scholarly journals Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lukas Wettstein ◽  
Tatjana Weil ◽  
Carina Conzelmann ◽  
Janis A. Müller ◽  
Rüdiger Groß ◽  
...  
Keyword(s):  
Serine Protease ◽  
Immune Defense ◽  
Innate Immune ◽  
Respiratory Pathogen ◽  
The Novel ◽  
Airway Epithelial ◽  
Protein Library ◽  
Epithelial Cultures ◽  
Alpha 1 Antitrypsin ◽  
Novel Coronavirus

AbstractSARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α1-antitrypsin (α1AT), a highly abundant circulating serine protease inhibitor. Here, we report that α1AT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that α1AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α1AT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of α1AT-containing drugs has prospects for the therapy of COVID-19.

scholarly journals Estradiol, Progesterone, Immunomodulation, and COVID-19 Outcomes

Endocrinology ◽  
2020 ◽  
Vol 161 (9) ◽  
Author(s):  
Franck Mauvais-Jarvis ◽  
Sabra L Klein ◽  
Ellis R Levin
Keyword(s):  
Immune Response ◽  
Distress Syndrome ◽  
Immune Dysregulation ◽  
Innate Immune ◽  
The Novel ◽  
Cytokine Storm ◽  
Inflammatory Infiltration ◽  
Biological Sex ◽  
17Β Estradiol ◽  
Novel Coronavirus

Abstract Severe outcomes and death from the novel coronavirus disease 2019 (COVID-19) appear to be characterized by an exaggerated immune response with hypercytokinemia leading to inflammatory infiltration of the lungs and acute respiratory distress syndrome. Risk of severe COVID-19 outcomes is consistently lower in women than men worldwide, suggesting that female biological sex is instrumental in protection. This mini-review discusses the immunomodulatory and anti-inflammatory actions of high physiological concentrations of the steroids 17β-estradiol (E2) and progesterone (P4). We review how E2 and P4 favor a state of decreased innate immune inflammatory response while enhancing immune tolerance and antibody production. We discuss how the combination of E2 and P4 may improve the immune dysregulation that leads to the COVID-19 cytokine storm. It is intended to stimulate novel consideration of the biological forces that are protective in women compared to men, and to therapeutically harness these factors to mitigate COVID-19 morbidity and mortality.

scholarly journals SARS-CoV-2 infection and the antiviral innate immune response

2020 ◽  
Author(s):  
Hui Yang ◽  
Yingying Lyu ◽  
Fajian Hou
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Clinical Manifestations ◽  
Innate Immune ◽  
World Health ◽  
The Novel ◽  
Global Public Health ◽  
Replication Process ◽  
Novel Coronavirus ◽  
Health Organization

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak began in December 2019, causing the illness known as the novel coronavirus disease 2019 (COVID-19). The virus spread rapidly worldwide to become a global public health emergency. As of 15 November 2020, more than 53 million confirmed cases and over one million deaths worldwide have been reported (World Health Organization, 2020). The SARS-CoV-2 genome was sequenced and studies are ongoing to further understand the epidemiology, clinical manifestations, etiological structure, cellular receptor angiotensin II converting enzyme (ACE2), and intracellular replication process of the virus. Currently, thousands of clinical trials related to SARS-CoV-2 are underway (https://clinicaltrials.gov/). However, no vaccines or drugs have yet been approved, until very recently, for direct treatment or prevention of COVID-19 and only supportive treatment has been applied clinically. This review will discuss the possible mechanism of the innate immune response to SARS-CoV-2 infection and provide insight into the development of related therapeutics.

scholarly journals Homology Modeling of TMPRSS2 Yields Candidate Drugs That May Inhibit Entry of SARS-CoV-2 into Human Cells

2020 ◽  
Author(s):  
Stefano Rensi ◽  
Russ B Altman ◽  
Tianyun Liu ◽  
Yu-Chen Lo ◽  
Greg McInnes ◽  
...  
Keyword(s):  
Serine Protease ◽  
Treatment Options ◽  
Clinical Effects ◽  
The Novel ◽  
Clinical Tool ◽  
Binding Score ◽  
Serine Protease Family ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease ◽  
High Binding Affinity

The most rapid path to discovering treatment options for the novel coronavirus SARS-CoV-2 is to find existing medications that are active against the virus. We have focused on identifying repurposing candidates for the transmembrane serine protease family member II (TMPRSS2), which is critical for entry of coronaviruses into cells. Using known 3D structures of close homologs, we created seven homology models. We also identified a set of serine protease inhibitor drugs, generated several conformations of each, and docked them into our models. We used three known chemical (non-drug) inhibitors and one validated inhibitor of TMPRSS2 in MERS as benchmark compounds and found six compounds with predicted high binding affinity in the range of the known inhibitors. We also showed that a previously published weak inhibitor, Camostat, had a significantly lower binding score than our six compounds. All six compounds are anticoagulants with significant and potentially dangerous clinical effects and side effects. Nonetheless, if these compounds significantly inhibit SARS-CoV-2 infection, they could represent a potentially useful clinical tool.

scholarly journals In search of drugs to counter the countermeasures of SARS-CoV-2 in evading host’s innate immune defense: a Molecular modeling approach.

2020 ◽  
Author(s):  
Shuvasish Choudhury ◽  
Anupom Borah ◽  
Muhammed Khairujjaman Mazumder ◽  
Purbajyoti Saikia ◽  
Debojyoti Moulick
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Molecular Modeling ◽  
Drug Target ◽  
Immune Defense ◽  
Innate Immune ◽  
The Novel ◽  
Host Proteins ◽  
Innate Immune Defense ◽  
Host Innate Immunity

Abstract The coronaviruses (CoV), including SARS-CoV, MERS-CoV and the novel SARS-CoV-2, evade the host innate immunity employing Papain-like protease (PLPro). PLPro performs deubiquitination and deISGylation of host proteins and signaling molecules, and thus antagonize the host’s innate immune response. Thus, PLPro is a promising drug target against SARS-CoV-2. The present study employs molecular modeling approaches to determine potential of different compounds as inhibitors of the PLPro. The results demonstrated that drugs like Stallimycin, and known PLPro inhibitors including Telaprevir, Grazoprevir and Boceprevir, were highly potent in inhibiting the enzyme. In addition, several plant-derived polyphenols were also found to be potent inhibitors.

COVID 19: Camostat and The Role of Serine Protease Entry Inhibitor TMPRSS2

2020 ◽  
Author(s):  
Stefan Bittmann
Keyword(s):  
Host Cell ◽  
Serine Protease ◽  
Cellular Protein ◽  
Host Cells ◽  
The Novel ◽  
Robert Koch Institute ◽  
Angiotensin Converting Enzyme 2 ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease

According to the latest research, the novel coronavirus uses the protein angiotensin-converting enzyme 2 (ACE-2) as a receptor for docking to the host cell. Essential for entry is the priming of the spike (S) protein of the virus by host cell proteases. A broadly based team led by infection biologists from the German Primate Centre and with the participation of the Charité Hospital in Berlin, the Hanover Veterinary University Foundation, the BG-UnfallklinikMurnau, the LMU Munich, the Robert Koch Institute and the German Centre for Infection Research wanted to find out how SARS-CoV-2 enters host cells and how this process can be blocked [1]. They have published their findings in the journal "Cell" [1]. The team of scientists was initially able to confirm that SARS-CoV-2 docks to the host cell via the ACE-2 receptor. They also identified Transmembrane serine protease 2 (TMPRSS2) as the cellular protein responsible for entry into the cell [1-3].

scholarly journals Homology Modeling of TMPRSS2 Yields Candidate Drugs That May Inhibit Entry of SARS-CoV-2 into Human Cells

2020 ◽  
Author(s):  
Stefano Rensi ◽  
Russ B Altman ◽  
Tianyun Liu ◽  
Yu-Chen Lo ◽  
Greg McInnes ◽  
...  
Keyword(s):  
Serine Protease ◽  
Treatment Options ◽  
Clinical Effects ◽  
The Novel ◽  
Clinical Tool ◽  
Binding Score ◽  
Serine Protease Family ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease ◽  
High Binding Affinity

The most rapid path to discovering treatment options for the novel coronavirus SARS-CoV-2 is to find existing medications that are active against the virus. We have focused on identifying repurposing candidates for the transmembrane serine protease family member II (TMPRSS2), which is critical for entry of coronaviruses into cells. Using known 3D structures of close homologs, we created seven homology models. We also identified a set of serine protease inhibitor drugs, generated several conformations of each, and docked them into our models. We used three known chemical (non-drug) inhibitors and one validated inhibitor of TMPRSS2 in MERS as benchmark compounds and found six compounds with predicted high binding affinity in the range of the known inhibitors. We also showed that a previously published weak inhibitor, Camostat, had a significantly lower binding score than our six compounds. All six compounds are anticoagulants with significant and potentially dangerous clinical effects and side effects. Nonetheless, if these compounds significantly inhibit SARS-CoV-2 infection, they could represent a potentially useful clinical tool.

scholarly journals Type I and Type III IFN Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures

2020 ◽  
Author(s):  
Abigail Vanderheiden ◽  
Philipp Ralfs ◽  
Tatiana Chirkova ◽  
Amit A. Upadhyay ◽  
Matthew G. Zimmerman ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Respiratory Illness ◽  
Cytokine Response ◽  
Innate Immune ◽  
Type I ◽  
Airway Epithelial ◽  
Potential Utility ◽  
Human Airway ◽  
Epithelial Cultures ◽  
Inflammatory Cytokine Response

ABSTRACTThe newly emerged human coronavirus, SARS-CoV-2, has caused a pandemic of respiratory illness. The innate immune response is critical for protection against Coronaviruses. However, little is known about the interplay between the innate immune system and SARS-CoV-2. Here, we modeled SARS-CoV-2 infection using primary human airway epithelial (pHAE) cultures, which are maintained in an air-liquid interface. We found that SARS-CoV-2 infects and replicates in pHAE cultures and is directionally released on the apical, but not basolateral surface. Transcriptional profiling studies found that infected pHAE cultures had a molecular signature dominated by pro-inflammatory cytokines and chemokine induction, including IL-6, TNFα, CXCL8. We also identified NF-κB and ATF4 transcription factors as key drivers of this pro-inflammatory cytokine response. Surprisingly, we observed a complete lack of a type I or III IFN induction during SARS-CoV-2 infection. Pre-treatment or post-treatment with type I and III IFNs dramatically reduced virus replication in pHAE cultures and this corresponded with an upregulation of antiviral effector genes. Our findings demonstrate that SARS-CoV-2 induces a strong pro-inflammatory cytokine response yet blocks the production of type I and III IFNs. Further, SARS-CoV-2 is sensitive to the effects of type I and III IFNs, demonstrating their potential utility as therapeutic options to treat COVID-19 patients.IMPORTANCEThe current pandemic of respiratory illness, COVID-19, is caused by a recently emerged coronavirus named SARS-CoV-2. This virus infects airway and lung cells causing fever, dry cough, and shortness of breath. Severe cases of COVID-19 can result in lung damage, low blood oxygen levels, and even death. As there are currently no vaccines or antivirals approved for use in humans, studies of the mechanisms of SARS-CoV-2 infection are urgently needed. SARS-CoV-2 infection of primary human airway epithelial cultures induces a strong pro-inflammatory cytokine response yet blocks the production of type I and III IFNs. Further, SARS-CoV-2 is sensitive to the effects of type I and III IFNs, demonstrating their potential utility as therapeutic options to treat COVID-19 patients.

scholarly journals Flagellin-stimulated Cl− secretion and innate immune responses in airway epithelia: role for p38

2008 ◽  
Vol 295 (4) ◽  
pp. L531-L542 ◽  
Author(s):  
Beate Illek ◽  
Zhu Fu ◽  
Christian Schwarzer ◽  
Tina Banzon ◽  
Stephen Jalickee ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lucifer Yellow ◽  
Innate Immune ◽  
Airway Epithelial ◽  
Airway Epithelia ◽  
Anion Secretion ◽  
Epithelial Cultures ◽  
Serous Cell ◽  
Tight Junction Permeability ◽  
Well Differentiated

Activation of an innate immune response in airway epithelia by the human pathogen Pseudomonas aeruginosa requires bacterial expression of flagellin. Addition of flagellin (10−7 M) to airway epithelial cell monolayers (Calu-3, airway serous cell-like) increased Cl− secretion ( ICl) beginning after 3–10 min, reaching a plateau after 20–45 min at Δ ICl = 15–50 μA/cm2. Similar, although 10-fold smaller, responses were observed in well-differentiated bronchial epithelial cultures. Flagellin stimulated ICl in the presence of maximally stimulating doses of the purinergic agonist ATP, but had no effects following forskolin. IL-1β (produced by both epithelia and neutrophils during infections) stimulated ICl similar to flagellin. Flagellin-, IL-1β-, ATP-, and forskolin-stimulated ICl were inhibited by cystic fibrosis transmembrane conductance regulator (CFTR) blockers GlyH101, CFTRinh172, and glibenclamide. Neither flagellin nor IL-1β altered transepithelial fluxes of membrane-impermeant dextran (10 kDa) or lucifer yellow (mol wt = 457), but both activated p38, NF-κB, and IL-8 secretion. Blockers of p38 (SB-202190 and SB-203580) reduced flagellin- and IL-1β-stimulated ICl by 33–50% but had smaller effects on IL-8 and NF-κB. It is concluded that: 1) flagellin and IL-1β activated p38, NF-κB, IL-8, and CFTR-dependent anion secretion without altering tight junction permeability; 2) p38 played a role in regulating ICl and IL-8 but not NF-κB; and 3) p38 was more important in flagellin- than IL-1β-stimulated responses. During P. aeruginosa infections, flagellin and IL-1β are expected to increase CFTR-dependent ion and fluid flow into and bacterial clearance from the airways. In cystic fibrosis, the secretory response would be absent, but activation of p38, NF-κB, and IL-8 would persist.

scholarly journals The Nod1, Nod2, and Rip2 Axis Contributes to Host Immune Defense against Intracellular Acinetobacter baumannii Infection

2013 ◽  
Vol 82 (3) ◽  
pp. 1112-1122 ◽  
Author(s):  
Pradeep Bist ◽  
Neha Dikshit ◽  
Tse Hsien Koh ◽  
Alessandra Mortellaro ◽  
Thuan Tong Tan ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Acinetobacter Baumannii ◽  
Airway Epithelial Cells ◽  
Immune Defense ◽  
Innate Immune ◽  
Lung Epithelial Cells ◽  
Airway Epithelial ◽  
Content Type ◽  
Mitogen Activated Protein

ABSTRACTAcinetobacter baumanniiis a major extensively drug-resistant lethal human nosocomial bacterium. However, the host innate immune mechanisms controllingA. baumanniiare not well understood. Although viewed as an extracellular pathogen,A. baumanniican also invade and survive intracellularly. However, whether host innate immune pathways sensing intracellular bacteria contribute to immunity againstA. baumanniiis not known. Here, we provide evidence for the first time that intracellular antibacterial innate immune receptors Nod1 and Nod2, and their adaptor Rip2, play critical roles in the sensing and clearance ofA. baumanniiby human airway epithelial cellsin vitro.A. baumanniiinfection upregulated Rip2 expression. Silencing of Nod1, Nod2, and Rip2 expression profoundly increased intracellular invasion and prolonged the multiplication and survival ofA. baumanniiin lung epithelial cells. Notably, the Nod1/2-Rip2 axis did not contribute to the control ofA. baumanniiinfection of human macrophages, indicating that they play cell type-specific roles. The Nod1/2-Rip2 axis was needed forA. baumanniiinfection-induced activation of NF-κB but not mitogen-activated protein kinases. Moreover, the Nod1/2-Rip2 axis was critical to induce optimal cytokine and chemokine responses toA. baumanniiinfection. Mechanistic studies showed that the Nod1/2 pathway contributed to the innate control ofA. baumanniiinfection through the production of β-defensin 2 by airway epithelial cells. This study revealed new insights into the immune control ofA. baumanniiand may contribute to the development of effective immune therapeutics and vaccines againstA. baumannii.

Comparative docking of SARS-CoV-2 receptors antagonists from repurposing drugs

2020 ◽  
Author(s):  
Micael Davi Lima de Oliveira ◽  
Kelson Mota Teixeira de Oliveira
Keyword(s):  
World Health Organisation ◽  
World Health ◽  
Lung Cells ◽  
The Novel ◽  
High Modulation ◽  
Main Protease ◽  
The World ◽  
Novel Coronavirus ◽  
Viral Receptors ◽  
Theoretical Results

According to the World Health Organisation, until 16 June, 2020, the number of confirmed and notified cases of COVID-19 has already exceeded 7.9 million with approximately 434 thousand deaths worldwide. This research aimed to find repurposing antagonists, that may inhibit the activity of the main protease (Mpro) of the SARS-CoV-2 virus, as well as partially modulate the ACE2 receptors largely found in lung cells, and reduce viral replication by inhibiting Nsp12 RNA polymerase. Docking molecular simulations were performed among a total of 60 structures, most of all, published in the literature against the novel coronavirus. The theoretical results indicated that, in comparative terms, paritaprevir, ivermectin, ledipasvir, and simeprevir, are among the most theoretical promising drugs in remission of symptoms from the disease. Furthermore, also corroborate indinavir to the high modulation in viral receptors. The second group of promising drugs includes remdesivir and azithromycin. The repurposing drugs HCQ and chloroquine were not effective in comparative terms to other drugs, as monotherapies, against SARS-CoV-2 infection.

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