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1.
Nat Commun ; 12(1): 5975, 2021 10 13.
Article in English | MEDLINE | ID: covidwho-1467103

ABSTRACT

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15-2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15-3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22-3.30, p = 6×10-3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15-2.13, p = 5×10-3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.


Subject(s)
COVID-19/etiology , COVID-19/pathology , Clonal Hematopoiesis/genetics , Hematopoietic Stem Cells/virology , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/immunology , Child , Child, Preschool , Clonal Hematopoiesis/immunology , Cohort Studies , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Mutation/immunology , Neoplasms/genetics , Risk Factors , SARS-CoV-2 , Severity of Illness Index
3.
Stem Cell Rev Rep ; 17(1): 241-252, 2021 02.
Article in English | MEDLINE | ID: covidwho-1082595

ABSTRACT

The global SARS-CoV-2 pandemic starting in 2019 has already reached more than 2.3 million deaths. Despite the scientific community's efforts to investigate the COVID-19 disease, a drug for effectively treating or curing patients yet needs to be discovered. Hematopoietic stem cells (HSC) differentiating into immune cells for defense express COVID-19 entry receptors, and COVID-19 infection hinders their differentiation. The importance of purinergic signaling in HSC differentiation and innate immunity has been recognized. The metabotropic P2Y14 receptor subtype, activated by UDP-glucose, controls HSC differentiation and mobilization. Thereon, the exacerbated activation of blood immune cells amplifies the inflammatory state observed in COVID-19 patients, specially through the continuous release of reactive oxygen species and extracellular neutrophil traps (NETs). Further, the P2Y14 subtype, robustly inhibits the infiltration of neutrophils into various epithelial tissues, including lungs and kidneys. Here we discuss findings suggesting that antagonism of the P2Y14 receptor could prevent the progression of COVID-19-induced systemic inflammation, which often leads to severe illness and death cases. Considering the modulation of neutrophil recruitment of extreme relevance for respiratory distress and lung failure prevention, we propose that P2Y14 receptor inhibition by its selective antagonist PPTN could limit neutrophil recruitment and NETosis, hence limiting excessive formation of oxygen reactive species and proteolytic activation of the kallikrein-kinin system and subsequent bradykinin storm in the alveolar septa of COVID-19 patients.


Subject(s)
COVID-19/therapy , Hematopoietic Stem Cell Transplantation , Inflammation/therapy , Receptors, Purinergic P2/genetics , Respiratory Distress Syndrome/therapy , Bradykinin/metabolism , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Chemotaxis/drug effects , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/virology , Humans , Inflammation/pathology , Inflammation/virology , Lung/pathology , Lung/virology , Neutrophils/metabolism , Neutrophils/pathology , Neutrophils/virology , Pandemics , Receptors, Purinergic P2/drug effects , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/pathogenicity
4.
Signal Transduct Target Ther ; 5(1): 172, 2020 08 27.
Article in English | MEDLINE | ID: covidwho-733534

ABSTRACT

No effective drug treatments are available for coronavirus disease 2019 (COVID-19). Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage, death, or long-term functional disability in survivors require clinical evaluation. We performed a parallel assigned controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease. The study enrolled 18 hospitalized patients with COVID-19 (n = 9 for each group). The treatment group received three cycles of intravenous infusion of UC-MSCs (3 × 107 cells per infusion) on days 0, 3, and 6. Both groups received standard COVID-treatment regimens. Adverse events, duration of clinical symptoms, laboratory parameters, length of hospitalization, serial chest computed tomography (CT) images, the PaO2/FiO2 ratio, dynamics of cytokines, and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed. No serious UC-MSCs infusion-associated adverse events were observed. Two patients receiving UC-MSCs developed transient facial flushing and fever, and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion. Mechanical ventilation was required in one patient in the treatment group compared with four in the control group. All patients recovered and were discharged. Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated. Phase 2/3 randomized, controlled, double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.


Subject(s)
Antibodies, Viral/blood , Betacoronavirus/immunology , Cord Blood Stem Cell Transplantation/methods , Coronavirus Infections/therapy , Hematopoietic Stem Cells/virology , Mesenchymal Stem Cell Transplantation/methods , Pneumonia, Viral/therapy , Adult , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Drug Combinations , Female , Glucocorticoids/therapeutic use , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/immunology , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Lopinavir , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Respiration, Artificial , Ritonavir , SARS-CoV-2 , Severity of Illness Index , Treatment Outcome
5.
Stem Cell Rev Rep ; 17(1): 266-277, 2021 02.
Article in English | MEDLINE | ID: covidwho-657397

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) plays an important role as a member of the renin-angiotensin-aldosterone system (RAAS) in regulating the conversion of angiotensin II (Ang II) into angiotensin (1-7) (Ang [1-7]). But at the same time, while expressed on the surface of human cells, ACE2 is the entry receptor for SARS-CoV-2. Expression of this receptor has been described in several types of cells, including hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs), which raises a concern that the virus may infect and damage the stem cell compartment. We demonstrate for the first time that ACE2 and the entry-facilitating transmembrane protease TMPRSS2 are expressed on very small CD133+CD34+Lin-CD45- cells in human umbilical cord blood (UCB), which can be specified into functional HSCs and EPCs. The existence of these cells known as very small embryonic-like stem cells (VSELs) has been confirmed by several laboratories, and some of them may correspond to putative postnatal hemangioblasts. Moreover, we demonstrate for the first time that, in human VSELs and HSCs, the interaction of the ACE2 receptor with the SARS-CoV-2 spike protein activates the Nlrp3 inflammasome, which if hyperactivated may lead to cell death by pyroptosis. Based on this finding, there is a possibility that human VSELs residing in adult tissues could be damaged by SARS-CoV-2, with remote effects on tissue/organ regeneration. We also report that ACE2 is expressed on the surface of murine bone marrow-derived VSELs and HSCs, although it is known that murine cells are not infected by SARS-CoV-2. Finally, human and murine VSELs express several RAAS genes, which sheds new light on the role of these genes in the specification of early-development stem cells. Graphical Abstract •Human VSELs and HSCs express ACE2 receptor for SARS-CoV2 entry. •Interaction of viral spike protein with ACE2 receptor may hyperactivate Nlrp3 inflammasome which induces cell death by pyroptosis. •SARS-CoV2 may also enter cells and eliminate them by cell lysis. •What is not shown since these cells express also Ang II receptor they may hyperactivate Nlrp3 inflammasome in response to Ang II which may induce pyroptosis. Our data indicates that Ang 1-7 may have a protective effect.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Animals , COVID-19/pathology , COVID-19/virology , Endothelial Cells/metabolism , Endothelial Cells/virology , Hematopoietic Stem Cells/metabolism , Hematopoietic Stem Cells/virology , Humans , Inflammasomes/genetics , Leukocyte Common Antigens/genetics , SARS-CoV-2/pathogenicity , Serine Endopeptidases/genetics , Virus Internalization
6.
Leukemia ; 34(7): 1726-1729, 2020 07.
Article in English | MEDLINE | ID: covidwho-459385

ABSTRACT

The scientific community faces an unexpected and urgent challenge related to the SARS-CoV-2 pandemic and is investigating the role of receptors involved in entry of this virus into cells as well as pathomechanisms leading to a cytokine "storm," which in many cases ends in severe acute respiratory syndrome, fulminant myocarditis and kidney injury. An important question is if it may also damage hematopoietic stem progenitor cells?


Subject(s)
Coronavirus Infections/epidemiology , Cytokine Release Syndrome/epidemiology , Hematopoietic Stem Cells/virology , Inflammasomes/immunology , Pandemics , Pneumonia, Viral/epidemiology , Severe Acute Respiratory Syndrome/epidemiology , Acute Kidney Injury/epidemiology , Acute Kidney Injury/immunology , Acute Kidney Injury/prevention & control , Acute Kidney Injury/virology , Angiotensin-Converting Enzyme 2 , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Cytokine Release Syndrome/virology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Cytokines/immunology , Furans/pharmacology , Gene Expression Regulation , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/immunology , Heterocyclic Compounds, 4 or More Rings , Humans , Immunity, Innate/drug effects , Immunologic Factors/pharmacology , Indenes , Inflammasomes/antagonists & inhibitors , Inflammasomes/genetics , Myocarditis/epidemiology , Myocarditis/immunology , Myocarditis/prevention & control , Myocarditis/virology , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Pyroptosis/drug effects , Pyroptosis/genetics , Pyroptosis/immunology , Risk Factors , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/prevention & control , Severe Acute Respiratory Syndrome/virology , Spike Glycoprotein, Coronavirus/genetics
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