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1.
PLoS One ; 17(7): e0270920, 2022.
Article in English | MEDLINE | ID: covidwho-1957103

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is the carboxypeptidase to degrade angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and improves the pathologies of cardiovascular disease and acute respiratory distress syndrome (ARDS)/acute lung injury. B38-CAP is a bacteria-derived ACE2-like carboxypeptidase as potent as human ACE2 and ameliorates hypertension, heart failure and SARS-CoV-2-induced lung injury in mice. Recombinant B38-CAP is prepared with E. coli protein expression system more efficiently than recombinant soluble human ACE2. Here we show therapeutic effects of B38-CAP on abdominal sepsis- or acid aspiration-induced acute lung injury. ACE2 expression was downregulated in the lungs of mice with cecal ligation puncture (CLP)-induced sepsis or acid-induced lung injury thereby leading to upregulation of Ang II levels. Intraperitoneal injection of B38-CAP significantly decreased Ang II levels while upregulated angiotensin 1-7 levels. B38-CAP improved survival rate of the mice under sepsis. B38-CAP suppressed the pathologies of lung inflammation, improved lung dysfunction and downregulated elevated cytokine mRNA levels in the mice with acute lung injury. Thus, systemic treatment with an ACE2-like enzyme might be a potential therapeutic strategy for the patients with severe sepsis or ARDS.


Subject(s)
Acute Lung Injury , COVID-19 , Respiratory Distress Syndrome , Sepsis , Acute Lung Injury/pathology , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2 , Animals , Carboxypeptidases/metabolism , Escherichia coli/metabolism , Humans , Lung/pathology , Mice , Peptidyl-Dipeptidase A/metabolism , Renin-Angiotensin System , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2 , Sepsis/complications , Sepsis/drug therapy , Sepsis/metabolism
2.
Life Sci Alliance ; 5(7)2022 07.
Article in English | MEDLINE | ID: covidwho-1780426

ABSTRACT

Immune responses are different between individuals and personal health histories and unique environmental conditions should collectively determine the present state of immune cells. However, the molecular systems underlying such heterogeneity remain elusive. Here, we conducted a systematic time-lapse single-cell analysis, using 171 single-cell libraries and 30 mass cytometry datasets intensively for seven healthy individuals. We found substantial diversity in immune-cell profiles between different individuals. These patterns showed daily fluctuations even within the same individual. Similar diversities were also observed for the T-cell and B-cell receptor repertoires. Detailed immune-cell profiles at healthy statuses should give essential background information to understand their immune responses, when the individual is exposed to various environmental conditions. To demonstrate this idea, we conducted the similar analysis for the same individuals on the vaccination of influenza and SARS-CoV-2. In fact, we detected distinct responses to vaccines between individuals, although key responses are common. Single-cell immune-cell profile data should make fundamental data resource to understand variable immune responses, which are unique to each individual.


Subject(s)
COVID-19 , Single-Cell Analysis , COVID-19 Vaccines , Humans , SARS-CoV-2 , Vaccination
4.
Nihon Yakurigaku Zasshi ; 157(2): 115-118, 2022.
Article in Japanese | MEDLINE | ID: covidwho-1714695

ABSTRACT

In the renin-angiotensin system (RAS), angiotensin II (AngII) converted by angiotensin converting enzyme (ACE) exerts a strong physiological activity via the AT1 receptor (AT1R). Thus, the ACE-AngII-AT1R axis positively regulates RAS. On the other hand, angiotensin converting enzyme 2 (ACE2) is known to negatively regulate RAS by degrading AngII into angiotensin 1-7 (Ang1-7). In the acute respiratory distress syndrome (ARDS), which is characterized by pulmonary hyperinflammation, the AngII-AT1R axis acts to exacerbate ARDS and the ACE2-AT2R axis acts protectively. More recently, ACE2 has been shown to be a receptor for SARS-CoV, the causative virus of severe acute respiratory syndrome (SARS), and SARS-CoV2, the causative virus of the 2019 coronavirus infection (COVID-19). Therefore, inhibition of the binding between ACE2 and virus spike protein is a drug discovery target for antiviral drugs against SARS-CoV and SARS-CoV2. In addition, when SARS and COVID-19 become severe, ARDS with cytokine storm is occured. We reported that soluble ACE2 protein and microbial-derived ACE2 like enzyme suppress pulmonary hyperinflammation due to SARS and COVID-19, respectively. In addition, it has been reported that the ACE2-soluble protein has an effect of suppressing the establishment of infection by inhibiting the binding between SARS-CoV2 and the cell membrane surface ACE2. Here, we describe the role of ACE2 in the pathophysiology of SARS/COVID-19 from the perspectives of inhibiting the progression to ARDS by suppressing pulmonary inflammation and suppressing the replication of the virus by inhibiting the binding of ACE2 to the spike protein.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , COVID-19/drug therapy , Humans , Peptidyl-Dipeptidase A/metabolism , Peptidyl-Dipeptidase A/pharmacology , RNA, Viral/metabolism , RNA, Viral/pharmacology , Renin-Angiotensin System/physiology , SARS-CoV-2
5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-324400

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is a receptor for cell entry of SARS-CoV-2, and recombinant soluble ACE2 protein inhibits SARS-CoV-2 infection as a decoy. ACE2 is a carboxypeptidase that degrades angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7) and thereby improves the pathologies of cardiovascular disease or acute lung injury. To address whether the carboxypeptidase activity of ACE2 is protective in COVID-19, we investigated the effects of B38-CAP, an ACE2-like enzyme, on SARS-CoV-2-induced lung injury. Expression of endogenous ACE2 protein was significantly downregulated in the lungs of SARS-CoV-2-infected hamsters or SARS-CoV-2 challenged human ACE2 transgenic mice, leading to elevation of Ang II levels. In vivo administration of recombinant SARS-CoV-2 Spike also downregulated ACE2 expression, elevated Ang II levels and considerably worsened the symptoms of acute lung injury in hamsters exposed to acid aspiration. Despite its ACE2-like catalytic core, B38-CAP neither bound to Spike nor neutralized cell entry of SARS-CoV-2. However, treatment with B38-CAP improved the pathologies of Spike-augmented acid-induced lung injury. In SARS-CoV-2-infected hamsters, B38-CAP significantly improved lung edema and pathologies of lung injury and downregulated IL-6 levels without affecting viral RNA loads. Moreover, in human ACE2 transgenic mice, B38-CAP also attenuated SARS-CoV-2-induced lung edema and pathologies and improved lung functions. These results provide the first experimental in vivo evidence that increasing ACE2-like enzymatic activity is a potential therapeutic strategy to alleviate lung pathologies in COVID-19.

6.
Int Immunol ; 33(10): 541-545, 2021 09 25.
Article in English | MEDLINE | ID: covidwho-1575598

ABSTRACT

The spatial organization of chromatin is known to be highly dynamic in response to environmental stress. However, it remains unknown how chromatin dynamics contributes to or modulates the pathogenesis of immune and infectious diseases. Influenza virus is a single-stranded RNA virus, and transcription and replication of the virus genome occur in the nucleus. Since viral infection is generally associated with virus-driven hijack of the host cellular machineries, influenza virus may utilize and/or affect the nuclear system. In this review article, we focus on recent studies showing that the three-dimensional structure of chromatin changes with influenza virus infection, which affects the pathology of infection. Also, we discuss studies showing the roles of epigenetics in influenza virus infection. Understanding how this affects immune responses may lead to novel strategies to combat immune and infectious diseases.


Subject(s)
Chromatin/metabolism , Histone-Lysine N-Methyltransferase/metabolism , Homeodomain Proteins/metabolism , Influenza A virus/immunology , Influenza, Human/pathology , Cell Cycle Proteins/metabolism , Chromosomal Proteins, Non-Histone/metabolism , Histone Code/physiology , Histone-Lysine N-Methyltransferase/genetics , Host-Pathogen Interactions/immunology , Humans , Neoplasms/pathology , Protein Structure, Tertiary , Severity of Illness Index , Virus Replication/physiology
7.
Nat Commun ; 12(1): 6791, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1532053

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is a receptor for cell entry of SARS-CoV-2, and recombinant soluble ACE2 protein inhibits SARS-CoV-2 infection as a decoy. ACE2 is a carboxypeptidase that degrades angiotensin II, thereby improving the pathologies of cardiovascular disease or acute lung injury. Here we show that B38-CAP, an ACE2-like enzyme, is protective against SARS-CoV-2-induced lung injury. Endogenous ACE2 expression is downregulated in the lungs of SARS-CoV-2-infected hamsters, leading to elevation of angiotensin II levels. Recombinant Spike also downregulates ACE2 expression and worsens the symptoms of acid-induced lung injury. B38-CAP does not neutralize cell entry of SARS-CoV-2. However, B38-CAP treatment improves the pathologies of Spike-augmented acid-induced lung injury. In SARS-CoV-2-infected hamsters or human ACE2 transgenic mice, B38-CAP significantly improves lung edema and pathologies of lung injury. These results provide the first in vivo evidence that increasing ACE2-like enzymatic activity is a potential therapeutic strategy to alleviate lung pathologies in COVID-19 patients.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , COVID-19/prevention & control , Lung Injury/prevention & control , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Acute Lung Injury , Angiotensin II , Animals , COVID-19/pathology , Carboxypeptidases , Chlorocebus aethiops , Cricetinae , Disease Models, Animal , Female , Humans , Lung/pathology , Male , Mice , Mice, Transgenic , Pulmonary Edema/pathology , Pulmonary Edema/prevention & control , Spike Glycoprotein, Coronavirus/drug effects , Vero Cells
9.
Proceedings for Annual Meeting of The Japanese Pharmacological Society ; 94(0):1-S01-2, 2021.
Article in English | J-STAGE | ID: covidwho-1145467
10.
Proceedings for Annual Meeting of The Japanese Pharmacological Society ; 93(0):2-ES-4, 2020.
Article | WHO COVID | ID: covidwho-8873

ABSTRACT

The respiratory virus infection COVID-19 caused by the new coronavirus SARS-CoV2 has been reported in China since December 2019. It has been reported that COVID-19 tends to be more severe in the elderly and in patients with underlying diseases including diabetes, heart disease, and chronic lung disease. In severe cases, patients require intensive cares including mechanical ventilation in the ICUs. So far, no biomarker that predicts the severity, or no therapeutic strategies to prevent the development of severe diseases has been established. Pathology of severe COVID-19 has two aspects: viral overgrowth and excess pulmonary inflammation. For the former, clinical trials using existing drugs such as remdesivir (nucleic acid drug), lopinavir/ritonavir combination drug (protease inhibitor), favipravir (polymerase inhibitor), and interferon (antiviral drugs) are being conducted in patients with severe COVID-19 in China. Furthermore the interest has been focused on immune globulin preparations enriched with pathogen-specific antibodies collected from the plasma of recovered patients. For the latter, clinical studies using tocilizumab (IL-6 receptor antibody) and ACE2 protein have been conducted with the purpose of reducing excessive inflammation of the lung. In addition, single cell analysis of immune cells and comprehensive repertoire analysis of TCR/BCR using patient blood are in progress overseas, which are useful to elucidate the mechanism of the severe disease progression and identify the useful biomarkers for it.

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