development and regeneration to cancer. Single cell analyses are uncovering the molecular diversity of cells, revealing a clearer picture of the variation among and between different cell types. New techniques are beginning to unravel how differences in cell state-transcriptional, epigenetic, and other characteristics-can lead to different cell fates among genetically identical cells, which underlies complex processes such as embryonic development, drug resistance, response to injury, and cellular reprogramming. Single cell technologies also pose significant challenges relating to processing and analyzing vast amounts of data collected. To realize the potential of single cell technologies, new computational approaches are needed. On March 17-19, 2021, experts in single cell biology met virtually for the Keystone eSymposium "Single Cell Biology" to discuss advances both in single cell applications and technologies.


Subject(s)
Cell Differentiation/physiology , Cellular Reprogramming/physiology , Congresses as Topic/trends , Embryonic Development/physiology , Research Report , Single-Cell Analysis/trends , Animals , Cell Lineage/physiology , Humans , Macrophages/physiology , Single-Cell Analysis/methods
12.
Int J Mol Sci ; 22(24)2021 Dec 07.
Article in English | MEDLINE | ID: covidwho-1597826

ABSTRACT

Organoids are tiny, self-organized, three-dimensional tissue cultures that are derived from the differentiation of stem cells. The growing interest in the use of organoids arises from their ability to mimic the biology and physiology of specific tissue structures in vitro. Organoids indeed represent promising systems for the in vitro modeling of tissue morphogenesis and organogenesis, regenerative medicine and tissue engineering, drug therapy testing, toxicology screening, and disease modeling. Although 2D cell cultures have been used for more than 50 years, even for their simplicity and low-cost maintenance, recent years have witnessed a steep rise in the availability of organoid model systems. Exploiting the ability of cells to re-aggregate and reconstruct the original architecture of an organ makes it possible to overcome many limitations of 2D cell culture systems. In vitro replication of the cellular micro-environment of a specific tissue leads to reproducing the molecular, biochemical, and biomechanical mechanisms that directly influence cell behavior and fate within that specific tissue. Lineage-specific self-organizing organoids have now been generated for many organs. Currently, growing cardiac organoid (cardioids) from pluripotent stem cells and cardiac stem/progenitor cells remains an open challenge due to the complexity of the spreading, differentiation, and migration of cardiac muscle and vascular layers. Here, we summarize the evolution of biological model systems from the generation of 2D spheroids to 3D organoids by focusing on the generation of cardioids based on the currently available laboratory technologies and outline their high potential for cardiovascular research.


Subject(s)
Adult Stem Cells/cytology , Organ Culture Techniques/methods , Organoids/cytology , Cell Differentiation , Heart/physiology , Humans , Models, Biological , Pluripotent Stem Cells/cytology , Regeneration , Spheroids, Cellular/cytology
13.
Front Immunol ; 12: 761949, 2021.
Article in English | MEDLINE | ID: covidwho-1581340

ABSTRACT

The decline in mucosal immunity during aging increases susceptibility, morbidity and mortality to infections acquired via the gastrointestinal and respiratory tracts in the elderly. We previously showed that this immunosenescence includes a reduction in the functional maturation of M cells in the follicle-associated epithelia (FAE) covering the Peyer's patches, diminishing the ability to sample of antigens and pathogens from the gut lumen. Here, co-expression analysis of mRNA-seq data sets revealed a general down-regulation of most FAE- and M cell-related genes in Peyer's patches from aged mice, including key transcription factors known to be essential for M cell differentiation. Conversely, expression of ACE2, the cellular receptor for SARS-Cov-2 virus, was increased in the aged FAE. This raises the possibility that the susceptibility of aged Peyer's patches to infection with the SARS-Cov-2 virus is increased. Expression of key Paneth cell-related genes was also reduced in the ileum of aged mice, consistent with the adverse effects of aging on their function. However, the increased expression of these genes in the villous epithelium of aged mice suggested a disturbed distribution of Paneth cells in the aged intestine. Aging effects on Paneth cells negatively impact on the regenerative ability of the gut epithelium and could indirectly impede M cell differentiation. Thus, restoring Paneth cell function may represent a novel means to improve M cell differentiation in the aging intestine and increase mucosal vaccination efficacy in the elderly.


Subject(s)
COVID-19 , Immunity, Mucosal/immunology , Immunosenescence/immunology , Paneth Cells/immunology , Peyer's Patches/immunology , Animals , Cell Differentiation/immunology , Mice , Mice, Inbred C57BL , SARS-CoV-2
14.
Dev Cell ; 57(1): 112-145.e2, 2022 01 10.
Article in English | MEDLINE | ID: covidwho-1587971

ABSTRACT

The human lung plays vital roles in respiration, host defense, and basic physiology. Recent technological advancements such as single-cell RNA sequencing and genetic lineage tracing have revealed novel cell types and enriched functional properties of existing cell types in lung. The time has come to take a new census. Initiated by members of the NHLBI-funded LungMAP Consortium and aided by experts in the lung biology community, we synthesized current data into a comprehensive and practical cellular census of the lung. Identities of cell types in the normal lung are captured in individual cell cards with delineation of function, markers, developmental lineages, heterogeneity, regenerative potential, disease links, and key experimental tools. This publication will serve as the starting point of a live, up-to-date guide for lung research at https://www.lungmap.net/cell-cards/. We hope that Lung CellCards will promote the community-wide effort to establish, maintain, and restore respiratory health.


Subject(s)
Lung/cytology , Lung/physiology , Cell Differentiation/genetics , Databases as Topic , Humans , Lung/metabolism , Regeneration/genetics , Single-Cell Analysis/methods
15.
Sci Immunol ; 5(44)2020 02 21.
Article in English | MEDLINE | ID: covidwho-1575907

ABSTRACT

Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses during cancer. It remains elusive how MDSCs differ from their normal myeloid counterparts, which limits our ability to specifically detect and therapeutically target MDSCs during cancer. Here, we sought to determine the molecular features of breast cancer-associated MDSCs using the widely studied mouse model based on the mouse mammary tumor virus (MMTV) promoter-driven expression of the polyomavirus middle T oncoprotein (MMTV-PyMT). To identify MDSCs in an unbiased manner, we used single-cell RNA sequencing to compare MDSC-containing splenic myeloid cells from breast tumor-bearing mice with wild-type controls. Our computational analysis of 14,646 single-cell transcriptomes revealed that MDSCs emerge through an aberrant neutrophil maturation trajectory in the spleen that confers them an immunosuppressive cell state. We establish the MDSC-specific gene signature and identify CD84 as a surface marker for improved detection and enrichment of MDSCs in breast cancers.


Subject(s)
Breast Neoplasms/pathology , Myeloid-Derived Suppressor Cells/pathology , Single-Cell Analysis , Transcriptome , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/immunology , Breast Neoplasms/immunology , Cell Differentiation/genetics , Female , Humans , Mice , Mice, Inbred Strains , Mice, Transgenic , Myeloid-Derived Suppressor Cells/immunology , RNA, Neoplasm/genetics , RNA, Neoplasm/immunology , Signaling Lymphocytic Activation Molecule Family/genetics , Signaling Lymphocytic Activation Molecule Family/immunology
16.
Sci Total Environ ; 808: 152072, 2022 Feb 20.
Article in English | MEDLINE | ID: covidwho-1550061

ABSTRACT

The combat against the Corona virus disease of 2019 (COVID-19), has created a chaos among the healthcare institutions and researchers, in turn accelerating the dire need to curtail the infection spread. The already established entry mechanism, via ACE2 has not yet successfully aided in the development of a suitable and reliable therapy. Taking in account the constant progression and deterioration of the cases worldwide, a different perspective and mechanistic approach is required, which has thrown light onto the cluster of differentiation 147 (CD147) transmembrane protein, as a novel route for SARS-CoV-2 entry. Despite lesser affinity towards COVID-19 virus, as compared to ACE2, this receptor provides a suitable justification behind elevated blood glucose levels in infected patients, retarded COVID-19 risk in women, enhanced susceptibility in geriatrics, greater infection susceptibility of T cells, infection prevalence in non-susceptible human cardiac pericytes and so on. The manuscript invokes the title role and distribution of CD147 in COVID-19 as an entry receptor and mediator of endocytosis-promoted entry of the virus, along with the "catch and clump" hypothesis, thereby presenting its Fundamental significance as a therapeutic target for potential candidates, such as Azithromycin, melatonin, statins, beta adrenergic blockers, ivermectin, Meplazumab etc. Thus, the authors provide a comprehensive review of a different perspective in COVID-19 infection, aiming to aid the researchers and virologists in considering all aspects of viral entry, in order to develop a sustainable and potential cure for the 2019 COVID-19 disease.


Subject(s)
Basigin , COVID-19 , Spike Glycoprotein, Coronavirus , Antibodies, Monoclonal, Humanized , Cell Differentiation , Female , Humans , SARS-CoV-2
17.
Viruses ; 13(11)2021 11 03.
Article in English | MEDLINE | ID: covidwho-1542790

ABSTRACT

The detailed characterization of human γδ T lymphocyte differentiation at the single-cell transcriptomic (scRNAseq) level in tumors and patients with coronavirus disease 2019 (COVID-19) requires both a reference differentiation trajectory of γδ T cells and a robust mapping method for additional γδ T lymphocytes. Here, we incepted such a method to characterize thousands of γδ T lymphocytes from (n = 95) patients with cancer or adult and pediatric COVID-19 disease. We found that cancer patients with human papillomavirus-positive head and neck squamous cell carcinoma and Epstein-Barr virus-positive Hodgkin's lymphoma have γδ tumor-infiltrating T lymphocytes that are more prone to recirculate from the tumor and avoid exhaustion. In COVID-19, both TCRVγ9 and TCRVγnon9 subsets of γδ T lymphocytes relocalize from peripheral blood mononuclear cells (PBMC) to the infected lung tissue, where their advanced differentiation, tissue residency, and exhaustion reflect T cell activation. Although severe COVID-19 disease increases both recruitment and exhaustion of γδ T lymphocytes in infected lung lesions but not blood, the anti-IL6R therapy with Tocilizumab promotes γδ T lymphocyte differentiation in patients with COVID-19. PBMC from pediatric patients with acute COVID-19 disease display similar γδ T cell lymphopenia to that seen in adult patients. However, blood γδ T cells from children with the COVID-19-related multisystem inflammatory syndrome are not lymphodepleted, but they are differentiated as in healthy PBMC. These findings suggest that some virus-induced memory γδ T lymphocytes durably persist in the blood of adults and could subsequently infiltrate and recirculate in tumors.


Subject(s)
COVID-19/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Neoplasms/immunology , RNA-Seq , Receptors, Antigen, T-Cell, gamma-delta/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Adult , Bronchoalveolar Lavage Fluid/immunology , COVID-19/complications , Cell Differentiation , Child , Head and Neck Neoplasms/immunology , Head and Neck Neoplasms/virology , Herpesvirus 4, Human/isolation & purification , Hodgkin Disease/immunology , Hodgkin Disease/virology , Humans , Lung/immunology , Lymphocyte Activation , Lymphocyte Count , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/physiology , Neoplasms/virology , Papillomaviridae/isolation & purification , Severity of Illness Index , Single-Cell Analysis , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocyte Subsets/physiology
18.
Cells ; 10(12)2021 11 23.
Article in English | MEDLINE | ID: covidwho-1538383

ABSTRACT

Dendritic cells (DCs) are the most potent antigen-presenting cells, and their function is essential to configure adaptative immunity and avoid excessive inflammation. DCs are predicted to play a crucial role in the clinical evolution of the infection by the severe acute respiratory syndrome (SARS) coronavirus (CoV)-2. DCs interaction with the SARS-CoV-2 Spike protein, which mediates cell receptor binding and subsequent fusion of the viral particle with host cell, is a key step to induce effective immunity against this virus and in the S protein-based vaccination protocols. Here we evaluated human DCs in response to SARS-CoV-2 S protein, or to a fragment encompassing the receptor binding domain (RBD) challenge. Both proteins increased the expression of maturation markers, including MHC molecules and costimulatory receptors. DCs interaction with the SARS-CoV-2 S protein promotes activation of key signaling molecules involved in inflammation, including MAPK, AKT, STAT1, and NFκB, which correlates with the expression and secretion of distinctive proinflammatory cytokines. Differences in the expression of ACE2 along the differentiation of human monocytes to mature DCs and inter-donor were found. Our results show that SARS-CoV-2 S protein promotes inflammatory response and provides molecular links between individual variations and the degree of response against this virus.


Subject(s)
Dendritic Cells/pathology , Dendritic Cells/virology , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Cell Adhesion Molecules/metabolism , Cell Differentiation , Cytokines/biosynthesis , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Inflammation/pathology , Lectins, C-Type/metabolism , Protein Domains , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Cell Surface/metabolism , STAT Transcription Factors/metabolism , Signal Transduction , Tissue Donors
19.
Nat Med ; 27(9): 1600-1606, 2021 09.
Article in English | MEDLINE | ID: covidwho-1526089

ABSTRACT

Clinical evidence suggests the central nervous system is frequently impacted by SARS-CoV-2 infection, either directly or indirectly, although the mechanisms are unclear. Pericytes are perivascular cells within the brain that are proposed as SARS-CoV-2 infection points. Here we show that pericyte-like cells (PLCs), when integrated into a cortical organoid, are capable of infection with authentic SARS-CoV-2. Before infection, PLCs elicited astrocytic maturation and production of basement membrane components, features attributed to pericyte functions in vivo. While traditional cortical organoids showed little evidence of infection, PLCs within cortical organoids served as viral 'replication hubs', with virus spreading to astrocytes and mediating inflammatory type I interferon transcriptional responses. Therefore, PLC-containing cortical organoids (PCCOs) represent a new 'assembloid' model that supports astrocytic maturation as well as SARS-CoV-2 entry and replication in neural tissue; thus, PCCOs serve as an experimental model for neural infection.


Subject(s)
Astrocytes/virology , Brain/virology , COVID-19/pathology , Pericytes/virology , Viral Tropism/physiology , Astrocytes/cytology , Brain/pathology , Cell Differentiation/physiology , Cells, Cultured , Humans , Interferon Type I/immunology , SARS-CoV-2 , Virus Replication/physiology
20.
Cell Rep ; 37(6): 109961, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1507742

ABSTRACT

Following infection or immunization, memory B cells (MBCs) and long-lived plasma cells provide humoral immunity that can last for decades. Most principles of MBC biology have been determined with hapten-protein carrier models or fluorescent protein immunizations. Here, we examine the temporal dynamics of the germinal center (GC) B cell and MBC response following mouse influenza A virus infection. We find that antiviral B cell responses within the lung-draining mediastinal lymph node (mLN) and the spleen are distinct in regard to duration, enrichment for antigen-binding cells, and class switching dynamics. While splenic GCs dissolve after 6 weeks post-infection, mLN hemagglutinin-specific (HA+) GCs can persist for 22 weeks. Persistent GCs continuously differentiate MBCs, with "peak" and "late" GCs contributing equal numbers of HA+ MBCs to the long-lived compartment. Our findings highlight critical aspects of persistent GC responses and MBC differentiation following respiratory virus infection with direct implications for developing effective vaccination strategies.


Subject(s)
Antibodies, Viral/immunology , Germinal Center/immunology , Immunologic Memory , Influenza A virus/physiology , Orthomyxoviridae Infections/immunology , T-Box Domain Proteins/physiology , Animals , Cell Differentiation , Female , Lymphocyte Activation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/virology
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